PHYSIOLOGICAL REVIEWS
Vol. 81, No. 3, July 2001
Printed in U.S.A.
Molecular Physiology of Kainate Receptors
JUAN LERMA, ANA V. PATERNAIN, ANTONIO RODRÍGUEZ-MORENO, AND JUAN C. LÓPEZ-GARCÍA
Instituto Cajal, Consejo Superior de Investigaciones Cientı́ficas, Madrid, Spain
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Lerma, Juan, Ana V. Paternain, Antonio Rodrı́guez-Moreno, and Juan C. López-Garcı́a. Molecular Physiology
of Kainate Receptors. Physiol Rev 81: 971–998, 2001.—A decade ago, our understanding of the molecular properties
of kainate receptors and their involvement in synaptic physiology was essentially null. A plethora of recent studies
has altered this situation profoundly such that kainate receptors are now regarded as key players in the modulation
of transmitter release, as important mediators of the postsynaptic actions of glutamate, and as possible targets for
the development of antiepileptic and analgesic drugs. In this review, we summarize our current knowledge of the
properties of kainate receptors focusing on four key issues: 1) their structural and biophysical features, 2) the
important progress in their pharmacological characterization, 3) their pre- and postsynaptic mechanisms of action,
and 4) their involvement in a series of physiological and pathological processes. Finally, although significant
progress has been made toward the elucidation of their importance for brain function, kainate receptors remain
largely an enigma and, therefore, we propose some new roads that should be explored to obtain a deeper
understanding of this young, but intriguing, class of proteins.
I. INTRODUCTION
Fast excitatory neurotransmission in the mammalian
nervous system is mainly mediated by glutamate. Albeit
the relevance of this amino acid for brain function has
been repeatedly underscored, it is impossible to overestimate it. On the one hand, glutamate acts as the transmitter at most excitatory synapses, and it is involved in
the induction of long-lasting changes in the efficacy of
neurotransmission, changes thought to be cellular correlates of memory formation. On the other, glutamate has a
crucial role during the ontogeny of the nervous system,
participating in the outgrowth of processes, in the formation and elimination of synapses, and in the activitydependent fine tuning of exquisitely precise patterns of
connectivity in several brain areas. Finally, alterations of
glutamatergic neurotransmission have been related to the
http://physrev.physiology.org
neuronal damage observed after episodes of ischemia and
hypoglycemia, as well as to the etiology of a series of
neurological conditions including epilepsy, Alzheimer’s
disease, Huntington’s chorea, and amyotrophic lateral
sclerosis. As a result of this multiplicity of functions, the
number of studies devoted to the understanding of
glutamate-mediated transmission has grown steadily
over the years. Therefore, it is hardly surprising that
ionotropic glutamate receptors, cationic channels responsible of converting the synaptic release of the
amino acid into an immediate neuronal response, are
among the most studied and best-understood molecules
of the nervous system (77).
It is now well established that there exist three subtypes of ionotropic glutamate receptors, subtypes that
have been named after their preferred ligands: ␣-amino-
0031-9333/01 $15.00 Copyright © 2001 the American Physiological Society
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I. Introduction
II. Molecular Biology of Kainate Receptors
A. Identification and distribution of kainate receptor subunits
B. Structural diversity
III. Functional Properties of Kainate Receptors
A. Biophysical properties
B. Desensitization of kainate receptors
C. Pharmacological profile
IV. Physiological Roles of Kainate Receptors
A. Involvement of kainate receptors in excitatory synaptic transmission
B. Presynaptic kainate receptors
V. Pathological Actions
VI. Future Directions
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pharmacological agents to test the potential of kainate
receptors as targets of antiepileptic drugs.
II. MOLECULAR BIOLOGY
OF KAINATE RECEPTORS
A. Identification and Distribution of Kainate
Receptor Subunits
Low-stringency, homology-based cloning studies performed during the early 1990s (10, 11, 40, 66, 114, 148, 185)
led to the discovery of five kainate receptor subunits
termed GluR5, GluR6, GluR7, KA1, and KA2, proteins with
molecular masses of ⬃100 kDa. The degree of similarity
among the primary structure of these proteins and other
ionotropic glutamate receptor subtypes was shown to be
low but significant: ⬃40% homologous to AMPA receptors
and ⬃20% to NMDA receptors. Based on their amino acid
sequence, kainate receptor subunits have been further
subdivided into two classes. GluR5, GluR6, and GluR7
share a 75– 80% homology, whereas KA1 and KA2 are 68%
similar. In contrast, the similarity between the two subclasses is just 45%. A remarkable observation related to
the existence of these two subgroups is that, in addition
to their marked differences in primary structure, the same
division can be traced based on two of their functional
characteristics. First, the heterologous expression of
GluR5–7 leads to the formation of homomeric channels
that can be gated by kainate (40, 152, 160). KA1 and KA2,
in contrast, do not form channels on their own but only
when coexpressed with the other subunits (66, 185). The
resulting receptors possess properties different from the
homomers, revealing the ability of KA1 and KA2 to coassemble into functional heteromeric channels (Figs. 1 and
2). Second, binding assays on recombinant receptors have
shown that KA1 and KA2 have a significantly higher affinity for kainate than GluR5–7. This observation has led to
the suggestion that the two classes correspond to the
high- and low-affinity kainate binding sites originally described by the early autoradiographic studies (112, 113).
Although definitive proof is still missing, in situ hybridization studies have lent some support to this idea by showing that the distribution of the low- and high-affinity radioligand binding sites roughly predicts the observed
localization of each subunit.
In addition to the identification of these bona fide
mammalian kainate receptors, several additional homologous proteins capable of binding kainate have been
cloned from other species including chick (58), frog (73,
179, 184), and goldfish (192). These kainate binding proteins cannot form functional channels alone or when
coexpressed with other subunits (65). It is likely that this
phenotype is the result of their inability of translating
ligand binding into channel opening. Evidence in favor of
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3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)preferring, N-methyl-D-aspartate (NMDA)-preferring, and
kainate-preferring receptors. The cloning of a large number of glutamate receptor proteins and the discovery of
their structural relationships has confirmed the legitimacy
of this pharmacological subdivision. At the same time, it
has paved the way to most of our current understanding
of the biophysical properties and the physiological role of
each subtype in the mammalian brain.
Nowhere is this fact better exemplified than in the
study of kainate receptors (27, 51, 90 –93). Although the
early classification schemes of glutamate receptors, based
solely of pharmacological and radioligand binding assays
(112, 197), did postulate the existence of a separate class
of molecules selective for kainate, the evidence supporting this idea was ambiguous. For example, the fact that a
given neuron could exhibit a rapidly desensitizing response upon the application of AMPA (or quisqualate,
another agonist commonly used in the early studies) and
a nondesensitizing response to kainate was interpreted as
an indication that each ligand was acting on a separate
molecular entity. However, the cloning of GluR1, the first
AMPA receptor subunit (68), led to the observation that
homomeric channels made of this protein could be activated by AMPA and by kainate. Furthermore, the characteristics of the responses elicited by each ligand on GluR1
were very similar to those observed previously in nerve
cells (15, 84, 87, 126). In this way, both agonists were
shown to act on the same receptor protein, placing in
serious doubt the mere existence of kainate receptors.
The subsequent cloning of additional glutamate receptor subunits led eventually to the unequivocal discovery of a group of true kainate receptors (10, 11, 40, 66,
185), channels with a strong preference for this agonist
over AMPA, which displayed rapidly desensitizing responses, similar to those observed in preparations like the
dorsal root ganglia (DRG) (71). Thus the cloning of a
number of kainate receptor subunits was a real breakthrough in the study of these molecules and constitutes
the foundation upon which the spectacular progress in
their understanding has been built over the last decade.
In this review, we summarize our current knowledge
on kainate receptors by first discussing their molecular,
biophysical, and pharmacological properties, arenas
where the insights derived from the analysis of AMPA and
NMDA receptors have been a very valuable asset. We then
highlight the possible roles of these receptor molecules
during synaptic transmission and illustrate their relevance for brain function with some recent examples
where the involvement of kainate receptors at the systems level has been demonstrated. Finally, we speculate
on the possibility that this receptor subtype may participate in certain pathological conditions, mainly epilepsy,
pointing to the necessity of developing more selective
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this idea has been obtained by the generation of functional chimeric receptors consisting of the GluR6 ligand
binding domain and the ion channel domain of the different kainate binding proteins (177).
The analysis by in situ hybridization of the distribution of kainate receptors has revealed that they are widely
expressed throughout the nervous system. However, the
expression patterns of the different subunits are very
heterogeneous (4, 191). Thus the GluR5 transcript is
mainly present in DRG neurons, in the subiculum, in the
septal nuclei, in the piriform and the cingulate cortices,
and in Purkinje cells of the cerebellum (Fig. 3). GluR6 is
most abundant in the cerebellar granule cells, in the dentate gyrus and the CA3 region of the hippocampus (Fig. 3),
and in the striatum. The GluR7 mRNA is expressed at low
levels throughout the brain but particularly in the deep
layers of the cerebral cortex, in the striatum, and in the
inhibitory neurons of the molecular layer of the cerebellum. KA1 is almost exclusively restricted to the CA3 region, although it is also expressed at lower levels in the
dentate gyrus, in the amygdala, and in the entorhinal
cortex. Finally, the KA2 message can be found in essentially every part of the nervous system. Although the
different kainate receptor subunits are already present in
the embryo, most of these patterns of expression emerge
during the early postnatal period (4). Thus the amount of
GluR5 mRNA peaks between postnatal day (P) 0 and P5
and then begins to decline toward its adult level by P12.
Similarly, the GluR6 and KA1 expression patterns observed within the hippocampal formation begin to differ
at around P0 (GluR6) and P12 (KA1).
It should be noted that the information gained by the
in situ hybridization analysis, albeit correct in general,
remains incomplete in the details. On the one hand, we
still need to know what particular subunits are expressed
by specific cell types within a given brain structure. For
instance, a recent analysis of the coexpression of GluR5
or GluR6 with glutamic acid decarboxylase (GAD), the
synthesising enzyme of GABA, revealed that many hippocampal interneurons contained both GAD and one of
the kainate receptor subunits (122) (Fig. 3). The percentage of interneurons that expressed GluR5 and GAD plus
those expressing GluR6 and GAD was larger than 100,
suggesting that a significant fraction of individual cells
expressed the two kainate receptor subunits. This finding
led to the subsequent demonstration that members of the
GluR5–7 subtype can coassemble to form heteromers (32,
122) (Fig. 4). On the other hand, the lack of subunitspecific kainate receptor antibodies has limited our understanding of their localization and compartmentalization within the nerve cell. The use of anti-GluR5/6/7 or
anti-GluR6/7 antibodies has mapped kainate receptors to
dendrites and postsynaptic membranes (56, 72, 132, 156).
However, the advent of better antibodies against these
proteins should help us to establish unambiguously where
in the neuron each of them is localized and to determine
what specific subunits mediate the different physiological
effects of kainate receptor activation. In particular, the
development of better antibodies against kainate receptors should help us to identify and dissociate between the
effectors of its presynaptic versus its postsynaptic actions, as discussed in section IV.
B. Structural Diversity
Kainate receptors are believed to share the same
transmembrane topology and stoichiometry as AMPA and
NMDA receptors (7, 67, 88, 143). Thus they are thought to
be tetramers in which each monomer carries its own
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FIG. 1. A: membrane topology of the kainate
receptor subunits. A single channel is believed to
be composed of four subunits. Each subunit is
⬃900 amino acids long (⬃100 kDa) and spans the
membrane three times (segments M1, M3, and M4)
such that the NH2-terminal domain of the protein is
extracellular and the COOH-terminal domain is intracellular. A fourth hydrophobic sequence (M2)
forms the pore of the channel. This segment is
thought to dip into the membrane forming a structure akin to a hairpin. The three highlighted residues correspond to sites susceptible to editing in
the mRNA of GluR6 subunits. When the three positions are edited, the resulting receptors exhibit
null permeability to calcium and a linear currentvoltage relationship. B: homomeric GluR6 channels are sensitive to kainate but insensitive to DL␣ -amino-3-hydroxy-5-methylisoxazole-propionic
acid (AMPA). The currents in response to kainate
(KA), glutamate (Glu), or domoate (Dom) desensitize very rapidly. AMPA fails to elicit any response
in GluR6 homomers, but it acts on GluR6/KA2 heteromeric channels.
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ligand binding site and contributes with a specific amino
acid stretch to form the channel lumen, the so-called M2
segment, composed of hydrophobic residues that dip into
the membrane forming a hairpin-like structure (Fig. 1A).
In addition to this hydrophobic sequence, each subunit
has three transmembrane segments (M1, M3, and M4)
arranged such that the NH2-terminal domain of each protein is extracellular and the COOH-terminal region lies
intracellularly (139, 167, 192). By analogy to the structural
data available for AMPA receptors (3), the glutamate
binding site of kainate receptors is supposed to consist of
the homologous residues distributed throughout both the
loop between M3 and M4 and the NH2-terminal domain
(163). However, the actual structure of the binding pocket
in kainate receptors is bound to be significantly different
from the AMPA receptor. These likely differences should
help to explain, among other things, why AMPA receptors
can bind kainate with high affinity, whereas kainate receptors bind AMPA very poorly or not at all (Fig. 1B). In
this regard, it is noteworthy that a specific residue of the
extracellular loop between M3 and M4 has been identified
as relevant for the moderate sensitivity of GluR5 to AMPA
(165). When this amino acid is transplanted to the equivalent position in GluR6 (N721), the chimeric receptor can
respond to the application of this agonist.
The identification of a number of isoforms derived
from alternative splicing has revealed that the structural
repertoire of the kainate receptor subtype is not limited to
the five proteins mentioned earlier. The rat GluR5, for
instance, can be found as two different variants (10):
GluR5–1, an isoform that contains 15 extra amino acids in
the NH2-terminal region, and GluR5–2, a protein with
three additional splice variants that differ in the sequence
of their COOH-terminal domains. GluR5–2a is 49 amino
acids shorter than the originally described GluR5–2 (now
known as GluR5–2b) because of the introduction of a
premature stop codon, whereas GluR5–2c contains an
extra in-frame exon that makes it 29 amino acids longer
than the GluR5–2b isoform (160) (Fig. 2A). Although it is
possible that GluR5–1 also exists with three different
COOH termini, the only isoform so far isolated presents
the COOH terminus as in GluR5–2b. Similarly, two splice
variants of the rat GluR7 have been discovered (Fig. 2C).
In this case, the insertion of 40 out-of-frame nucleotides in
the COOH-terminal sequence of GluR7b leads to the production of a slightly shorter protein that bears no significant homology in this region to any of the known ionotropic glutamate receptors (152). No alternative splicing
has been reported for the rat GluR6, KA1, and KA2 subunits. However, the mouse GluR6 has been found to exist
as two splice variants that differ in their COOH-terminal
domains (59).
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FIG. 2. Structure and function of GluR5 and GluR7 receptors. A: the rat GluR5 can be found as two different variants:
GluR5–1, which contains 15 extra amino acids in the NH2-terminal region, and GluR5–2. GluR5–2 has been found to have
three splice variants that differ in the sequence of their COOH-terminal domains. GluR5–2a is 49 amino acids shorter than
the GluR5–2b because of the introduction of a premature stop codon. GluR5–2c contains an extra in-frame exon that
makes it 29 amino acids longer than the GluR5–2b isoform. The COOH-terminal domain for GluR5–1 is as in GluR5–2b.
B: typical responses induced by different agonists at homomeric GluR5–2a receptors. Kainate induces faster and deeper
desensitization at heteromeric GluR5/KA2 receptors (unpublished data). [From Sommer et al. (160). Reprinted by
permission of Oxford University Press.] C: GluR7 undergoes alternative splicing at the COOH-terminal domain. The
insertion of a 13-amino acid segment out of the reading frame of the transcript leads to the generation of a protein 9
amino acids shorter (GluR7b). D: both isoforms can form homomeric channels sensitive to glutamate and kainate but
insensitive to domoate and AMPA. Heteromeric GluR7/KA1, in contrast, responds to the application of AMPA. [Data from
Schiffer et al. (152). Reprinted from Neuron with permission of Elsevier Science.]
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The role of the different kainate receptor splice variants is unknown. The 15 additional extracellular amino
acids present in GluR5–1 do not map directly to the
putative glutamate binding pocket of the receptor, but the
possible influence of these residues on ligand binding has
not been tested directly. Similarly, the possibility that this
sequence may be involved in some type of intersubunit
interaction remains unexplored. The rest of the known
splice variants bear modifications in the COOH-terminal
region. It is well established that the COOH-terminal domains of the different ionotropic glutamate receptor subtypes are important for their interaction with an increasing number of proteins involved in the organization and
maintenance of synaptic structure. In the case of kainate
receptors, this interaction is best exemplified by their
ability to bind to members of the SAP90/PSD-95 class of
proteins (54). Thus it is possible that the differences
among the splice variants confer them with the selectivity
necessary to interact with specific intracellular partners,
providing the synapse with a system for the control of the
activity of kainate receptors. This idea has not been explored in detail yet.
Another source of structural variability for kainate
receptors is mRNA editing. As is the case for the GluR2
AMPA receptor (161), GluR5 and GluR6 (but not GluR7,
KA1, and KA2) are susceptible of undergoing this kind of
posttranscriptional modification at a specific position of
their M2 segment, the so-called glutamine/arginine (Q/R)
site. It has been shown that the presence of a R residue at
this position in GluR2 is enough to change the rectification properties of AMPA receptors and, more importantly,
to abolish their calcium permeability, a dominant trait
observed in homomeric as well as in heteromeric AMPA
channels (155, 161). In the case of homomeric kainate
receptors assembled from GluR6(R), the Q-to-R substitution also decreases the permeability to calcium (20, 41)
whilst increasing their chloride permeability (19). At the
same time, the presence of a R at this site transforms the
rectification properties of these receptors from inwardly
rectifying to linear or slightly outwardly rectifying and
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FIG. 3. Expression pattern of GluR5
and GluR6 mRNA. In the cerebellum (A),
GluR5 is expressed in the Purkinje cell
layer (P.C.L.) and in Golgi cells of the
granule cell layer (G.C.L.), whereas GluR6
is abundantly expressed by the granule
cells (B). The asterisks indicate unlabeled
Purkinje cell bodies. Insets show a magnification of the Purkinje cell layer. In the
hippocampus, GluR5 is mainly expressed
by interneurons (C), and GluR6 is predominantly expressed in the principal
cells (D). Double in situ hybridization
with glutamic acid decarboxylase (GAD)
and either GluR5 (E) or GluR6 (F) probes
is shown. The expression of GAD is labeled red (white arrowheads). The expression of GluR5 or GluR6 is labeled blue
(black arrowheads). Coexpression appears as a brown precipitate (black arrows). E and F correspond to a close view
of the CA1 and CA3 regions, respectively.
S.O., stratum oriens; S.P., stratum pyramidale; S.R., stratum radiatum; S.L., stratum
lucidum. [C–F from Paternain et al. (122).]
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reduces the unitary conductance of the channels (41, 86,
164). It should be noted, however, that the edition at the
Q/R site is not the only change capable of altering the
calcium permeability of GluR6 homomeric channels. Two
additional positions prone to mRNA editing have been
identified in the M1 segment of this subunit: the I/V site,
where a valine can substitute for an isoleucine, and the
Y/C site, where a tyrosine can be replaced by a cysteine
(86). Editing at these positions modulates the effect of the
Q/R site in calcium flow such that the fully edited subunit
exhibits null passage of this cation. The mechanism of
interaction among these three sites remains to be elucidated.
Heteromeric GluR5(Q)/GluR5(R) or GluR6(Q)/
GluR6(R) receptors retain the rectification properties and
the null permeability to calcium of the fully edited homomers (86, 160), indicating that the characteristics conferred by the presence of a R at M2 are dominant. In fact,
this dominant character has recently been used to demonstrate that heteromeric receptors containing solely
GluR5–7 subunits can exist. For instance, the coexpression of GluR6(Q) with GluR5(R) leads to the appearance
of receptors with the characteristics of GluR6 channels
but, at the same time, their current-voltage relationship is
outward rectifying (32, 122). It must be noted, however,
that not all of the functional changes introduced by mRNA
editing are dominant as, for instance, GluR6(Q)/GluR6(R)
channels remain chloride impermeable (19). Similarly, the
reduction of the unitary conductance observed in the fully
edited homomers is partly reverted in heteromeric assemblies. Thus the coexpression of KA2, a subunit unsusceptible to mRNA editing, with GluR5(R) or GluR6(R) generates receptors with unitary conductance larger than for
the corresponding homomeric channels (70, 164).
As mentioned above, M2 is thought to form the pore
of the channel. Therefore, it has been proposed that, in
principle, the presence of a positively charged R within
this segment is sufficient to explain the functional behavior of the edited receptor. First, the existence of a ring of
positive charges at the pore reduces unitary conductance
because of an increase in the energy barrier for the flow
of positive charges, an increase with a more significant
effect on divalent cations such as calcium. At the same
time, the electrostatic cloud of positive charges could
favor the passage of anions like chloride, although, in
order for this to occur, it seems necessary to maximize
the reduction of the energy barrier by editing all of the
Q/R sites. Finally, the presence of an R residue at the pore
prevents the entry of polyamines, molecules responsible
for the inward rectification observed in kainate as well as
in other receptors. This fact leads to the linear or to the
outwardly rectifying current-voltage relationships observed in the edited channels (16, 19, 79). However, this
model fails to account for the calcium permeability of
GluR6 and its dependence on the editing at the M1 segment, as mentioned above.
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FIG. 4. Pharmacological and functional properties of
some heteromeric kainate receptors. A: heteromeric GluR6/
KA2 kainate receptors desensitize in response to glutamate
but not to (RS)-s-amino-3(3-hydroxy-5-tert-butylisoxazol-4yl)propanoic acid (ATPA), a drug previously thought to be a
GluR5-specific agonist. In contrast, GluR5/KA2 heteromers
fully desensitize in the presence of ATPA, whereas GluR5/
GluR6 heteromers exhibit only a partial desensitization at
high concentrations of this compound. B: dose-response
curves of ATPA for GluR5/KA2 and for GluR6/KA2 heteromers. The EC50 values of the agonist for the two assemblies
are 6.3 and 84 ␮M, respectively. C: dose-response curves of
ATPA for GluR5/GluR6 heteromers. Preincubation with concanavalin A (ConA), a lectin that eliminates receptor desensitization, reduces the EC50 from 21 to 1.1 ␮M. [Modified
from Paternain et al. (122).]
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III. FUNCTIONAL PROPERTIES
OF KAINATE RECEPTORS
A. Biophysical Properties
The kinetic properties of the kainate receptor subtype have been studied mostly in heterologous expression
systems. Under these conditions, stationary noise analysis has revealed that the single-channel conductance of
homomeric GluR5(Q) or GluR6(Q) receptors is in the
picosiemens range with values of 2.9 and 5.4, respectively
(164). A detailed study of the resolvable channel openings
has revealed the existence of three subconductance levels
that are approximately twice or three times the size of the
smallest current (164). It is interesting to consider these
data in relationship to the tetrameric model proposed for
AMPA receptors, where current through the channel is a
function of the number of agonist molecules bound to the
receptor (143). Do the subconductance levels observed in
kainate receptors correspond to the opening of channels
bearing a different number of ligand molecules, or is it the
expression of a fundamentally distinct process? In any
case, the existence of subconductance states may help to
explain why studies performed under nonstationary conditions have obtained larger conductance values for
GluR6 receptors. The larger conductance may reflect a
preponderance of channels working at the higher subconductance levels (172).
As mentioned above, Q/R editing reduces the singlechannel conductance of GluR5 and GluR6 receptors by
more than one order of magnitude, an effect that is partly
reversed by the coexpression of the KA2 subunit (70, 164).
Thus the conductance of homomeric GluR5(R) channels
is less than 200 fS, but it increases to 950 fS upon coassembly with KA2. Similarly, GluR6(R) homomers have a
single-channel conductance between 230 and 260 fS,
whereas the value for GluR6(R)/KA2 heteromers lies between 570 and 700 fS. The effect of KA2 on the conductance of homomeric GluR5(Q) or GluR6(Q) receptors is
more subtle: an increase to 4.5 and 7.1 pS, respectively,
which is accompanied, in the case of GluR5(Q), by a
decrease in burst length (164). A paradoxical effect of the
addition of KA2 subunits, the molecules with the highest
affinity for kainate, to assemblies of GluR5 or GluR6 is
that the heteromers exhibit a reduced affinity for the
ligand (70, 164). This fact illustrates how little we understand about subunit interactions in kainate receptors and
underscores other related questions that await an answer:
how many KA1 or KA2 subunits can be incorporated into
a receptor before it loses its functionality? Is it possible to
find a subunit combination that has the highest affinity
and the largest unitary conductance or does a compromise always exist between the two properties?
Some studies have tried to determine the single-channel conductance of kainate receptors expressed in neurons. In DRG cells, for instance, a value of 2– 4 pS was
determined (71) and three subconductance levels similar
to those found for GluR5(Q) of GluR5(Q)/KA2 were observed. These findings agree with the fact that DRG neurons express GluR5 abundantly. In addition, the conductance of kainate receptors expressed in cerebellar granule
neurons has been determined to be ⬃1 pS under conditions that reduce their desensitization (129) and ⬃4 pS in
immature, proliferating cells (159).
B. Desensitization of Kainate Receptors
Rapid desensitization is one of the most characteristic features of kainate receptors (Fig. 5A). The time
course of current decay upon the constant presence of
agonist follows a single exponential curve (94, 124), although double exponential decays have also been described (94, 144, 189). However, in addition to the fact
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Two additional facts about mRNA editing of kainate
receptors deserve attention. First, the process is developmentally regulated, and it has been shown that a significant proportion of edited receptors exists both in embryonic and adult brains. The majority of GluR6 editing
occurs earlier than for GluR5, and it is more thoroughly
completed in the mature nervous system: up to 95% of
GluR6 transcripts are edited, compared with 50-60% observed for the GluR5 subunit (9, 119 –121, 153). Second,
there seems to exist a site- and cell-specific regulation of
kainate receptor mRNA editing. Studies of single hippocampal neurons in culture have shown that a given cell
can coexpress several edited variants and, furthermore,
that the degree of editing varies significantly across the
different sites within the same neuron (144). Thus some
cells have been found to possess, for instance, mRNA
fully edited at the I/V site but totally unedited at the Q/R
position. At the same time, only half of these transcripts
appear edited at the Y/C site. Similar findings have been
obtained in developing cerebellar granule cells (5) and in
adult hippocampal neurons (102). The mechanisms responsible for the generation of this heterogeneity remain
a matter of speculation and, similarly, its functional implications are not understood. For instance, mice with
mutations at the Q/R editing site in GluR5 have been
found to exhibit a reduction of kainate receptor-mediated
currents in their sensory neurons (147), but the responses
of these animals to painful stimuli are not altered. Furthermore, they do not show developmental abnormalities
or deficits in the performance of several behavioral tasks.
These observations stand in sharp contrast to the finding
that knocking out the editing enzyme of the AMPA receptor subunit GluR2 leads to the generation of epileptic
animals (45).
977
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LERMA, PATERNAIN, RODRÍGUEZ-MORENO, AND LÓPEZ-GARCÍA
Volume 81
that the speed of desensitization is dependent on the
receptor subtype and on the cell type being analyzed, its
actual value has been difficult to determine for different
reasons (92). On the one hand, if the desensitization time
constant is obtained purely from the measurement of
current decay upon agonist perfusion, then a slow binding
process could constitute a source of errors. On the other
hand, the speed of current relaxation upon ligand application approaches the level of resolution of fast perfusion
systems, raising the possibility that solution changes
could also modify the measured desensitization rate. One
way to circumvent these problems has been to measure
the time constant of current relaxation at very high concentrations of agonist. Under these conditions, the binding rate is no longer a limiting factor and, as ligand
concentration increases, the rate of current decay approaches an asymptotic value: the value of the real desensitization time constant. With the use of this strategy,
it has been determined (124) that GluR6 homomers and
native hippocampal kainate receptors have desensitization time constants of ⬃11–13 ms, a value similar to what
has been found for recombinant channels in excised
patches (63, 172) or lifted cells (164, 165). Whether the
small difference that persists between the two measurements is due to an effect of the excision of the patch on
the channel properties, as has been described for the
NMDA receptor (151), remains to be determined.
The recovery from the desensitized state proceeds
slowly for kainate receptors, and it is dependent on the
nature of the agonist (Fig. 5B). For instance, when glutamate is applied, two pulses evoke responses of similar
sizes if they are separated by 15 s. In contrast, 1 min has
to elapse when the desensitizing stimulus is a pulse of
kainate (124). Another factor capable of affecting recovery from desensitization is the subunit composition (166).
Thus GluR5 homomeric receptors recover in minutes,
whereas the time constant of recovery for GluR5/KA2
heteromers is just 12 s. As mentioned earlier, the incorporation of KA2 subunits to kainate receptors reduces the
affinity for the ligand. Thus it is possible that the faster
recovery is due to a faster rate of agonist dissociation.
However, it is unlikely that the exit from the desensitized
state is a simple function of ligand unbinding because
domoate, an agonist that desensitizes the receptors only
partially, dissociates from the binding site with a faster
time constant than the recovery time of the channel (94,
165). In any case, the profound differences in time scale
between desensitization and recovery imply that the equilibrium between the two states is strongly displaced toward the former. In other words, the receptors spend
most of their time in the desensitized state.
What are the implications of this propensity of kainate receptors to dwell on an inactive state? To visualize
them more clearly, it is helpful to first look at the kinetic
properties of their activation (Fig. 6). In cultured hippocampal neurons, glutamate has an EC50 of 330 ␮M; 3 ␮M
of this agonist does not induce a significant response, and
3 mM is a saturating concentration (124). In contrast,
desensitization occurs at ligand concentrations two orders of magnitude lower, which elicit no activation of the
channel (EC50 ⫽ 2.8 ␮M). A similar situation has been
observed in recombinant GluR6 homomers or when kainate is used as the agonist. In this case, the EC50 for
activation is 22 ␮M, whereas it is just 0.31 ␮M for inactivation (124). These observations imply that kainate receptors are very sensitive to resting levels of glutamate and,
Downloaded from http://physrev.physiology.org/ by 10.220.33.4 on July 4, 2017
FIG. 5. Desensitization properties of kainate receptors. A: the onset of kainate receptor desensitization is faster at
higher concentrations of the ligand. At very high concentrations of the agonist, the constant rate of this process is
approached by the asymptote of the rate of current relaxation. The desensitization rates for GluR6 homomeric channels
and for native receptors of hippocampal neurons are virtually identical. The desensitization of GluR5/GluR6 heteromers
occurs significantly faster. B: the exit from the desensitized state is much slower than its onset, and it is dependent on
the nature of the agonist. Thus the recovery of the channels upon exposure to glutamate is completed in ⬃15 s. In
contrast, ⬃1 min is necessary for complete recovery after exposure to kainate.
979
NEURONAL KAINATE RECEPTORS
July 2001
more importantly, that a large fraction of channels are
already inactive before they can be activated, two factors
that must have a profound influence in their physiological
role. In addition, it is important to note that the kainate
receptor activation and inactivation curves overlap to a
significant extent (Fig. 6). This fact indicates that there
exist concentrations of agonist (around 100 ␮M, in the
case of glutamate) high enough to open the channels and,
at the same time, low enough to produce only an incomplete desensitization. The current elicited by these concentrations of agonist has been termed “window current”
by analogy to the one predicted by Hodgkin and Huxley
during their study of the activation-inactivation curves of
voltage-gated sodium channels (124). Although the window current remains to be directly measured, some physiological effects of kainate receptor activation lend indi-
TABLE
rect support to its existence, as will be discussed in
section IVA (see Fig. 11C).
C. Pharmacological Profile
A major hindrance in our way to understand kainate
receptors has been the lack of specific agonists (Tables 1
and 2) and antagonists (Table 3). Although a clear pharmacological boundary has been traced between NMDA
and the other ionotropic glutamate receptor classes, the
separation between AMPA and kainate receptors has only
been vaguely sketched and, for the longest time, the two
types have been pooled together into what has been
called the non-NMDA receptor subtype. For instance,
AMPA has a negligible effect on recombinant kainate
1. Agonist sensitivity of recombinant kainate receptors
Glutamate
Kainate
Domoate
AMPA
(S)-5-IW
Me-Glu
ATPA
Con A
GluR5
GluR5/KA
GluR6
GluR6/KA
GluR5/GluR6
GluR7
GluR7/KA
⫹D
⫹D
⫹PD
⫹
⫹D
⫹
⫹
⫹
⫹D
⫹D
⫹PD
⫹
⫹D
⫹D
⫹D
⫹PD
⫺
⫺
⫹D
⫺
⫹
⫹D
⫹D
⫹PD
⫹PD
⫹ND
⫹D
⫹D
⫹?
⫹D
⫹PD
⫹D
⫹D
⫺
⫺
⫺
⫹D
⫹D
⫺
⫹D
⫹D
⫹ND
⫹
⫹PD
⫹
Modest
⫹
⫹D
⫹
⫹, Sensitive; ⫺, insensitive; D, desensitizing response (⬎90%); PD, partially desensitizing response (⬍80%); ND, nondesensitizing response.
AMPA, ␣-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; ATPA, (RS)-s-amino-3(3-hydroxy-5-tert-butylisoxazol-4-yl)propanoic acid; Con A,
concanavalin A; (S)-5-IW, (S)-5-iodowillardiine; Me-Glu, (2S,4R)4-methylglutamate.
Downloaded from http://physrev.physiology.org/ by 10.220.33.4 on July 4, 2017
FIG. 6. Activation and inactivation properties of native kainate receptors. A: the current elicited by the application
of a saturating concentration of kainate is substantially reduced by the administration of a previous pulse of glutamate
in a dose-dependent manner. B: the open symbols correspond to the dose-response curve of receptor activation by
glutamate. The solid gray symbols show the corresponding response to kainate after the receptors had been exposed to
the indicated concentrations of glutamate. As can be seen, there is an interval of glutamate doses over which both curves
cross over. This observation indicates that there are concentrations of the agonist high enough to open the channels and,
at the same time, low enough to produce incomplete desensitization. The theoretical current predicted to exist under
steady-state conditions of receptor activation is represented (dotted bell-shaped curve), and it reveals a steady activation
of kainate receptors at 100 ␮M glutamate. [From Paternain et al. (124).]
980
TABLE
LERMA, PATERNAIN, RODRÍGUEZ-MORENO, AND LÓPEZ-GARCÍA
Volume 81
2. Agonist pharmacology of native and recombinant kainate receptors
EC50, ␮M
Hippocampal
neurons
Glutamate
Kainate
Domoate
(S)-5-IW
SYM2081
ATPA
AMPA
310–330a,b
22–23b,c
c,d
Not active
DRG cells
GluR5
GluR6
GluR7
R5/R6
58d
12–16d,f
0.7d
0.14e
631h
33.6h
1.2h
83o
270–762a,i,k,l,m
299,a 1.8j
5,900n
mM rangen
Not activen
Not activeo
1,338q
0.6g/1.3p
260–520d,e
2.1g
3,000h
Not activeo
1j,k
Not activeg
Not activea
n
Not active
21q/1.1r
Active
Determinations carried out after concanavalin A treatment are not included except for ATPA and (S)-5-IW in dorsal root ganglion (DRG) cells.
Ref. 124; b Ref. 189; c Ref. 94; d Ref. 71; e Ref. 194; f Ref. 146; g Ref. 29; h Ref. 160; i Ref. 136; j Ref. 78; k Ref. 198; l Ref. 172; m Ref. 63; n Ref. 152; o Ref.
166; p Ref. 169; q,r Ref. 122 (q and r before and after treatment with concanavalin A, respectively).
a
1. Agonist pharmacology
The affinity of kainate for its different receptor subunits is very variable (Table 2). As mentioned earlier,
TABLE
radioligand binding assays have identified two subclasses
of kainate receptors with different affinity. The high-affinity subunits KA1 and KA2 have a dissociation constant
(Kd) of ⬃4 –15 nM (66, 191). This figure is one order of
magnitude higher than for GluR5–7, the low-affinity subunits (11, 160) (Kd ⫽ 50 –100 nM). However, functional
studies on recombinant receptors have revealed that the
actual effective concentrations of kainate are much
higher and vary depending on the subunit. Thus the EC50
for the GluR5 subunit (160) is 33.6 ␮M, 299 ␮M for the
GluR6 subunit (164) (although other values have been
reported) (78), and ⬎1 mM for the GluR7 subunit (152). A
similar situation has been found for glutamate, the endogenous agonist (Table 2). These figures illustrate that kainate receptors do not have a high affinity for their prototypical activators. This conclusion can be extended to the
native channels because the EC50 values for kainate and
glutamate measured in hippocampal and DRG neurons
are similar to those obtained on some recombinant receptors (94, 124, 189).
In addition to kainate and glutamate, several molecules have been shown to activate kainate receptors with
a certain degree of specificity. Domoate, one of the first to
be identified, is 20- to 25-fold more effective than kainate
3. Antagonist pharmacology of kainate receptors
IC50, ␮M
Native Kainate Receptors
CNQX
NBQX
NS-102
LY294486
LY293558
LY382884
SYM2206
GYKI53405 (LY293606)
GYKI53655 (LY300168)
IC50, ␮M
pKb, ␮M
GluR5
GluR6
6.1(Hip)d
2.9(DRG)a
2.2(Hip)d
0.6(DRG)e
1(DRG)a
1(DRG)k
20% at 100 ␮Ml
6.5(DRG)b
6–7(DRG)a,b
5(DRG)b
11 (5.4)a
6.2(DRG)a
3.9e
2.5 (6.2)a
Ki ⫽ 6.8e
2.8a
⬃5f
Inactive at 100 ␮Mi
Inactive at 100 ␮Ma
Inactive
Inactive at 100 ␮Mg
AMPA receptors
0.92d
0.16a
4.1d
⬎30e
0.47 (5.4)a
87k
1g
4,h 8m
0.9–1.5i,j
Numbers in parentheses indicate the corresponding pKb values when available. The type of cells from which the data were obtained is also
indicated. Ki, inhibitory constant. a Ref. 12; b Ref. 188; c Ref. 124; d Ref. 125; e Ref. 157; f Ref. 173; g Paternain and Lerma, unpublished data; h Ref. 135;
i
Ref. 123; j Ref. 187; k Ref. 14; l Ref. 142; m Ref. 13.
Downloaded from http://physrev.physiology.org/ by 10.220.33.4 on July 4, 2017
receptors (40, 66). It is inactive in GluR6 and GluR7 and
has an EC50 of 3 mM for the GluR5 subunit (160). Similarly, AMPA does not activate native kainate receptors in
cultured hippocampal neurons or only at high concentrations in DRG cells (71, 94, 194). In contrast, kainate, albeit
showing a clear preference for kainate receptors, has a
very significant effect on AMPA channels at relatively low
doses. The difference in EC50 between the two receptors
lies around a mere 5- to 30-fold higher affinity for kainate
receptors (29, 71, 94, 188). At the same time, the classic
non-NMDA receptor antagonists, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), 6,7-dinitroquinoxaline-2,3-dione
(DNQX), and 6-nitro-7-sulfamoylbenzoquinoxaline-2,3-dione (NBQX) (69), show at best a three- to fivefold selectivity between AMPA and kainate receptors (12, 98, 188).
Thus the realization that kainate could activate both receptor subtypes, and that the classic battery of competitive antagonists was also unable to distinguish between
them, led the field to a stagnation that lasted until the
mid-1990s, a state that, fortunately, has begun to change.
July 2001
NEURONAL KAINATE RECEPTORS
tors is significantly lower, only 200-fold (60). Although its
pharmacological profile is incomplete, SYM 2081 does not
seem to show the subunit specificity observed for ATPA
and for (S)-5-iodowillardiine, as it elicits rapidly desensitizing currents on GluR5 and GluR6 homomeric channels
(38, 78, 189, 198). Lastly, SYM 2081 has also been used as
a functional antagonist of the kainate receptors (96). The
activation and desensitization curves of GluR6 channels
in response to this agonist (78) and to glutamate (124)
show a minimal overlap. Therefore, its presence at low
concentrations drives the receptor to an inactive state,
preventing its subsequent opening by other agonists.
2. Antagonist pharmacology
The quest for specific kainate receptor antagonists
has not been as successful as the search for agonists. As
mentioned above, the first generation of non-NMDA receptor blockers such as CNQX, DNQX, and NBQX cannot
distinguish between kainate and AMPA receptors. The
molecule 5-nitro-6,7,8,9-tetrahydrobenzo[g]indole-2,3-dione-3-oxime (NS-102) was then proposed as a selective
kainate receptor antagonist based on its ability to block
low-affinity [3H]kainate binding to cortical membranes
(76). However, functional assays have yielded contradictory results regarding its specificity for kainate over
AMPA receptors. Thus it was first shown that NS-102
blocked recombinant GluR6 and kainate receptors at a
concentration 20 times lower than required for AMPA
channels (173). However, it was later found that the IC50
values of this antagonist for kainate and for AMPA receptors in cultured hippocampal neurons was very similar
(2.2 and 4.1 ␮M, respectively). More importantly, ⬃30% of
the current through either channel subtype remained unaffected at the solubility limit of NS-102, a fact that has
greatly constrained its usage (125, 188).
The development of a new series of decahydroxyisoquinoline carboxylates appears to indicate the path to follow
in the development of highly specific kainate receptor antagonists. The molecule LY293558 [(3S,4aR,6R,8aR)-6-(2(tetrazol-5-yl)ethyl)decahydroxyisoquinoline-3-carboxylate],
a noncompetitive antagonist of AMPA receptors (IC50 ⫽ 0.5
␮M), also blocks GluR5-mediated responses (IC50 ⫽ 2.5 ␮M)
with no effect on GluR6 homomers (13) (IC50 ⬎300 ␮M).
A related derivative, LY294486 [(3SR,4aRS,6SR,8aRS)-6((((tetrazol-5-yl)methyl)oxy)methyl)-1,2,3,4,4a,5,6,7,8,8adecahydroxyisoquinoline-3-carboxylate], has a significantly higher selectivity for GluR5 than for AMPA receptors (IC50 ⫽ 4 ␮M and 30 –100 ␮M, respectively) and
no effect on GluR6 or GluR7 homomeric channels (29).
Lastly, the compound LY382884 [(3S,4aR,6S,8aR)-6-(4carboxyphenyl)methyl-1,2,3,4,4a,5,6,7,8,8a-decahydroxyisoquinoline-3-carboxylate] has an even higher selectivity
for GluR5 over the other kainate receptor subunits and,
more importantly, over AMPA receptors (14, 157).
Downloaded from http://physrev.physiology.org/ by 10.220.33.4 on July 4, 2017
on DRG cells and on recombinant GluR5 subunits (71,
160), although it is inactive on GluR7 homomers (152). It
induces a slowly desensitizing response, and it shows a
50-fold preference for kainate over AMPA receptors (71).
This selectivity has been now largely surpassed by a new
generation of agonists among which (RS)-s-amino-3(3hydroxy-5-tert-butylisoxazol-4-yl)propanoic acid (ATPA)
is the prime example (89). The EC50 of ATPA is 0.6 ␮M for
native kainate receptors in DRG neurons and 2.1 ␮M for
recombinant GluR5 subunits (29), an order of magnitude
more effective than kainate. At the same time, its affinity
for AMPA receptors is about 500 times lower (340 ␮M in
cerebellar Purkinje cells). Nevertheless, these figures
must be interpreted with caution because they have been
measured from receptors treated with concanavalin A, a
molecule that reduces the desensitization of the receptor
and artificially increases its affinity (see below). In addition, it must also be noted that ATPA has been hitherto
regarded as a GluR5-specific agonist. It is inactive on
GluR6 homomeric channels, and it exhibits a potency
1,000-fold weaker for displacing [3H]kainate from GluR7
than from GluR5 in binding assays (29). However, it has
been recently shown (122) that ATPA can also act on
GluR5/KA2 (EC50 ⫽ 6.3 ␮M), GluR6/KA2 (EC50 ⫽ 84 ␮M),
and GluR5/GluR6 heteromers (EC50 ⫽ 21 ␮M). Furthermore, each of these assemblies exhibits a different desensitization profile in response to the agonist (Fig. 4). These
findings may lead us to revisit previous findings where the
selective activation of GluR5 is presumed to be responsible for the presynaptic effects of hippocampal kainate
receptors, as discussed later.
Some derivatives of willardiine have also been advanced as selective kainate receptor agonists. Among
them, (S)-5-trifluoromethylwillardiine is the most effective (EC50 ⫽ 74 nM on DRG cells), but its selectivity for
kainate over AMPA receptors is only 50-fold, a relatively
low figure (194). On the other hand, (S)-5-iodowillardiine
shows a ⬃130-fold selectivity for kainate receptors, but
its affinity is lower (194) (EC50 ⫽ 140 nM). As is the case
for ATPA, (S)-5-iodowillardiine produces desensitizing
currents on GluR5 but not on GluR6 or GluR7 homomers.
In fact, it has been demonstrated that a single amino acid
in the loop between M3 and M4 confers GluR5 with this
differential sensitivity (166). However, this observation
fails to explain why GluR6/KA2 heteromers are also responsive to this molecule (166). Finally, it is noteworthy
that replacing iodine for fluoride transforms this drug into
an AMPA receptor agonist with a 50-fold selectivity over
kainate receptors (61, 194).
SYM 2081, the (2S-4R) diastereomer of 4-methylglutamate, is one of the latest additions to the list of specific
kainate receptor agonists. It displays a selectivity three
orders of magnitude larger for kainate than for AMPA
receptors both in binding and in functional assays, but the
selectivity of this molecule for kainate over NMDA recep-
981
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LERMA, PATERNAIN, RODRÍGUEZ-MORENO, AND LÓPEZ-GARCÍA
IV. PHYSIOLOGICAL ROLES
OF KAINATE RECEPTORS
The first evidence of a role for kainate receptors in
synaptic function was obtained in the peripheral nervous
system. Early studies had shown that peripheral dorsal
root nerves from immature rats, specifically C fibers, were
depolarized by kainate (1, 35). Subsequent studies demonstrated that kainate application could elicit rapidly desensitizing responses on acutely dissociated DRG cells
(71), an effect markedly different from the nondesensitizing currents mediated by the kainate activation of AMPA
receptors in central neurons. The realization that kainate
induced a desensitizing response in recombinant kainate
receptors (66, 160) and that the mRNA of the different
subunits were expressed by a population of DRG cells
(10, 171) led to the notion that kainate receptors were
responsible for the response of the DRG neurons. This
provided the first example of a physiological role for this
kind of receptors, and recent studies have explored in
more detail the actual molecular composition of the DRG
kainate receptors. The pharmacological and biophysical
profile of the channels resembles more closely the one
observed for homomeric channels made of GluR5(Q) subunits: they are sensitive to LY293558, a GluR5 antagonist
(13), and exhibit the same subconductance levels and
desensitization rate (194) resolved for this subunit in
heterologous expression systems (164, 166).
It is illustrative to remember that glutamate is released by C fibers at their termination site in the dorsal
horn (75). This fact raises the possibility that the kainate
receptors present at the DRG cells act as autoreceptors,
modulating the release of the amino acid upon peripheral
stimulation (see NOTE ADDED IN PROOF). In addition to this, it
has been found that high-intensity stimulation of the primary afferent fibers evoke an excitatory postsynaptic current (EPSC) mediated by kainate receptors in the spinal
cord (96), suggesting that this receptor subtype may be
directly involved in nociception. Further support for this
idea comes from the observation that several kainate
receptor antagonists have shown analgesic activity in a
variety of animal models of pain, as discussed in section
IVA.
In contrast to what is observed in the DRG cells,
AMPA receptor activation masks the existence of kainate
receptors in essentially every central neuron. This fact
made it difficult at first to unequivocally demonstrate their
existence beyond the peripheral nervous system. However, a series of early observations clearly pointed to their
presence throughout the brain. For instance, it was well
known that kainate could act as a potent convulsive agent
when administered in vivo (6, 31) and, more importantly,
that the ingestion of contaminated mussels and the ensuing intoxication with domoate, a more selective agonist,
also led to the appearance of seizures and produced am-
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Despite this progress, the real breakthrough in the
pharmacological distinction between AMPA and kainate
receptors has been the advent of a series of 2,3-benzodiazepines that prevent the activation of AMPA receptors in
a selective and noncompetitive manner (178). Among
them, GYKI 53655 (also known as LY300168) and its active stereoisomer LY303070 are the most effective and
specific antagonists (123, 187). The IC50 of GYKY 53655
for AMPA receptors is ⬃1 ␮M, and it has no effect on
kainate receptors at concentrations as high as 100 ␮M. As
a result, the use of this molecule has made it possible to
unmask the kainate receptors present in neurons, advancing very significantly the study of their physiological role.
Other molecules related to GYKI 53655, such as GYKI
52466 and GYKI 53405, have been also used to discriminate between the two receptor subtypes (12, 39, 123).
Although the affinity of these derivatives for AMPA receptors is comparable to the affinity of GYKI 53655, high
concentrations can reduce the activity of kainate receptors, a fact that has limited their applicability. Similarly,
SYM 2206, another diastereomer of 4-methylglutamate,
has recently been used as a selective blocker of AMPA
receptors (96, 128, 142), but the detailed pharmacological
characterization of this molecule has not been completed
(Table 3).
One final pharmacological tool that has been greatly
used during the study of kainate receptors is the lectin
concanavalin A. This molecule binds to a series of
N-glycosylated residues present in this receptor subtype
(43, 44), leading to a reduction of the fast desensitization
observed upon ligand binding (71, 118, 193). It is active in
native as well as in recombinant receptors, although the
sensitivity of GluR7 is lower compared with the rest of the
subunits (152). However, its practical use is limited because of several reasons. First, concanavalin A binds
nonspecifically to sugars in cell membranes (43, 44), a fact
that restricts its accessibility into more physiologically
relevant preparations such as brain slices. Second, in
addition to its effect on desensitization, concanavalin A
seems to increase the affinity of kainate receptors by one
or two orders of magnitude (78, 124), a fact that may lead
to confusions about the actual biophysical and pharmacological properties of the channels. It has been proposed
(92, 124) that the lectin could uncover quiescent receptors
in a high-affinity, previously desensitized state that become conductive after the binding of concanavalin A.
However, the actual mechanism underlying this increase
in affinity remains to be elucidated. Third, it has been
observed that other subtypes of glutamate receptors can
also be modulated by treatment with concanavalin A. For
instance, the currents through homomeric channels composed of GluR1 or NMDAR1– 4a subunits are increased in
the presence of the lectin (44).
Volume 81
July 2001
NEURONAL KAINATE RECEPTORS
983
nesia (168). It had also been established that certain brain
areas such as the CA3 and the CA1 regions of the hippocampus were particularly sensitive to the depolarizing
and neurotoxic effects of kainate (25, 116, 138, 186). Thus
concentrations of kainate unsuitable for activating AMPA
receptors were nevertheless able to induce epileptiform
activity (138). In addition, autoradiographic studies had
revealed a discrete band of high-affinity kainate binding
sites along stratum lucidum, the site of termination of the
mossy fibers (49, 113). When the granule cells were destroyed, there was a parallel reduction in the number of
binding sites (137) and a decrease in the susceptibility to
the toxicity (36) and epileptogenic activity induced by
kainate (53). These observations suggested that the putative kainate receptors were localized presynaptically, a
hypothesis further supported by some ultrastructural evidence (23, 132) and by early studies showing that kainate
could stimulate transmitter release from slices from a
variety of brain regions (46, 47).
Despite this significant body of evidence, the ambiguity associated with a possible effect of kainate on
AMPA receptors did not allow any definitive conclusion
about the actual involvement of legitimate kainate receptors. It was only in 1993 that pure kainate receptor responses were recorded from embryonic hippocampal
neurons in culture by predesensitizing AMPA channels
(94). Under these conditions, it was observed that kainate
elicited a small, rapidly desensitizing current that showed
strong inward rectification, akin to what had been reported for homomeric GluR6(Q) receptors (40, 66). Indeed, the subsequent analysis of the kainate receptor
mRNA content of individual neurons revealed that most
hippocampal cells in culture expressed GluR6 and, furthermore, that there was a correlation between the
GluR6(Q)/GluR6(R) ratio and the degree of rectification
observed (144). Later studies have confirmed and extended these observations by demonstrating the existence of kainate receptors in several brain cell types
including glial progenitors (127), cerebellar (129) and trigeminal ganglion neurons (146), and postnatal hippocampal cultures (189). It is interesting to note that, in the
latter case, the properties of the kainate receptors are
significantly different from those found in cultures from
embryonic neurons: the currents do not desensitize fully,
and no inward rectification is observed. These features
resemble the characteristics of GluR5(R) ensembles and
can, in principle, be explained by the age-related changes
in the levels of expression of this receptor subunit (4)
and by the developmental shift in the editing at the Q/R
site (9).
A. Involvement of Kainate Receptors in Excitatory
Synaptic Transmission
The demonstration that pure kainate receptors did
exist in nerve cells prompted the obvious question about
their involvement in synaptic transmission. The advent of
GYKI 53655 has made it possible to explore directly
whether the stimulation of excitatory neurons is accompanied by the postsynaptic activation of kainate receptors
in several brain areas. The initial observations made in
hippocampal cell cultures seemed to indicate that this
was not the case. Despite the fact that these neurons
expressed functional kainate receptors, no EPSC could be
recorded in the presence of AMPA and NMDA receptor
antagonists (93). However, subsequent studies performed
in brain slices have identified a collection of synapses that
possess kainate receptors and have begun to reveal certain aspects of their physiological role (51).
The mossy fiber pathway, the connection between
the dentate gyrus granule cells and the CA3 pyramidal
neurons of the hippocampus, was the first synapse shown
to employ kainate receptors (Fig. 7). The repetitive stimulation of the mossy fibers in the presence of GYKI 53655
and 2-amino-5-phosphonovalerate (APV), antagonist of
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FIG. 7. Kainate receptors mediate a
slow postsynaptic current in the hippocampal CA3 region. A: schematic representation of the experimental arrangement. B:
synaptic currents elicited on a CA3 neuron
in the absence (left) or presence (right) of
the AMPA receptor blocker GYKI 53655.
The repetitive stimulation of the mossy fiber pathway is accompanied by a kainate
receptor-mediated excitatory postsynaptic
current (EPSC) resistant to GYKI 53655.
This current is not observed upon repetitive
stimulation of the associational-commissural
fibers or of the mossy fibers in a GluR6
knockout mouse (C). [B from Castillo et al.
(22). Reprinted from Neuron with permission
of Elsevier Science. C from Mulle et al. (115).
Reprinted by permission from Nature, Macmillan Magazines Ltd.]
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choice of the NMDA receptor subtype, was associated
with the appearance of a current with slow rise and decay
time constants that disappeared when CNQX was added
to the bath (21, 176). In addition to its slow kinetic properties (a feature common to most kainate receptor synapses hitherto described), several characteristics of this
current are noteworthy. First, the need for repetitive stimulation to open the receptor channels has been interpreted by some groups as evidence for their putative
extrasynaptic (and not postsynaptic) location (8, 90, 108).
In this model, the glutamate accumulated after tetanic
stimulation would spill away from the synapse, acting on
receptors located far from the release site. Nevertheless,
the observation that the kinetic features of the kainate
receptor-mediated current are not affected by blocking
the uptake of glutamate would seem to argue against this
possibility (111). It should be kept in mind, however, that
glutamate uptake is very sensitive to temperature variations (180). As the aforementioned experiments were performed at room temperature, it is conceivable that the
glutamate carriers were already inactive, consequently
explaining the lack of effect of the antagonists. In any
case, if the kainate receptors activated by the mossy
fibers are extrasynaptic, then they must be located rather
close to the release sites. In favor of this idea, it has been
observed that reducing the diffusion of glutamate by increasing the viscosity of the extracellular medium increases the size of the observed current (111).
Second, the activation of kainate receptors is not
observed at other excitatory connections received by the
CA3 neurons (21, 176). For instance, the repetitive activation of the associational-commissural pathway, axons
that interconnect ipsi- and contralateral CA3 cells, generates an EPSC that is completely blocked by GYKI 53655
and APV (Fig. 7B). This result is in agreement with the
early localization data (49, 113), and it indicates that the
targeting of kainate receptors to the synapse is not unspecific within a given cell but that it is regulated by a
mechanism yet to be discovered.
Third, the kainate receptor that mediates the synaptic current is probably heteromeric. On the one hand, the
GluR5-specific antagonists LY293558 and LY294486 block
the kainate-mediated response (174). On the other hand,
the activation of the mossy fiber pathway in GluR6 knockout mice is not accompanied by a residual EPSC in the
presence of AMPA and NMDA receptor blockers (115)
(Fig. 7C). The recent observation that GluR5 and GluR6
can form heteromeric channels provides a plausible explanation to unify these disparate observations (14, 32,
122).
One final issue regarding the existence of kainate
receptors at the mossy fiber pathway is their involvement
in long-term potentiation of transmission at this synapse.
Early findings had shown that the induction of this plastic
change was resistant to CNQX and kynurenic acid (22,
74). However, the more selective kainate receptor blocker
LY382884 has been recently shown to prevent the synaptic potentiation at this pathway (14). The reason for the
discrepancy among these experiments is unknown. Similarly, it remains to be determined whether LY382884 exerts its action by blocking pre- or postsynaptic kainate
receptors, a problem with an additional complication: the
uncertainty about the locus of induction of mossy fiber
long-term potentiation (99).
The search for postsynaptic kainate receptors in the
pyramidal cells of CA1 has been unsuccessful (17, 50, 93).
However, it has been demonstrated that the interneurons
present in strata radiatum and oriens of this hippocampal
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FIG. 8. Excitatory synapses on interneurons but not on CA1 pyramidal cells
have a kainate receptor-mediated component. The stimulation of the Schaffer collaterals in the presence of GYKI 53655 can
elicit a kainate receptor-mediated excitatory postsynaptic current on CA1 interneurons (A, C) but not on pyramidal cells (A,
B). The subsequent addition of 6-cyano-7nitroquinoxaline-2,3-dione (CNQX) is very
effective in blocking the residual synaptic
current (C). The currents shown in C have
been enlarged in D. [Data in B–D from
Frerking et al. (50).]
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NEURONAL KAINATE RECEPTORS
985
region contain a population of postsynaptic kainate receptors at the connection they receive from the principal
cells (30, 50) (Fig. 8). In contrast to what has been observed at the mossy fiber pathway, the activation of the
interneuron receptors does not require stimulation of the
afferent axons at high frequency (30). Instead, individual
stimuli elicit a slow EPSC sensitive to LY293558, suggesting that the activated channels contain GluR5 subunits.
The impact of these receptors in synaptic transmission is
unknown, but it has been proposed that their activation is
associated with an overinhibition of the CA1 pyramidal
cells (30). This idea is based largely on the observation
that bath application of kainate induces a large increase in
the firing rate of the interneurons. However, it is hard to
accommodate considering the known epileptogenic effects of kainate (6, 31). In addition, this conclusion stands
in contrast to the reports on a reduction of the size of the
evoked inhibitory postsynaptic current (IPSC) induced by
the exogenous administration of kainate (29, 140) or by
the direct activation of glutamatergic pathways (110), as
discussed below. Furthermore, the fact that bath-applied
kainate necessarily acts on synaptic, as well as on extrasynaptic receptors, complicates any interpretation of that
finding in terms of the phasic activation of the synaptically localized channels. In this regard, an alternative
proposal (50) suggests that the massive activation of synaptic kainate receptors might lead to the eventual death of
the interneurons, and to the appearance of epileptic discharges concomitant to the reduction of the inhibitory
drive. Although the size of the kainate-mediated EPSC is
10-fold smaller than the AMPA-mediated current, the
longer duration of the former and its correspondingly
longer integration time are consistent with this possibility. Furthermore, kainate application can indeed result in
the neurotoxic death of the interneurons in the CA1 region (64, 162). Whether this cell death occurs on a time
scale compatible with the epileptogenic effect of kainate
remains to be demonstrated.
Postsynaptic kainate receptors have been identified
in brain regions other than the hippocampus such as the
cerebellum (18), the striatum (24), the spinal cord (96),
and the amygdala (95). In neurons of the basolateral
amygdala (95), for instance, the stimulation of external
capsule afferent fibers elicits an EPSC resistant to GYKI
53655 and APV but sensitive to LY293558. These kainate
receptor-mediated synaptic responses have not been observed following the stimulation of local circuits within
the amygdala (e.g., the projection from the basal nucleus)
(95). Thus, as is the case for the CA3 neurons, kainate
receptors at the basolateral amygdala seem to be compartmentalized. In addition, the activation of the primary
afferent sensory fibers produces a kainate receptor-mediated EPSC on the spinal neurons of the dorsal horn (96).
As is the case for the hippocampal currents, the onset and
decay time constants of the spinal EPSC are slow compared with the AMPA receptor-mediated response in the
same cells. A remarkable feature of this current is that it
can only be elicited upon the stimulation of the afferent
axons at an intensity strong enough to activate the highthreshold A␦ and C fibers, raising the possibility that the
kainate receptor subtype may be exclusively involved in
nociception at this level (96). This hypothesis has received significant support from experiments showing that
the application of opiate agonists can reduce the amplitude of the kainate receptor EPSC (96), and from the
observation that this receptor subtype is present at synapses on identified spinothalamic projection neurons
(96). Moreover, several kainate receptor antagonists possess analgesic activity in a number of animal models of
pain. For instance, SYM 2081, presumably acting as a
functional antagonist, increases the latency of escape in
the hot-plate and the tail-flick tests (96), whereas
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FIG. 9. Kainate receptors mediate synaptic transmission between cones and offcenter bipolar cells in the squirrel retina.
A: an off-center bipolar cell is recorded
from the inner nuclear layer (INL) of the
retina, and a synaptically connected cone
is depolarized (B). This manipulation elicits a fast postsynaptic response in the bipolar cell that rapidly declines due to receptor desensitization. The somatic application (C) of kainate (D) or glutamate (E)
to a bipolar cell is accompanied by a GYKI
53655-resistant, desensitizing response similar to the one observed after the depolarization of the cone. [From DeVries and
Schwartz (37). Reprinted by permission
from Nature, Macmillan Magazines Ltd.]
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Volume 81
LY382884 decreases the frequency of paw licking induced
by the subcutaneous injection of Formalin (157).
Postsynaptic kainate receptors are commonly assumed to coexist with other glutamate receptor subtypes,
in particular with AMPA receptors and, in fact, there is
indirect evidence that this is actually the case for some
synapses (50). However, it has been clearly demonstrated
that certain synaptic contacts solely contain kainate receptors. In this regard, the connection between the cones
and the off-center bipolar cells of the squirrel retina is a
prime example (37). The depolarization of an individual
cone leads to the appearance of a fast EPSC in this class
of bipolar cells (Fig. 9). This EPSC is not affected by the
addition of GYKI 53655 and APV, but it is blocked by
CNQX, clearly indicating its dependence on kainate receptors. In contrast to what has been observed at all other
kainate receptor synapses, the kinetic properties of the
EPSC resemble those described for recombinant and for
somatodendritic, extrasynaptic channels (94, 124): fast
activation and desensitization time constants, an essentially complete inactivation in the continuous presence of
the agonist, and a slow recovery from the desensitized
state. It has been proposed that these properties of the
receptors have profound implications for retinal function,
controlling the gain of the bipolar cell output (37). Thus,
in the dark, the cones release glutamate relentlessly, but
the desensitization of the kainate channels prevents the
continuous depolarization and the saturation of the offcenter cell. The hyperpolarization of the cones upon illumination would interrupt transmitter release, allowing for
the slow recovery of the receptors from the inactive state.
If darkness were reestablished before the recovery is
complete, the depolarization of the bipolar cell would be
smaller depending on the duration of the illumination
period (37). This mechanism for the transmission of
graded, phasic signals in response to tonic release constitutes an elegant counterpart by an ionotropic receptor to
the well-understood action of metabotropic glutamate receptors on on-center bipolar cells (106, 117).
One final example of synapses purely containing kainate receptors is found in the cerebral cortex (Fig. 10).
The stimulation of thalamocortical axons elicits an EPSC
that consists of a fast AMPA receptor-dependent component and a slower one, mediated by the activation of
kainate receptors (85). However, the spontaneous EPSC
recorded from cortical neurons never exhibit the two
components but, instead, they fall into two separate
classes corresponding to the activation of each of the
different receptor subtypes (85). In other words, despite
the fact that a given cortical neuron can express both
AMPA and kainate receptors, they never seem to colocalize at synaptic sites (Fig. 10, B and C). Furthermore, there
is a dynamic switch that governs during development the
number of synapses of each class (85). Thus the occurrence of the critical period for activity-dependent plastic
changes in the thalamocortical pathway coincides with a
reduction in the number of synapses that possess kainate
receptors and with a parallel increase in the abundance of
AMPA receptor-containing contacts (Fig. 10E). A similar
phenomenon has been observed after the induction of
long-term potentiation at this pathway (Fig. 10D), indicating that the redistribution can occur within minutes (85).
These results highlight once more the necessity to identify
what synaptic proteins interact with the kainate receptors
to help us understand the mechanisms that control their
function and their regulation. At the same time, the existence of such a rapid switch for modifying the receptor
subtype present at the synaptic contact is reminiscent of
what has been observed at the so-called silent synapses
(103), contacts devoid of AMPA channels that only pos-
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FIG. 10. Kainate receptors are
present at thalamocortical synapses. The
stimulation of thalamocortical axons is
followed by an excitatory postsynaptic
current (EPSC) with two phases: a fast,
AMPA receptor-mediated component
and a slow, GYKI 53655-resistant, kainate
receptor-mediated component (A). The
two phases do not coexist at the same
synaptic contacts. Instead, each synapse
has solely kainate (B) or AMPA receptors (C). The induction of long-term potentiation at these synapses leads to a
reduction in the number of kainate receptor-containing synapses (D). A similar phenomenon is observed during postnatal development (E), where the slow
phase of the EPSC disappears by postnatal day 8. [From Kidd and Isaac (85).
Reprinted by permission from Nature,
Macmillan Magazines Ltd.]
July 2001
NEURONAL KAINATE RECEPTORS
987
sess NMDA receptors. The functional implications of
those thalamocortical kainate receptor-only synapses remain unresolved.
Another unresolved issue regarding the synaptic activation of kainate receptors is the slow kinetic properties
of the response. With the exception of the channels found
at the squirrel retina (37), the time constants determined
for the activation and desensitization of kainate receptors
in cultured cells and in heterologous systems predict
synaptic responses markedly different from those actually measured. One possible explanation for these differences is that the composition of the synaptic receptors is
dissimilar to any of the combinations of recombinant
subunits hitherto analyzed or, alternatively, that postsynaptic kainate receptors contain additional, unidentified
subunits capable of altering the kinetic features of the
response. Similarly, the interaction of the receptors with
other synaptic proteins (54), as discussed above, is likely
to have an effect on the properties of the channel. Furthermore, the kainate receptor subunits possess consensus sites for the action of a series of protein kinases and
have been shown to undergo phosphorylation in a variety
of systems (55, 136, 172, 181, 196). The effects of such
covalent modification on the behavior of the native chan-
nels remain largely unexplored. Lastly, the prolonged duration of the response could be the manifestation of the
window current predicted by the overlap between the
activation and the desensitization curves of the kainate
receptors (124). It is conceivable that the concentration of
glutamate that reaches the channels is high enough to
open a few of them and, at the same time, insufficient to
cause complete desensitization. This possibility would be
even more appealing if the receptors were not directly
underneath the release site but if, instead, glutamate had
to spill to the periphery of the synapse to reach them. The
determination of the exact localization of the kainate
receptors at the synapse will help to answer this question,
although indirect observations suggest that diffusion of
glutamate far from the release site is unlikely to account
for the slow kinetic properties of the response (18, 111).
B. Presynaptic Kainate Receptors
In addition to their postsynaptic role, kainate receptors have been found to modulate transmitter release by a
presynaptic mechanism. As mentioned above, a number
of early experiments pointed to a possible presynaptic
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FIG. 11. Kainate modulates the reliability of GABAergic transmission in the hippocampus. A: electrical stimuli are
delivered to stratum oriens and the evoked inhibitory postsynaptic currents (IPSC) are recorded from CA1 pyramidal
cells. B: the amplitude of the IPSC decreases in the presence of kainate or glutamate. This reduction is reversible (B) and
dose dependent (C), reaching a maximum around 100 ␮M in the case of glutamate. D: effect of kainate on the trial-to-trial
fluctuation of the evoked IPSC. The mean IPSC amplitude and its coefficient of variation (CV2) were measured before
and during the application of kainate. There was a parallel reduction of both parameters that followed the predicted
relation for a presynaptic effect of kainate. Further evidence in favor of a presynaptic locus for kainate action has been
gathered from the observed decrease in the frequency of miniature IPSC (E), as revealed by an increase in the interval
between successive events in the presence of the agonist (F, left). The amplitude of the miniature IPSC is not affected
by kainate (F, right). [B–F modified from Paternain et al. (124) and Rodrı́guez-Moreno et al. (141).]
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localization of this receptor subtype, although the lack of
specific pharmacological agents made it unfeasible to
establish the actual identity of the receptors under analysis. The use of GYKI 53655 has largely eliminated these
ambiguities, making it possible to revisit and extend those
original experiments. As a result, it is now largely accepted that kainate receptors are present at a subset of
both excitatory and inhibitory terminals, where they affect release by a series of mechanisms that are beginning
to be unraveled.
Studies on the effect of kainate receptor activation
on glutamate release from synaptosomes have yielded
disparate results. On the one hand, a GYKI 52466-resistant, kainate-induced increase in transmitter released
from cortical synaptosomes has been reported (130), an
effect mimicked by the addition of kainate or domoate to
synaptosomal preparations enriched for CA3 terminals
(104, 105). On the other hand, observations made on CA1
synaptosomes have revealed no effect of kainate on glutamate release but only an intriguing effect on the release
of aspartate (199). Finally, other reports have revealed a
kainate-mediated decrease in the influx of calcium in the
CA3 region (2) and a decrease of glutamate release from
hippocampal synaptosomes (28) in the presence of GYKI
52466. Thus, although the evidence seems to indicate that
kainate receptors are present on isolated synaptic terminals, it is not clear whether they stimulate or inhibit
transmitter release, although it appears that the effect is
synapse specific.
Experiments performed on brain slices have provided additional evidence for the participation of kainate
receptors on the regulation of excitatory synapses of the
Schaffer collateral (28, 80, 175) and mossy fiber pathways
(81, 154, 175). It has been observed that the administration of kainate to hippocampal slices in the presence of
GYKI 52466 is accompanied by a biphasic modulation of
the NMDA receptor-mediated EPSC on CA1 neurons (28).
After an initial period of enhanced release, the agonist
induced a reversible reduction of the EPSC amplitude.
This reduction was sensitive to LY294486, suggesting the
involvement of GluR5-containing receptors in the phenomenon (175). This biphasic behavior can be explained
by proposing an early depolarization of the terminal and
the subsequent reduction of calcium influx due to the
inactivation of the calcium channels involved in the release process (28, 80). Nevertheless, the observed decrease of the excitatory drive is a surprising observation
considering the known epileptogenic effects of kainate.
Interestingly, lower concentrations of the agonist were
effective in inducing only the increase of the synaptic
response (28). Therefore, the exogenous application of
kainate will not suffice to obtain a definitive answer on
the modulation of excitatory neurotransmission by this
receptor subtype. Indeed, subsequent studies should aim
to establish the actual concentration of glutamate that
reaches the receptors during normal and excessive synaptic excitation and, as recently shown for the mossy
fiber pathway (154), test whether endogenous glutamate
can cause a kainate receptor-mediated reduction of glutamate release.
The modulation of GABA release by the activation of
kainate receptors has also been reported in the hippocam-
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FIG. 12. A: the hippocampal CA1 interneurons express two populations of kainate
receptors. One of them is presumably somatodendritic and is responsible for the depolarization of the cell upon kainate application. The second one, in contrast, is probably
located at the presynaptic terminal and is
responsible for the inhibition of transmitter
release. B: at a low concentration, glutamate
acts preferentially on the presynaptic population: it inhibits release but does not provoke the massive firing of the interneurons as
judged by its minimal effect on the frequency
of spontaneous IPSC. C: at a low concentration, ATPA acts preferentially on the somatodendritic population: it does not inhibit release but causes a marked increase of the
frequency of spontaneous IPSC. D: the effect
of different agonists on the frequency of
spontaneous IPSC plotted versus the reduction of the amplitude of the evoked IPSC.
Some agonists such as glutamate (G) and
kainate (K) are more effective on decreasing
the IPSC amplitude, whereas other such as
ATPA (AT) and AMPA (AM) act primarily by
depolarizing the interneurons. The numbers
that accompany each letter refer to the concentrations used in the experiments shown.
[B–D from Rodrı́guez-Moreno et al. (142).]
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NEURONAL KAINATE RECEPTORS
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pus (29, 30, 50, 52, 110, 140) (Fig. 11) and in the hypothalamus (97). In the case of the hippocampus, the literature
is more homogeneous about the effect, and all of the
available studies agree that the application of kainate in
the presence of GYKI 53655 causes a reversible decrease
of the evoked IPSC amplitude (29, 30, 50, 52, 110, 140).
Unfortunately, despite this general agreement, the exact
role of kainate receptors on its action is a matter of
dispute.
Three lines of evidence lent initial support to the idea
that kainate receptors were acting directly on the presynaptic terminal in the hippocampus (140). First, kainate
increased the failures of transmission between pairs of
hippocampal neurons in culture. Second, kainate reduced
the frequency of miniature IPSC in hippocampal slices
(Fig. 11, E and F), an effect, however, not observed by
other groups (50, 52). Third, the coefficient of variation of
the synaptic responses changed in parallel to the reduction of the IPSC amplitude (Fig. 11D). These results were
placed in doubt after the realization that inhibitory interneurons possessed postsynaptic kainate receptors (30,
50). It was then argued that the massive activation of this
cell type caused an activity-dependent depression of the
evoked IPSC, a depression that had no relationship to a
direct action of kainate on its putative presynaptic receptors. Although the presence of kainate does induce a
marked increase in the spontaneous interneuronal firing
rate (30, 50), a phenomenon known for more than 15
years (48), further studies have shown that the reduction
of the evoked IPSC amplitude is independent of this phenomenon. On the one hand, the use of different kainate
receptor agonists has allowed for the dissociation of the
two events (142). Thus glutamate, the endogenous ligand,
produces a decrease of the IPSC amplitude without affecting the spontaneous activity of the interneurons. In
contrast, low concentrations of the kainate-receptor agonist ATPA increase the firing rate of the GABAergic cells
but do not induce any decrease of the IPSC amplitude
(Fig. 12). Moreover, the direct stimulation of the interneurons by high-frequency electrical stimulation is not accompanied by a reduction of the IPSC size comparable to
what is observed after the application of kainate (142).
Finally, it has been possible to record directly from synaptically connected interneuron-pyramidal cell pairs. Under these conditions, kainate continues to induce a decrease of the unitary IPSC amplitude in the absence of
repetitive firing of the presynaptic neuron in culture (140)
and in slices (52).
The observation that the spontaneous activity of
GABAergic neurons is strongly increased by the presence
of kainate has prompted a second alternative explanation
for the inhibitory effect of this agonist on the IPSC amplitude: the involvement of GABA receptors as the real
mediators of the phenomenon (52). In this scenario, kainate would depolarize the interneurons causing them to
fire repeatedly and to release an excessive amount of
GABA. The resultant increase in the extracellular concentration of this amino acid would then have two interrelated actions. First, it would lead to the activation of
presynaptic GABAB receptors, molecules known to downregulate release from inhibitory terminals (109, 170, 195).
Although initial experiments had shown that the presence
of GABAB receptor blockers had no effect on the kainatemediated inhibition (50, 141), subsequent studies (52)
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FIG. 13. Synaptically released glutamate reduces
GABAergic inhibition in the hippocampus via kainate receptors. A: glutamate released upon activation of the
Schaffer collaterals can act on AMPA (A) and N-methyl-Daspartate (NMDA) (N) receptors, but it can also spill to a
neighboring inhibitory synapse to activate kainate receptors (K) and reduce the release of GABA (GA). B: the
amplitude of an IPSC evoked by the stimulation of the
stratum oriens is reduced if a train of stimuli delivered to
the Schaffer collaterals precedes it. This decrease is resistant to AMPA receptor antagonists, but it is sensitive to
CNQX (C), revealing its dependence on kainate receptors.
[B and C from Min et al. (110).]
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have revealed a partial blockade of the effect of kainate
by the GABAB receptor antagonist SCH50911. Second, an
excess of extracellular GABA would also lead to the
opening of the GABAA channel subtype and to a concomitant decrease in the input resistance of the CA1 neuron.
Indeed, it has been observed that kainate induces a decrease in the input resistance of the CA1 neurons, a
change that reduces the half-width of the synaptic responses and the amplitude of GABA-induced somatic currents (52). The addition of GABAA receptor antagonists
prevents this change in the passive properties of the
pyramidal cell membrane, suggesting that a fraction of the
effect of kainate has a postsynaptic locus and is indirectly
mediated by the activation of this GABA receptor subtype (52).
In principle, the sum of these two actions of the
inhibitory transmitter could account for the effect of kainate on the IPSC amplitude. However, it has been found
that the synaptic activation of excitatory pathways can
mimic the effect of bath-applied kainate (110). Under
these conditions, there is no massive surge of GABA
release but, nevertheless, the size of the evoked IPSC is
significantly reduced after a brief, high-frequency train of
pulses to the Schaffer collaterals in the presence of GYKI
52466 and APV (Fig. 13). Furthermore, this depression is
not affected by the application of GABAB receptor antagonists, and it is abolished by kynurenic acid, a widespectrum glutamate receptor blocker (110). These findings demonstrate that, under more physiologically
relevant conditions, kainate receptor activation has a real
effect on release from inhibitory terminals, which is independent of the possible action of GABA. In this regard, it
is important to remark that the net effect of low concentrations of kainate in the in vivo preparation is an increase
of tissue excitability. In fact, one of the clearest electrophysiological evidences of kainate action in vivo is a
reduction of GABAergic inhibition, as judged by paired
pulse stimulation (140) (Fig. 14).
In summary, a significant body of evidence, pioneered by the study of Fisher and Alger (48), indicates
that kainate reduces the efficacy of the inhibitory connections in the hippocampus. Although some indirect
actions of the agonist may contribute to its global
effect, it can be concluded that the activation of kainate
receptors located at the GABAergic terminal is also
involved in the genesis of the reduction. What is the
molecular composition of the receptors responsible for
this modulatory action? On the one hand, the observations that LY294486 blocks the action of kainate (29),
and that a large number of presumptive interneurons
express the GluR5 mRNA (122), point to the involvement of this subunit in the phenomenon. On the other
hand, the reduction of the evoked IPSC as well as the
large increase in interneuronal firing are still observed
in mice lacking the GluR6 subunit (17), suggesting that
this subunit does not participate in the presynaptic
modulation of GABAergic neurotransmission.
Finally, it is necessary to consider the mechanisms
whereby a cationic channel can exert an inhibitory effect on
the release process. It has been proposed that the depolarization induced by an ionotropic receptor could lead to the
inactivation of voltage-gated sodium or calcium channels
present at the terminal (100, 109). Indeed, as mentioned
above, evidence for this type of mechanism has already been
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FIG. 14. The intrahippocampal infusion of kainate in vivo is accompanied by a
decrease in recurrent inhibition. A: kainate
is delivered via a dialysis fiber located near
the recording extracellular electrode. B:
two pulses 40 ms apart are delivered to the
Schaffer collaterals. In the absence of kainate, the population response to the second pulse is significantly reduced due to
the polysynaptic activation of inhibitory,
recurrent fibers. In the presence of kainate, the amplitude of the second response
increases with time, an indication of a reduction in the hippocampal inhibitory
drive. An additional effect of kainate is the
generation of double population spikes
(bottom right record in B), which are reminiscent of status epilepticus. In fact, interictal epileptic spikes can also be seen in
the hippocampal electrical activity (C).
[B and C are from Rodrı́guez-Moreno et al.
(141).]
July 2001
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NEURONAL KAINATE RECEPTORS
obtained for the activation of kainate receptors at excitatory
synapses in the hippocampus (80). Nevertheless, it has been
found that the effect of kainate is sensitive to the presence
of pertussis toxin (141), pointing to the involvement of G
proteins in this regulatory process (Fig. 15). Moreover, protein kinase C (PKC) inhibitors can also block the action of
kainate, further delineating the signaling pathway involved
in the modulation of inhibitory neurotransmission (141). It is
worthwhile to emphasize that the recruitment of the PKC
pathway is not secondary to the depolarization of the terminal since reducing the influx of sodium ions does not affect
the action of kainate (141). Therefore, it has been proposed
that there is a physical link between kainate receptors and
the G protein involved in the process, a link that could be
either direct or through an intermediary molecule. A similar
type of association between an ionotropic receptor and the
signal transduction machinery has been documented for the
AMPA receptor (62, 83, 131, 182, 183). In addition, a goldfish
kainate binding protein with significant homology to the rat
kainate receptor subunits has been shown to interact with a
pertussis toxin-sensitive G protein, an interaction that modifies the affinity of the binding proteins for the ligand (190,
200). Lastly, the binding of SYM 2081 decreases after incubation of hippocampal membranes with pertussis toxin (33),
and a similar effect of the toxin has been observed on the
kainate-mediated inhibition of GABA release from synaptosomes (34), further suggesting a direct coupling between
kainate receptors and G proteins in the mammalian brain.
V. PATHOLOGICAL ACTIONS
The epileptogenic action of kainate has been well
known for decades, but the actual involvement of its
specific receptors has just begun to be unraveled. The first
indication that the activation of kainate receptors could
elicit epileptiform discharges in vitro came from studies
where low concentrations of the agonist, insufficient to
activate AMPA receptors, could induce repetitive discharges in the hippocampus (48, 158, 186). In contrast, the
results obtained after the systemic or the intracerebral
administration of kainate in vivo have been more difficult
to interpret, and the evidence on the participation of
kainate receptors has only accrued during the last 10
years. As mentioned above, one of the earliest observations in this regard was that the accidental ingestion of
domoate, an agonist with a 50-fold preference for kainate
over AMPA receptors, produces seizures and amnesia
(168). More recently, it has been discovered that certain
allelic variants of the human GluR5 subunit (GRIK1)
(149), but not of GluR6 (GRIK2) (150), confer an increased susceptibility to the development of juvenile absence seizures. In addition, the level of kainate receptor
mRNA seems to be altered in the hippocampus of patients
suffering from temporal lobe epilepsy (107).
In addition to this body of circumstantial evidence,
the putative role of kainate receptors on epilepsy has
received more direct support from two experimental
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FIG. 15. The modulation of GABA release by
kainate receptors involves a metabotropic cascade. A: the reduction of the IPSC amplitude produced by kainate is eliminated by preincubating
the hippocampal slice with pertussis toxin (PTx),
with the protein kinase C (PKC) inhibitors staurosporine (Stauro), calphostin C (Calph-C), and
bisindolylmaleimide (Bis) or with the phospholipase C (PLC) inhibitor U-73122. In contrast,
H-89, an inhibitor of the cAMP-dependent protein
kinase, had no effect on the kainate-mediated
reduction. B: a cocktail composed of antagonists
of AMPA, NMDA, and metabotropic glutamate
receptors, muscarinic acetylcholine receptors,
GABAB receptors, opiate receptors, and adenosine receptors does not prevent the inhibitory
action of kainate. C: schematic representation of
the cascade that links kainate receptor activation
to the reduction of GABA release. The mechanism whereby the receptor interacts with the G
protein is unknown. Similarly, the substrates
phosphorylated by PKC that ultimately lead to the
modulation of the release machinery remain to be
discovered. [Data in A and B modified from Rodrı́guez-Moreno and Lerma (140) and Rodrı́guezMoreno et al. (142).]
992
LERMA, PATERNAIN, RODRÍGUEZ-MORENO, AND LÓPEZ-GARCÍA
VI. FUTURE DIRECTIONS
Our understanding of kainate receptors trails significantly behind our insights on the workings of the other
ionotropic glutamate receptor subtypes. We have just begun to explore the structural determinants of kainate
receptor function, a field where the detailed dissection of
the AMPA receptor subtype has had a profound heuristic
value. In this regard, it is surprising to observe the limited
mutational analysis performed on kainate receptors,
which in most cases has been aimed simply at extending
findings previously obtained in AMPA receptors. However, several important questions still await an answer.
Why can AMPA receptors bind kainate but kainate receptors cannot bind AMPA? Discovering the structural elements involved in this discrimination should assist in the
design of kainate receptor-selective drugs. Why are KA1
and KA2 not able to form functional channels on their
own and yet the conductance of heteromeric GluR5/KA2
assemblies is almost twice as large as for homomeric
GluR5 channels? What regions of the molecule mediate
intersubunit interactions in heteromeric channels? Is it
possible that the binding site is actually formed at the
interface between two subunits as is the case for acetylcholine receptor (82)? These issues have been hitherto
neglected despite their relevance for the understanding of
the function of this receptor subtype.
Similarly, there are many unsolved questions about
the physiological role of kainate receptors. Why are the
properties of the postsynaptic kainate currents so different from the characteristics observed in recombinant receptors? We have already speculated in this regard, but
the actual answer still eludes us. Clearly, the use of paired
recordings and the analysis of unitary KAR-mediated
postsynaptic currents will be instrumental in determining
the actual properties of these receptors at synaptic sites.
Another intriguing fact about the kainate receptor-mediated component of the EPSC is their small amplitude. If
the synaptic current through the AMPA receptors is so
much larger, what is the significance of such a small
kainate receptor EPSC? Its longer duration and its concomitantly longer integration time provide a clue, but is
this the whole answer? Could it be that AMPA and kainate
receptors never coexist, as in the case of the thalamocortical synapses (85), and we have not paid close attention?
Furthermore, as presynaptic kainate receptors act
through the activation of a G protein and the recruitment
of PKC in inhibitory neurons (141), why could a similar
phenomenon not occur at the postsynaptic membrane to
amplify the effect of their activation? We have also considered the idea that the kainate receptors are not located
exactly under the release site but in the periphery of the
synapse, a possibility that would certainly have deep implications for their function.
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fronts. First, the clear antiepileptic action of benzodiazepines and barbiturates, positive modulators of GABA
receptors, and the discovery that kainate receptors modulate the reliability of GABAergic synapses have suggested a simple model for the epileptogenic action of this
agonist. The decrease in the efficacy of inhibitory connections induced by kainate receptors would create an imbalance favoring excitation, leading eventually to the development of seizures. In agreement with this model, the
intrahippocampal application of kainate at concentrations known to reduce the amplitude of the IPSC in slices
triggers the appearance of a firing pattern reminiscent of
status epilepticus (140). Furthermore, the concentration
of glutamate in the extracellular fluid during an episode of
ischemia reaches ⬃100 ␮M (8), a value identical to the
concentration that modulates GABAergic synapses most
effectively through the activation of kainate receptors
(124) (Fig. 11C). Second, it has been found that mice
lacking the GluR6 subunit exhibit a reduced susceptibility
to seizures after the systemic administration of kainate
(115). This effect of the mutation was evident at low
doses of the agonist, but it was negligible at higher concentrations. Thus it will be important to determine
whether mice lacking the other kainate receptor subunits
have a similar phenotype and whether any synergistic
effect of the mutations can be revealed in double-knockout animals. At the same time, it is important to keep in
mind that, as kainate also increases the spiking frequency
of inhibitory neurons, its epileptogenic action is likely to
depend on the balance between this phenomenon and the
reduction of GABA release.
In addition to their role in epilepsy, kainate receptors have started to receive attention regarding their
possible involvement in other pathophysiological phenomena. As discussed earlier, they are present at the
spinal afferent synapses (96), and their blockade has
been proven to have analgesic actions (96, 157), raising
the possibility that its antagonists can be used in the
treatment of certain forms of chronic pain. In addition,
chromosome 21 harbors the locus of the GRIK1 gene
(42, 134), a finding that has prompted the suggestion of
a possible role for GluR5 in Down’s syndrome (26, 57).
Moreover, a mutant gene associated with a form of
familial amyotrophic lateral sclerosis also maps to this
chromosome (42), but any linkage between this and the
GRIK genes remains to be discovered. Lastly, a series of
correlative studies have shown a reduction of the
GluR6 and KA2 mRNA in the hippocampus of patients
with schizophrenia (133) and a moderate linkage between some genotype variants of the GRIK2 gene and
the age of onset of Huntington disease (101, 145). The
actual relationship, if any, between kainate receptors
and any of these diseases is unknown.
Volume 81
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NEURONAL KAINATE RECEPTORS
NOTE ADDED IN PROOF
A number of recent publications, which appeared while
this review was being considered for publication, have presented convincing additional evidence showing that kainate receptors are also able to regulate the release of glutamate at
excitatory synapses. In particular, GluR6 kainate receptor activation markedly depressed the release of glutamate at mossy
fibers (29b, 81, 154), where they have been postulated to play a
significant role in synaptic plasticity (14, 29a). Similarly, kainate
was found to suppress EPSCs evoked by dorsal root fiber stimulation (84a), indicating that presynaptic kainate receptors may
also regulate primary afferent sensory transmission. Although
the relevance of these processes and the underlying mechanisms have not been established unequivocally, it is worth noting that presynaptic kainate receptors may play a dual role in
overall excitability (see Ref. 6a). In addition, a role for RNA
editing of kainate receptors has been recently revealed. In mice
engineered to lack the GluR6 Q/R editing site, Vissel et al. (177a)
found that NMDA-independent LTP could be more easily induced than in normal mice and that these mutant mice were
more vulnerable to kainate-induced seizures. This constitutes
the first indication that the Q/R site editing of GluR6 RNA may
modulate both seizure susceptibility and synaptic plasticity,
therefore providing evidence for a critical biological role of
kainate receptor editing.
We thank Drs. M. A. Nieto and M. T. Herrera for the in situ
hybridization studies, Dr. O. Herreras for the in vivo studies, and
D. Guinea for technical assistance. We also appreciate the generous gift of GYKI 53655 from Eli Lilly (Indianapolis, IN). We are
indebted to Drs. G. Swanson and P. Castillo for kindly providing
us with their original records illustrated in Figures 2 and 7,
respectively.
Work in the laboratory of J. Lerma has been supported by
grants from the Spanish Ministry of Education and Culture
(DGICYT Grants PB93/0150 and UE96/0007 as well as DGESIC
Grants PM-0008/96 and PM99 – 0106), the Ministry of Health
(FISSS Grant 95/0869), the Comunidad de Madrid (Grant 08.5/
0042/1998), and the European Union (Grant BIO2-CT930243).
J. C. López-Garcı́a is the recipient of a long-term fellowship
awarded by EMBO.
Address for reprint requests and other correspondence: J.
Lerma, Instituto Cajal, CSIC, Av. Doctor Arce 37, 28002 Madrid,
Spain (E-mail: [email protected]).
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