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Encyclopedia of Hormones. Copyright 2003, Elsevier Science (USA). All rights reserved.
Membrane Receptor Signaling
in Health and Disease
ALFREDO ULLOA -AGUIRRE ,
GUADALUPE MAYA -NÚÑEZ ,
AND
CARLOS TIMOSSI
Instituto Mexicano del Seguro Social, Mexico
I. INTRODUCTION
II. G-PROTEIN-COUPLED RECEPTORS AND G-PROTEINS
IN HEALTH
III. G-PROTEIN-COUPLED RECEPTORS IN DISEASE
IV. DEFECTS IN G-PROTEIN-COUPLED
SIGNAL TRANSDUCTION
V. ENZYME-LINKED RECEPTORS IN HEALTH AND DISEASE
VI. ION-CHANNEL-LINKED RECEPTORS IN HEALTH
AND DISEASE
VII. SUMMARY
The primary function of cell surface receptors is
to recognize a specific signal or ligand from
among an immense number of chemically
diverse substances and to act as signal transducers and amplifiers of the stimulus or message
carried by external, systemic, or local stimuli.
Extracellular signal-evoked receptor activation
triggers a cascade of intracellular events; this
usually culminates in a highly specific biological
response, either stimulatory or inhibitory, of a
given cell function.
I. INTRODUCTION
The three main classes or superfamilies of cell surface
receptor proteins are defined according to the way in
which they evoke intracellular signaling: (1) by
G-protein coupling, (2) by enzyme coupling, and (3)
by ion channel linkage. G-Protein-coupled receptors
are seven-transmembrane-helix protein molecules
that mediate their intracellular actions through the
activation of one or more members of the guaninenucleotide-binding signal-transducing proteins
(G-proteins), which carry the information received
by the receptor molecule to cellular effectors such as
enzymes and ion channels. Activated effectors modify, in turn, levels of particular second messengers that
regulate a wide variety of cellular processes. Enzymecoupled receptors function directly as enzymes or
through associated enzymes. Most have a single
transmembrane (TM) segment with a ligand-binding
site outside the cell and a catalytic site inside the cell.
A majority of these receptors are protein kinases or
MEMBRANE RECEPTOR SIGNALING IN HEALTH AND DISEASE
are associated with protein kinases that trigger a
cascade of protein –protein interactions and phosphorylations on activation by their cognate ligands.
Finally, ion-channel-linked receptors or transmittergated ion channels are multisubunit ionotropic
receptor molecules that rapidly mediate signals
carried by a small number of neurotransmitters
across the synapse of the central and peripheral
nervous systems. In these particular receptors, ligand
binding leads to opening of an intrinsic pore, through
which ions can flow down their electrochemical
gradients, transforming a chemical signal into charge
flux across the membrane. The activity of a given
family or type of membrane receptor can be
influenced, positively or negatively, by signaling
pathways from other receptors (i.e., receptor crosstalking) in a variety of ways, generating the functional flexibility required by complex systems.
This article focuses on how membrane receptors
and their coupled signal transducers evoke intracellular signals in normal and abnormal conditions.
Special emphasis is given to the G-protein-coupled
receptor (GPCR) – G-protein system, for which nearly
2000 receptors have been cloned since initial cloning
of bovine opsin, the photoreceptor of the rod cell.
II. G-PROTEIN-COUPLED RECEPTORS
AND G-PROTEINS IN HEALTH
A. GPCRs
G-protein-coupled receptors are a large and functionally diverse superfamily of membrane receptors; they
consist of a single polypeptide chain of variable length
that traverses the lipid bilayer seven times, forming
characteristic transmembrane helices connected by
alternating extracellular and intracellular sequences
or loops (Fig. 1). Many signaling cascades use this
class of receptor to convert external (e.g., photons
and odorants) and internal (e.g., neurotransmitters,
peptides, and glycoproteins) stimuli to intracellular
responses. G-Protein-linked receptors characteristically bind large G-proteins, which in turn act as
mediators of receptor-evoked effector activation. The
nature of the second-messenger pathways activated in
response to ligand binding to a given GPCR is
essentially determined by the type of G-protein(s)
coupled to the receptor (see later). The regulation of
receptor– G-protein signal selectivity and specificity is
highly complex and involves the activation of a
network of mechanisms and pathways that eventually
lead to biological responses. Based on nucleotide and
amino acid sequence similarities, the GPCRs can be
645
grouped into three main families: (1) family A, the
rhodopsin/b2-adrenergic receptor-like family, which
comprises receptors that respond to a large variety of
stimuli, including photons, odorants, neurotransmitters, and glycoprotein hormones; (2) family B, the
glucagon/vasoactive intestinal peptide (VIP)/calcitonin receptor-related family, which includes receptors
for a variety of peptide hormones and neuropeptides,
including parathyroid hormone, corticotropin-releasing hormone, VIP, calcitonin, glucagon, growth
hormone-releasing hormone, and secretin; and
(3) family C, the metabotropic glutamate/calciumrelated family, which includes the taste receptors, the
metabotropic glutamate and calcium receptors, the
putative pheromone receptors, and the g-aminobutyric acid (GABA) receptors. Other receptors belonging to the GPCR superfamily are grouped in family D
(pheromone-like receptors) and family E (cyclic AMP
receptors).
Agonist binding to GPCRs provokes changes in the
conformation of the receptor molecule involving
particularly the relative positions of the seven-TM
domains; the molecular perturbations of the membrane-embedded helices (Fig. 1) are thought to cause
changes in the cytoplasmic (i.e., the intracellular
loops) face of the receptor, promoting G-protein
coupling and activation. Most of the primary
sequence homology among the different groups of
these types of receptors is contained within the
hydrophobic TM domain (particularly for families A
and B) or the intracellular loops (for the metabotropic
neurotransmitter/calcium receptors). Receptors for
small ligands (e.g., molecules that bind to some
receptors belonging to family A, such as the retinal
chromophore and biogenic amines) characteristically
bind the ligand through a pocket or crevice,
involving highly conserved residues located in the
middle and extracellular third of hydrophobic TM
helices. Receptors for small peptides bind their
ligands through regions comprising either the extracellular loops or both the TM domains and the
extracellular loops, whereas for moderate-sized peptides, binding usually occurs in both the extracellular
loops and the amino-terminal segment. For larger
ligands, such as the glycoprotein hormone receptors,
the binding site usually resides within a large
extracellular amino-terminal sequence alone. Similar
to peptide receptors belonging to family A, binding of
peptide ligands to receptors in family B involves the
extracellular loops. In the calcium-sensing and the
metabotropic glutamate receptors, the principal
determinants for both ligand binding and signal
specificity reside in the large amino terminus; receptor
646
MEMBRANE RECEPTOR SIGNALING IN HEALTH AND DISEASE
FIGURE 1 (A) Model of the proposed seven-transmembrane-spanning domains of a prototypic GPCR belonging to
family A. Some structural characteristics of these particular receptors are shown. The structure also shows the location
of some mutations that lead to constitutive activation of the receptor (e.g., glycoprotein hormone, rhodopsin, and
adrenergic receptors). Reproduced from Ulloa-Aguirre et al. (1999), with permission. (B) Counterclockwise orientation
of GPCRs from TM domains I –VII. The closed loop structure is representative of receptors for peptide ligands. In this
arrangement, the core is composed mainly of TM domains II, III, V, and VI, whereas domains I and IV are peripherally
sequestered. Proximity between helix II and helix VII is characteristic of this family of GPCRs. G-Proteins are closely
associated with the intracellular domains.
activation requires, however, interactions of the
liganded amino-terminal domain with membraneassociated domains.
In these particular membrane receptors, the
G-protein-coupling domains lie within the divergent
sequences of their intracytoplasmic domains and/or
in residues located in the cytoplasmic face of the TM
domains. In fact, mutations in residues located in the
intracellular loops or in the TM helices may lead to
loss of function or gain of function of the altered
receptor (see later). Activation of the receptor and,
consequently, of the G-proteins requires not only
disruption of intra- and interhelical interactions and
the occurrence of TM movements, but also disruption
of interactions between specific residues located in the
intracellular loops [e.g., in family A receptors, the
highly conserved aspartic acid/glutamic acid – arginine – tyrosine (D/ERY) sequence located at the
boundary of TM-III and the loop-2 intracellular
sequence (Fig. 1)] and residues forming a pocket
through interhelical interactions. Thus, agonist binding provokes a series of conformational changes in
the receptor molecule that eventually lead to an
enhanced accessibility of the G-proteins to the
receptor regions involved in G-protein activation.
Several mechanisms regulate the functional level
and activity of GPCRs. Continuous or prolonged
stimulation of a cell generally results in progressively
attenuated responses to subsequent stimulation by
the same agonist. This decrease in cellular responsiveness to further stimulation, or desensitization,
protects the cell from excessive stimulation. Early
desensitization occurs rapidly and involves phosphorylation of residues located in the intracellular
domains by second-messenger-dependent activated
kinases or by a special class of serine/threoninespecific kinases called G-protein-coupled receptor
kinases. The subsequent binding of a group of soluble
inhibitory proteins, the arrestins, amplifies the
desensitization process and turns off the receptor by
impeding its coupling to G-proteins. Arrestins have
also been shown to couple GPCRs to the activation of
particular types of kinases, the Src-like kinases, and to
facilitate the formation of multimolecular complexes,
MEMBRANE RECEPTOR SIGNALING IN HEALTH AND DISEASE
including components of the mitogen-activated protein kinase (MAPK) and JUN N-terminal kinase
(JNK) pathways (see later). In this vein, some adapter
proteins bearing PDZ [a 90-amino acid repeat
initially recognized in the postsynaptic density
(PSD)-95 proteins] or SH2 or SH3 (Src homology)
domains (all involved in downstream protein– protein interactions) provide the molecular basis for
direct, heterotrimeric G-protein-independent interactions between GPCRs and several intracellular
signaling molecules, such as the small G-protein Ras
(see later). A more profound receptor deactivation
process, long-term desensitization, may be observed
after a prolonged time of agonist exposure; long-term
desensitization, which involves a decrease in the net
complement of receptors specific for a particular
agonist, is subserved by several biochemically distinct
mechanisms, including receptor down-regulation
(i.e., loss in total cellular content of functional
receptors) and internalization.
B. Heterotrimeric G-Proteins (Large GTPases)
Extracellular signals received by GPCRs are coupled
by G-proteins to the regulation of effector enzymes
that provoke generation of second messengers.
G-Proteins are signal-transducing molecules belonging to a superfamily of proteins regulated by guanine
nucleotides. These heterotrimeric proteins have a-,
b-, and g-subunits that are encoded by distinct genes.
G-Proteins are defined by their a-subunits; Gaproteins can be divided into four main classes (Gas,
Gai, Gaq, and Ga12), grouped on the basis of amino
acid identity and effector regulation. The Ga subunits
are highly diverse and their tissue distribution varies,
being either ubiquitous (or nearly ubiquitous) or
expressed in selected tissues. The Gas class includes
Gas and Gaolf and is involved in the activation of the
various types of the enzyme adenylyl cyclase to
enhance the synthesis of the second messenger, cyclic
adenosine monophosphate (cAMP), which in turn
activates protein kinase A; the Gas subunit may also
participate in the regulation of Ca2þ and Naþ
channels. The Gaq class includes Gaq, Ga11, and
Ga14 – 16; proteins of this class are predominantly
associated with activation of the enzyme phospholipase Cb1 – 4, which catalyzes hydrolysis of the lipid
phosphatidylinositol 4,5-bisphosphate (PIP2) to form
two second messengers, inositol 1,4,5-trisphosphate
(InsP3) and diacylglycerol (DAG). Proteins of the Gaq
class also activate protein kinase C (PKC). The Gai
class includes Gagust, Gat, Gai, Gao, and Gaz, which
mediate a variety of effects, such as inhibition of
647
adenylyl cyclase, activation of Kþ channels, Ca2þ
channel closure, and inhibition of inositol phosphate
turnover. Finally, the Ga12 class is defined by Ga12
and Ga13; signaling pathways regulated by these
G-proteins include modulation of the sodium – proton
exchanger NHE1 as well as regulation of cell growth
and differentiation.
The b- and g-subunits of G-proteins bind tightly
to each other in diverse ways; although this diversity
may theoretically yield 30 or more different bg
complexes, bg dimerization is highly specific, allowing for differential effector regulation by unique Gbg
complexes. Both the Ga subunits and the Gbg dimer
play a major role in intracellular signal transduction,
and the presence of all components of the heterotrimer is required for a receptor to trigger intracellular signaling.
The G-protein-mediated signaling is initiated on
receptor activation (Fig. 2). In the inactive (“off”)
state, the a-subunit of the heterotrimer is bound to a
molecule of guanosine diphosphate (GDP); the GDPbound Ga subunit can interact with receptors, an
association that is greatly enhanced by the Gbg
complex. Activation of a GPCR is followed by
activation of the trimeric Ga/bg-protein complex by
guanine nucleotide. Receptor-promoted and Mg2þdependent GDP ! guanosine 50 -triphosphate (GTP)
FIGURE 2 Regulatory cycle of a trimeric G-protein. The
unoccupied receptor interacts with a specific agonist, leading to
the activation of the receptor. Activated receptor (Ra) interacts
with the trimeric G-protein, promoting Mg2þ-dependent
GDP – GTP exchange and subunit dissociation, allowing
interaction with effectors (E). The sites of action of pertussis
toxin (PTX) and cholera toxin (CTX) are shown (see text for
details). The H21 mutation on Gas blocks signal transduction
by preventing GTP activation. Inorganic phosphate ion (Pi) is
released from GTP. GAPs, GTPase-activating proteins; Ei,
inactive effector; Ea, activated effector.
648
MEMBRANE RECEPTOR SIGNALING IN HEALTH AND DISEASE
exchange within the Ga guanine nucleotide-binding
site leads to a conformational change of the subunit
that causes G-protein activation and dissociation of
the trimeric complex into Ga-GTP and Gbg (“on”
state). Both of these complexes can then activate or
inhibit signaling pathways by engaging in interactions
with effectors (enzymes or ion channels); Gbg
activation results solely as a consequence of its release
from the Ga/bg complex. Termination of signaling
depends on the intrinsic GTPase activity of the asubunit, which leads to hydrolysis of GTP to GDP,
promoting dissociation of the Ga subunit from
effector and reassociation with the bg dimer, switching the G-protein complex to the “off” membraneassociated state. GTP hydrolysis by Ga is regulated by
GTPase-activating proteins (GAPs) specific for a
given member of the heterotrimeric G-protein family.
Some effectors in G-protein-mediated signaling pathways may act as GAPs on cognate Ga subunits; other
proteins, known as regulators of G-protein signaling
(RGS proteins), also act as GAPs that selectively and
potently deactivate Ga subunits by accelerating the
rate of intrinsic GTPase activity.
In addition to involvement in acute signaling functions, GPCRs also induce longer term
effects on gene expression and cell proliferation.
Signaling pathways involved in cell proliferation
are stimulated by several extracellular ligands that
transmit signals from the plasma membrane,
through the cytoplasmic space, and finally to the
nucleus. Similar to tyrosine kinase-linked receptors
(see later), GPCRs may activate intracellular
signaling in relationship with mitogenic effects.
These GPCR-triggered proliferative effects are
mediated by Ga-proteins of the Gaq, Gai/Go, Gas,
or Ga12/Ga13 class as well as by the corresponding
bg dimers. Growth-promoting GPCRs activate the
mitogen-activated protein kinase cascade and ultimately regulate the expression of genes essential
for proliferation. This occurs through mechanisms
that may or may not involve the small GTPbinding G-protein Ras. In addition, a family of
enzymes closely related to MAPK, the JUN kinases
(stress-activated protein kinases), selectively phosphorylate and regulate the activity of the c-JUN
protein (a transcription factor that induces the
expression of genes linked to growth responses)
under the influence of certain GPCRs, an effect
mediated by the Ras-related small GTP-binding
proteins Rac1 and Cdc42.
From the previous discussion, it is clear that
structural alterations in key residues of the receptor
molecules or the G-proteins may lead to altered
function of the GPCR – G-protein system. Thus,
mutations in sites involved in ligand binding usually
result in altered receptors that are unable to recognize
the signaling molecule and to become activated (lossof-function mutations), whereas mutations in sites
involved in receptor activation or G-protein coupling
may lead either to loss of function or to constitutive
activation (activation in the absence of ligand; gain-offunction mutations) of the receptor molecule. Other
mutations may cause improper folding, altered intracellular trafficking, and reduced membrane expression
of the receptor molecule. On the other hand, G-protein
function may be altered in a number of disease states
as a result of both adaptive and maladaptive mechanisms, including mutations in genes encoding G-protein
subunits, changes in expression levels of G-protein
subunit mRNAs or proteins, or posttranslational
modifications of G-proteins. Both somatic and germline mutations in genes encoding GPCRs and
G-proteins have been found to cause human disease.
Examples of some of these mutations and their impact
on intracellular signaling and cell function are
discussed in the following sections.
III. G-PROTEIN-COUPLED RECEPTORS
IN DISEASE
Structural alterations in GPCRs lead to abnormal
function of the receptor molecule. Diseases caused by
such alterations are shown in Table 1.
A. Rhodopsin/Retinitis Pigmentosa
Rhodopsin is the photoreceptor in rod cells; it
mediates vision in dim light and is coupled to the
retinal G-protein transducin (Gt). Rhodopsin-activated Gt allows light to excite neurons by freeing them
from neurotransmitter inhibition. Mutations in rhodopsin lead to misfolding and abnormal trafficking of
the nascent receptor protein, causing retention of the
mutant protein in the endoplasmic reticulum and
death of the rod cells. This causes retinitis pigmentosa,
a disease encompassing a clinically variable and
genetically heterogeneous group of inherited retinopathies, in which mutated rhodopsin leads to loss of
night vision and of the peripheral visual field. Retinal
pigmentary changes are characteristic of this disease
and result from the release of pigment by degenerating
rod cells in the retinal pigment epithelium. Numerous
inactivating mutations have been linked to retinitis
pigmentosa; mutations in the TM domain, in cysteine
residues forming disulfide bonds, or in the carboxylterminal domain of the receptor may cause severe or
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MEMBRANE RECEPTOR SIGNALING IN HEALTH AND DISEASE
TABLE 1 Examples of Diseases Caused by Mutations in G-Protein-Coupled Receptors
a
Disease
Receptor involved
Function
Retinitis pigmentosa
Color blindness
Idiopatic hypogonadotropic hypogonadism
Altered gonadal function
Precocious puberty
Leydig cell hypoplasia
Ovarian dysgenesis
Altered thyroid function
Resistance to TSH
Hyperfunctioning thyroid adenoma
Multinodular goiter
Congenital hyperthyroidism
Nephrogenic diabetes insipidus
Altered parathyroid function
Familial (benign) hypocalciuric hypercalcemia
Neonatal severe hyperparathyroidism
Autosomal dominant hypocalcemia
Isolated glucocorticoid deficiency
Hirschsprung’s disease
Jansen-type metaphyseal chondrodysplasia
Blomstrand disease
Dwarfism [little (lit) mouselike]
Rhodopsin
Red/green opsins
GnRH
# or "
#
#
LH
LH
FSH
"
#
#
TSH
TSH
TSH
TSH
Vasopressin
#
"
"
"
#
Calcium sensing
Calcium sensing
Calcium sensing
ACTH
Endothelin-B
PTH –PTHrP
PTH –PTHrP
GHRH
#
#
"
#
#
"
#
#
b
a
GnRH, gonadotropin-releasing hormone; LH, luteinizing hormone; FSH, follicle-stimulating hormone; TSH, thyroid-stimulating
hormone; ACTH, adrenocorticotropic hormone; PTH, parathyroid hormone; PTHrP, PTH-related protein; GHRH, growth hormonereleasing hormone.
b
# , Loss of function; " , gain of function.
mild forms of the disease, depending on the location
of the mutation. Families with a severe phenotype of
retinitis pigmentosa carry a mutation at the site (Lys296) of chromophore (11-cis-retinal) attachment; this
alteration disrupts the inactive conformation of opsin,
resulting in a constitutively active receptor that activates transducin in the absence of external stimulus
(light) and the covalently linked chromophore.
expression of the V2R. Vasopressin-2 receptor
mutations may be located in either region of the
receptor and may interfere with receptor synthesis or
with proper AVP binding or efficient coupling to the
Gs-protein. This latter alteration usually leads to
expression of a partial phenotype of NDI.
B. Vasopressin Receptor
The receptor for the hypothalamic releasing peptide
gonadotropin-releasing hormone (GnRH) is located
in the cell surface of the pituitary cells that synthesize
the gonadotropins luteinizing hormone (LH) and
follicle-stimulating hormone (FSH). This receptor is
preferentially coupled to the Gq/11-protein and its
activation by GnRH agonists stimulates synthesis and
secretion of LH and FSH. Resistance to GnRH by
inactivating mutations leads to distinct forms of
inherited (autosomal recessive) hypogonadotropin
hypogonadism, a disorder characterized by delayed
puberty, absence of secondary sexual characteristics,
and low gonadotropin and sex-steroid levels.
Although inactivating mutations in the GnRH
receptor may be distributed along the entire coding
sequence of the receptor, they have been mainly
The function of arginine vasopressin (AVP), a
hormone secreted by the posterior pituitary, is to
control blood osmolality. AVP controls the reabsorption or water by regulating the number of water
channels present in the lumenal surface of the distal
tubule and in the collecting duct of the nephron.
The antidiuretic effect of AVP is exerted through the
vasopressin-2 receptor (V2R), which is linked to the
effector enzyme adenylyl cyclase. Inactivating
mutations in the V2R lead to nephrogenic diabetes
insipidus (NDI), a disease characterized by the
inability of the kidney to retain water and concentrate
urine. Individuals affected with the X-linked type of
NDI bear mutations that alter the structure or
C. Gonadotropin-Releasing Hormone Receptor
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MEMBRANE RECEPTOR SIGNALING IN HEALTH AND DISEASE
localized within the third to fifth TM domains. These
mutations affect ligand binding, signal transduction,
and/or processing of the receptor, leading to altered
intracellular trafficking and reduced cell surface
expression. Mutations of the GnRH receptor may
result in a wide spectrum of phenotypes, from partial
to complete hypogonadism.
D. Adrenocorticotropic Hormone Receptor
Adrenocorticotropic hormone (ACTH) is an anterior
pituitary hormone that, acting via its specific receptor,
regulates adrenocortical growth and controls corticosteroid production and secretion. The ACTH
receptor (ACTHR) is related to the small subfamily
of melanocortin receptors and couples to the Gs –
adenylyl cyclase pathway. Hereditary isolated glucocorticoid deficiency, a rare autosomal recessive
inherited disease, may result from ACTH receptor
unresponsiveness to ACTH. Patients with ACTH
resistance, either homozygous or compound heterozygous for inactivating ACTHR mutations, typically
exhibit deficient production of cortisol and adrenal
androgens in the presence of markedly elevated
endogenous plasma ACTH levels. Aldosterone levels
are usually normal and respond appropriately to
maneuvers that activate the renin – angiotensin axis.
Inactivating mutations of the ACTHR leading to
familial glucocorticoid deficiency may be scattered
throughout the ACTH receptor molecule, affecting
receptor structure, membrane expression, ligand
affinity, and/or signal transduction. The etiology of
familial glucocorticoid deficiency might be heterogeneous and genes other than that of the ACTHR
might be involved and may cause the same
phenotype.
E. Glycoprotein Hormone Receptors
Glycoprotein hormone receptors have large extracellular domains (300 – 400 amino acids in length)
and bind structurally complex ligands. From the
functional point of view, these receptors comprise
two halves: an extracellular amino-terminal half
(exodomain) and a membrane-associated carboxylterminal half (endodomain). Although the exodomain alone is capable of high-affinity ligand binding,
interaction with the endodomain [which comprises
the seven-TM domains, the three extra- and intracellular loops, the carboxyl-terminal tail, and a short
extracellular extension of the first TM domain
(Fig. 1)] is necessary to generate and transmit an
intracellular signal. In humans, the thyrotropin
[thyroid-stimulating hormone (TSH)] receptor and
LH receptor are coupled to both the Gs – adenylyl
cyclase – cAMP pathway and the G q – phospholipase Cb –phosphoinositide/diacylglycerol pathway,
whereas the FSH receptor is predominantly coupled
to the Gs-protein. All glycoprotein hormone receptors, particularly the TSH and LH receptors, are
sensitive to naturally occurring mutations, leading to
cell hypo- or hyperfunction.
Thyrotropin is the pituitary glycoprotein hormone that stimulates thyroid development, growth,
and function. Thyrotropin receptor gene mutations
leading to loss of function of the receptor molecule
have been associated with inherited hypothyroidism
with TSH resistance; mutations may localize to the
amino-terminal region and/or the fourth TM helix of
the receptor. Mutations in the amino-terminus
usually affect ligand binding, whereas alterations in
TM domains may potentially impair receptor membrane expression. Whereas most of the patients with
resistance to TSH due to TSH receptor (TSHR)
mutations exhibit “compensated hypothyroidism”
(i.e., normal serum concentrations of thyroid hormones in the presence of hyperthyrotropinemia),
profound hypothyroidism with thyroid hypoplasia
may also rarely occur. Reciprocally, mutations leading to constitutive activation of the TSHR and clinical
hyperthyroidism may be found at both the somatic
and the germ-line levels; the former is usually
associated with autonomously functioning toxic
(hyperfunctioning) thyroid adenomas, whereas the
latter is associated with familial (autosomal dominant) nonimmune hyperthyroidism, a very rare
disorder. Both conditions lead to activation of
adenylyl cyclase, via Gs, increased cAMP production,
and eventually to thyroid hyperplasia or expansion of
the adenoma. Spontaneous mutations in the TSHR
gene leading to hyperfunctioning thyroid adenomas
may be located in the TM domains, the extracellular
loops, the third intracellular loop, or, rarely, in the
amino-terminus (e.g., Arg310Cys). Exceptionally,
activating mutations of the TSHR may be found in
multinodular goiter.
The target glands for LH are the gonads, where LH
stimulates androgen production by the Leydig cells of
the testes and the theca cells of the ovarian follicle. This
gonadotropin also stimulates estrogen and progesterone production by the corpus luteum. In the inactivating mutations of the LH receptor (LHR) gene, the
altered receptor interferes with the intrauterine development of the male external genitalia, causing a wide
spectrum of phenotypic alterations, ranging from
extreme forms, in which the patients present as 46,
XY females (severe Leydig cell hypoplasia), to milder
MEMBRANE RECEPTOR SIGNALING IN HEALTH AND DISEASE
forms associated with hypergonadotropic hypogonadism, microphallus, and hypoplastic male external
genitalia. Inactivating LHR mutations may be localized in the amino-terminus, the TM domains, or the
third intracellular loop. In women, inactivating
mutations in the LHR gene may lead to hypergonadotropic hypogonadism, menstrual disorders,
enlarged cystic ovaries, and infertility. In the case of
activating LHR mutations, the autonomous activation of the receptor causes sporadic or familial
pseudo-precocious puberty, a phenotype observed
only in males. Somatic activating mutations of the
LHR have been found only in Leydig cell adenomas.
Activating mutations of the LHR are usually located
in the TM domains or in the third intracellular loop of
the receptor.
Follicle-stimulating hormone is involved in the
regulation and maintenance of essential reproductive
processes, such as gametogenesis and follicular development. The target cells of FSH are the Sertoli cells of
the testes and the granulosa cells of the ovary.
Inactivating mutations in the FSHR gene have been
described in selected populations and in some sporadic
cases. In females, inactivating mutations in the FSHR
cause gonadal dysgenesis and/or premature ovarian
failure, whereas in men mutations may provoke poor
quality sperm. Inactivating mutations in the FSHR
have been identified mainly in the amino-terminal
domain, and less frequently in the third intra- and
extracellular loops of the receptor. The five mutations
reported so far in the extracellular domains altered
binding capacity and signal transduction by disturbing
the trafficking of the receptor to the membrane,
whereas the intracellular loop-3 mutation altered
signal transduction but not membrane receptor
expression. Only one naturally occurring activating
mutation (located in intracellular loop 3) in the FSHR
has been identified so far. Nevertheless, other sites for
mutations (artificially-induced; not yet described to
occur naturally) that may provoke constitutive activation of the FSHR include a leucine in position 460 in
the TM-III residue (a residue highly conserved in
$ 70% of family A GPCRs) and a leucine in position
477 of intracellular loop 2 (a residue present in all
human glycoprotein hormone receptors).
F. Parathyroid Hormone/Parathyroid
Hormone-Related Peptide Receptor
Parathyroid hormone (PTH) plays a critical role in the
regulation of calcium homeostasis in kidney and bone.
Its actions are mediated by two closely related GPCRs,
the PTH1 receptor, which responds equally to PTH
651
and PTH-related peptide (PTHrP), and the PTH2
receptor, which responds to PTH. Agonist occupancy
of these receptors leads to activation of both the Gs –
adenylyl cyclase and the Gq – phospholipase C signal
transduction pathways. Mutations in the cytoplasmic
ends of TM domains II and VI may induce constitutive
activity of the PTH/PTHrPR – Gs protein system and
thus lead to a rare type of short-limbed dwarfism
(called Jansen-type metaphyseal chondrodysplasia)
resulting from decelerated chondrocyte differentiation
and associated with marked hypercalcemia and
hypophosphatemia in the presence of normal serum
concentrations of PTH and PTHrP. Parathyroid
hormone and PTHrP receptors are also important
during fetal skeletal development; signaling through
these receptors controls the differentiation of growth
plate chondrocytes into hypertrophic cells. Thus,
mutations that completely inactivate the PTH/PTHrP
receptor may be lethal in utero; in fact, mutations
resulting in impaired PTH/PTHrP binding (e.g., in the
highly conserved Pro-132 amino acid residue of the
amino-terminal domain or in the sequence of the fifth
TM domain) and in severe receptor dysfunction lead
to Blomstrand chondrodysplasia, an autosomal recessive inherited disease characterized by a striking
increase in bone density and markedly accelerated
skeletal maturation.
G. Growth Hormone-Releasing Hormone
Growth hormone-releasing hormone (GHRH) is a
hypothalamic peptide involved in the regulation of
the synthesis and secretion of growth hormone, a
pituitary hormone that is responsible of regulating
growth. Growth hormone deficiency causes short
stature and metabolic derangements. The GHRH
receptor (GHRHR) is coupled to the Gs – adenylyl
cyclase pathway and mutations in the receptor
molecule may lead, in humans, to growth failure,
analogous to that showed by rodent experimental
models bearing a GHRHR gene missense mutation
that impairs receptor expression.
H. Calcium-Sensing Receptor
Extracellular calcium is essential for a large array of
vital processes and its concentration in extracellular
fluids is under strict control by a homeostatic system
that includes the kidney, bones, intestines, and the
parathyroid and thyroid glands. Extracellular Ca2þ
sensing occurs through a receptor coupled to the Gq –
phospholipase C signaling pathway. Several tissues
express this receptor; in the parathyroid gland, the
calcium-sensing receptor (CaR) plays a central role in
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MEMBRANE RECEPTOR SIGNALING IN HEALTH AND DISEASE
the regulation of PTH secretion. Loss-of-function
mutations in the CaR result in two inherited diseases,
familial (benign) hypocalciuric hypercalcemia and
neonatal severe hyperparathyroidism; the former
results from mutations in only one allele of the CaR
gene, whereas the latter arises from mutations in both
alleles. Mutations in the benign form of the disease are
mainly localized either in the first 300 amino acid
residues of the amino-terminal domain or in proximity
to TM-I of the receptor. These mutations may cause
decreased CaR sensitivity for extracellular calcium or
may exert dominant negative actions on the normal
receptor, leading to a more severe syndrome.
IV. DEFECTS IN G-PROTEIN-COUPLED
SIGNAL TRANSDUCTION
Abnormalities in G-protein function may be caused
by: (1) posttranslational modifications of G-proteins
by bacterial toxins, (2) mutations (either loss- or gainof-function mutations) in genes encoding G-proteins,
and (3) changes in expression levels of G-protein
subunit mRNA or functional protein. Examples of
structural alterations in G-proteins leading to abnormal signal transduction are shown in Table 2.
A. Posttranslational Modifications—Cholera
Toxin and Pertussis Toxin
Cholera toxin causes adenosine diphosphate (ADP)
ribosylation of an arginine residue in position 201
within the GTP-binding domain of Gas, markedly
reducing the intrinsic GTPase activity of the subunit
(Fig. 2), leading to constitutive activity of the protein
and increased levels of cAMP independent of the
normal extracellular signal. Infection by Vibrio
cholerae affects the intestinal tract, causing excess
fluid secretion by the epithelial cells and massive
diarrhea. Pertussis toxin, produced by Bordetella
pertussis, covalently modifies several subunits of the
Gai class by ADP-ribosylation on the fourth cysteine
residue from the carboxyl-terminus of the protein,
leading to uncoupling of the modified G-protein from
the receptor and disruption of signal transduction;
this is the mechanism whereby exposure to pertussis
toxin causes hypoglycemia and histamine sensitivity.
clinical disorders. Activating (oncogenic) mutations
in this G-protein subunit (specifically in Arg-201 or
Gln-227, which lead to inhibition of GTPase intrinsic
activity) have been identified as the cause of several
disorders, including subsets of growth hormonesecreting pituitary tumors, testicular and ovarian
stromal Leydig cell tumors, toxic thyroid adenomas,
and the McCune– Albright syndrome, a sporadic
disease characterized by increased hormone production and/or cellular proliferation in a number of
tissues. Less frequently, Gas mutations may lead to
nonfunctioning pituitary and thyroid adenomas,
ACTH-secreting adenomas, parathyroid neoplasms,
and differentiated thyroid carcinomas. Screening
studies of different types of human tumors for
mutations in Gai(2) have revealed similar amino acid
substitutions in a proportion of ovarian, adrenal, and
nonfunctioning pituitary tumors. Conversely, heterozygous germ-line GNAS1 gene mutations that
decrease expression or function of Gas cause Albright
hereditary osteodystrophy, a disorder associated with
a constellation of developmental defects (including
obesity, short stature, bony abnormalities, and
mild mental retardation), as well as reduced responsiveness to multiple hormones (including PTH, TSH,
and glucagon). Altered expression and/or function of
G-proteins may be found in a number of other
abnormal conditions, including neuropsychiatric
disorders, alcoholism, hypertension, and diabetes
mellitus. Defects in G-proteins in such disorders
may also be secondary to other alterations in cell
function.
V. ENZYME-LINKED RECEPTORS IN HEALTH
AND DISEASE
More than 50 receptors belong to the superfamily of
enzyme-linked receptors, including the receptors for
growth hormone, insulin, cytokines, and growth
factors. The enzyme-coupled receptor superfamily
can be separated into the following main families:
(1) tyrosine kinase receptors, (2) tyrosine kinaseassociated receptors, (3) tyrosine phosphatase receptors, (4) guanylyl cyclase receptors, and (5) serine/
threonine kinase receptors.
B. Mutations in the Ga-Protein
A. Tyrosine Kinase and Tyrosine
Kinase-Associated Receptors
Germ-line and somatic mutations of the human
GNAS1 gene, located on chromosome 20q13.11,
which encodes the Gas protein, have been implicated
in abnormal signal transduction and in several
Tyrosine kinase receptors are membrane-spanning
proteins with large amino-terminal extracellular
domains bearing the ligand binding site, a juxtamembrane domain, a protein kinase catalytic domain, and
653
MEMBRANE RECEPTOR SIGNALING IN HEALTH AND DISEASE
TABLE 2 Examples of Diseases Caused by Mutations in Ga-Proteins
Disease
Vibrio cholerae (cholera toxin)
Bordetella pertussis (pertussis toxin)
Albright hereditary osteodystrophy,
pseudohypoparathyroidism type 1a
Nonfunctioning pituitary adenoma, adrenal and sex cord
tumors
McCune –Albright syndrome
Growth hormone-secreting tumors
Nonfunctioning pituitary adenomas, ACTH-secreting
adenoma, toxic thyroid adenoma, papillary thyroid
carcinoma
Pseudohypoparathyroidism type 1a and testotoxicosis
Nonfunctioning pituitary adenoma, adrenal and sex cord
tumors
a
G-protein involved/(mutation)
Function
Gas ADP-ribosylation
Gai ADP-ribosylation
Gas
"
#
#
Gai2 (Arg179Cys/His or Gln205Arg)
"
Gas (Arg201His/Cys)
Gas (Arg201His/Cys or Gln227Leu/Arg)
Gas (Arg201His/Cys or Gln227Leu/Arg)
"
"
"
Gas (Ala366Ser)
Gai2
#/"
"
a
# , Loss of function; " , gain of function.
a carboxyl-terminal tail. Based on the structure of
their extracellular domains, members of this class of
membrane receptor can be grouped into 16 subfamilies, which include the platelet-derived growth factor
receptor, the fibroblast growth factor (FGF) receptor,
the epidermal growth factor (EGF) receptor, the
insulin receptor, the nerve growth factor receptor,
the hepatocyte growth factor (HGF) receptor, and the
vascular endothelial growth factor receptor subfamilies. Receptors belonging to this superfamily dimerize
on ligand binding; dimerization is then followed by
auto- or transphosphorylation of the receptor, which
then interacts with associated adapter proteins or
effector enzymes bearing SH2 domains, leading to the
activation of a variety of signaling pathways and
nuclear factors (Fig. 3). Protein kinase-associated
receptors, such as the growth hormone and prolactin
receptors, associate with tyrosine kinases belonging
to the JAK kinase (for Janus kinase) family. Members
of this family phosphorylate target proteins on ligand
binding and receptor dimerization, eventually leading
to gene transcription; target proteins include the Stat
(signal transduction and activation of transcription)
proteins. Abnormal or ligand-independent activation
of the signaling cascades mediated by tyrosine kinase
or tyrosine kinase-associated receptors may lead to
altered cell proliferation and tumorigenesis (e.g.,
some mutated forms of the EGF and HGF receptors)
or to severe skeletal dysplasias due to activation of
cell cycle inhibitors (e.g., those induced by mutations
in the FGF receptor), whereas inactivating mutations
may cause abnormal embryogenesis (e.g., the patch
mutation that affects neural crest development in
mice) or to a variety of disorders, such as severe
insulin resistance (e.g., leprechaunism and the
Rabson – Mendenhall syndrome) and dwarfism (e.g.,
growth hormone receptor mutations), depending on
the particular receptor involved.
B. Tyrosine Phosphatase Receptors
Protein tyrosine phosphorylation and dephosphorylation are mechanisms crucial for the regulation of
numerous cellular events. Receptor-like protein tyrosine phosphatases (PTPs) are ligand-regulated phosphatases that participate in intracellular signal
transduction by countering the activities of receptors
with tyrosine kinase activity. Receptor-like PTPs are
subdivided into five types based on common features
exhibited by their extracellular domains: (1) type I
receptor-like PTPs, represented by the hematopoietic
cell-restricted CD45 family (with its corresponding
isoforms); (2) type II molecules, such as the LAR-like
PTPs [e.g., LAR, PTPs, and PTPd in mammals,
preferentially expressed (with the exception of LAR)
in neurons and implicated in neuronal development],
which contain tandem repeats of immunoglobulinlike and fibronectin type III-like domains resembling
neural cell adhesion molecules; (3) type III molecules,
which exhibit fibronectin type III repeats; (4) PTPa
and PTP1, which have a small extracellular domain;
and (5) PTPj and PTPg, which exhibit aminoterminal carbonic anhydrase-like domains. Many
PTPs may be involved in growth defects and diseases.
For example, CD45, a PTP receptor present in
lymphoid cells, has been shown to be necessary for
multiple signaling events in both B and T cells; loss of
CD45 in mice has profound consequences for
654
MEMBRANE RECEPTOR SIGNALING IN HEALTH AND DISEASE
FIGURE 3 (A) Signaling through tyrosine kinase receptors. Ligand (L) (e.g., epidermal growth factor) binding
provokes dimerization of the liganded receptor; this is followed by activation of the receptor’s intrinsic tyrosine kinase,
leading to transphosphorylation of the receptors, docking of SH2 domain-bearing proteins [including Grb2 (growth
factor receptor-binding protein 2), phopholipase Cg (PLCg), and phosphatidylinositol 3-OH kinase (PI-3K)], and
activation of multiple signaling pathways. (B) Activation of intracellular signaling by tyrosine kinase-associated
receptors. Ligand (e.g., growth hormone) binding provokes receptor dimerization, recruitment of JAK tyrosine kinase,
and subsequently tyrosine phosphorylation of JAK, the receptor, and the Stat (for signal transduction and activation of
transcription) proteins; Stats then dimerize and translocate to the nucleus to induce transcription of specific target genes.
(C) Signaling through serine/threonine kinase receptors [e.g., the transforming growth factor-b receptor (TGF-bR)].
Binding of TGF-b to its type II receptor in concert with a type I receptor (R) leads to formation of a receptor complex
and phosphorylation of the type I receptor, which subsequently phosphorylates a receptor-regulated SMAD (R-Smad)
protein. The SMAD, complexed with Smad4, moves into the nucleus and activates TGF-b target genes. (D) Putative
transmembrane organization of a ligand-gated ion channel [e.g., the nicotinic acetylcholine receptor (AChR)], showing
the four-transmembrane model for this receptor. M, Transmembrane domain; P, potential phosphorylation sites. Inset:
Front view of the model of peripheral (muscle) AChR with a pore at the center of the pentamer.
lymphocyte development and signal transduction.
Targeted deletion of a LAR-like PTP in mice leads to
abnormal neonatal death rates, and targeted homozygous disruption of the Ptprs gene (which encodes
PTPs) causes multiple growth defects, including
stunted growth, developmental delay, and several
neurological disorders.
C. Guanylyl Cyclase Receptors
The single-transmembrane-domain-signaling guanylyl cyclase (GC) receptors have cytoplasmic domains
bearing guanylyl cyclase activity; on activation by
their cognate ligands, the receptors promote the
production of the second messenger cyclic guanosine
monophosphate (GMP), which in turn binds and
activates a cyclic GMP-dependent protein kinase
known as G-kinase, subsequently triggering serine
or threonine phosphorylation on specific proteins.
The guanylyl cyclase A and B receptors bind
natriuretic peptides (involved in the regulation of
cardiovascular and renal function), whereas the GC
C receptor binds heat-stable enterotoxins. The
orphan GC D, E, and F receptors are expressed in
MEMBRANE RECEPTOR SIGNALING IN HEALTH AND DISEASE
sensory tissues. Nearly 29 genes encoding putative
guanylyl cyclases have been discovered in the
nematode Caenorhabditis elegans, which suggests
that numerous guanylyl cyclase receptors still remain
to be discovered in mammals. Salt-independent
chronic elevation of blood pressure, which corresponds to the phenotype observed in nearly 50%
of subjects with essential hypertension, is found in
GC A gene-disrupted mice. On the other hand,
mice missing the GC C receptor are resistant to Sta,
a heat-stable enterotoxin from Escherichia coli that
is thought to be responsible for diarrhea in adults
and infants.
D. Serine/Threonine Kinase Receptors
Transmembrane receptors with serine and threonine
kinase activity are distinct molecules that bind
members of the transforming growth factor-b
(TFG-b) superfamily of related polypeptide growth
factors (including TFG-b1 – 3, bone morphogenetic
proteins, anti-Müllerian hormone, and activins) that
are involved in a large array of cellular processes,
such as growth, proliferation, differentiation, lineage
determination, apoptosis, adhesion, and motility.
The TFG-b receptor family consists of two subfamilies, type I receptors (formerly known as activin
receptor-like kinases) and type II receptors. The
TFG-b receptor-mediated intracellular signaling is
initiated when the TFG-b type II receptor, which is
basally phosphorylated in a ligand-independent
manner, binds its ligand and activates via phosphorylation at serine and threonine residues (present
within the GS domain, a highly conserved 30-amino
acid region) an associated TFG-b type I receptor
(Fig. 3). The activated TFG-b receptor complex then
phosphorylates and activates proteins of the SMAD
family, which in a complex form move into the
nucleus and activate TGF-b-responsive genes.
Down-regulation or loss of serine/threonine kinase
functional receptors, aberrant signal – signal transduction pathways due to Smad alterations,
mutations in ligand, or loss of functional genes that
control the transcription and translation of TGF-b
and TGF-b-related peptides may contribute to the
development of several diseases. Because the effects
of TGF-b on target cells include negative regulation
of cell proliferation, disruption of TGF-b signaling
could therefore predispose or even cause cancer (e.g.,
gastrointestinal cancer, head and neck carcinomas,
ovarian cancer, and T-cell lymphoma). Mutations in
the anti-Müllerian hormone or its receptor lead to
persistent Müllerian duct syndrome, whereas
655
mutations in Gdf5/Cdmp1 (a ligand belonging to
the growth and differentiation factor subfamily of
TGF-b) result in hereditary chondrodysplasia. Likewise, mutations in Alk1 (a type I receptor) may lead
to hereditary hemorrhagic telangiectasia. Finally,
SMAD mutations are associated with colon cancer
(Smad2 and Smad4), pancreatic cancer (Smad4), and
other cancers.
VI. ION-CHANNEL-LINKED RECEPTORS
IN HEALTH AND DISEASE
Channels are pores in the cell membrane; ions flow
through these pores across the membrane, depolarizing or hyperpolarizing the cell. The ligand-gated ion
channels are grouped into two major functional
families: (1) the nicotinic acetylcholine (ACh),
serotonin, and glutamate-gated ion channels, which
allow passage of cations (Ca2þ) at excitatory
synapses, and (2) the GABA A and GABA C receptor
(GABA B receptors are GPCRs) and the glycine-gated
channels, which permit passage of anions at inhibitory synapses. At the amino acid sequence level, the
nicotinic ACh, serotonin, GABA, and glycine-gated
channel subunits are homologous; these receptors
assemble as heteropentamers of different gene products and/or splice variants. The glutamate-gated
channels differ from the other amino-acid-gated
channels in that they are composed of four subunits,
each containing three (instead of four) TM segments;
these channel receptors may be subdivided according
to agonist selectivity into the a-amino-3-hydroxy-5methyl-4-isoxazole propionic acid (AMPA),
N-methyl-D -aspartate (NMDA), and kainate subtypes. The TM segments of these multisubunit
receptors are arranged around a large, poorly
selective central pore, the properties of which are
essentially determined by the amino acid residues
forming the second TM segment. In these receptors,
ligand binding provokes a transient open-channel
state, during which passive flux occurs. The nicotinic
ACh receptor is the model for structure – function
relationship studies on the superfamily of ligandgated ion channel receptors and is the best known
from the structural and functional points of view.
This receptor has an a2,b(dg) or (ed) pentameric
composition; each subunit has a large extracellular
amino-terminal domain, four TM domains, a large
intracellular loop between the third and fourth TM
domains, and an extracellular carboxyl-terminal
domain (Fig. 3). The functional events associated
with the ACh receptor include (1) binding of
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MEMBRANE RECEPTOR SIGNALING IN HEALTH AND DISEASE
the neurotransmitter, (1) opening of the channel via
rotation of two pore-lining a-helices, which moves
the helices apart, (3) conduction across the pore, and
(4) desensitization.
Ligand-gated ion channels in the neuronal plasma
membrane function as effective, cell surface signal
transducers via interactions with a number of
extracellularly or intracellularly stimulated protein
kinases. Channel phosphorylation may gate the
channel, may facilitate interaction with other regulatory PDZ domain-bearing proteins (linking the
receptor channel to the cytoskeleton and to appropriate intracellular signal transduction pathways,
which may eventually lead to gene expression),
and/or may regulate receptor desensitization and
clustering. Current evidence demonstrates that
ligand-gated cation channels may be additionally
located presynaptically on nerve terminals in the
peripheral and central nervous systems, where they
function to modulate neurotransmitter release.
Alterations in the primary sequence leading to
modification in gating kinetics may associate with
pathological processes or channelopathies. For
example, mutation of the extracellular charged
arginine ring in the glycine receptor can impair
channel function by decreasing the sensitivity of
glycine activation, reducing channel conductance,
shifting the normal multisubconductance states to
lower values, and decoupling ligand binding from
channel gating. Mutations in the a1-subunit of the
glycine receptor lead to hyperekplexia (excess startle
response), whereas structural alterations in the Ach
receptor may cause frontal lobe nocturnal epilepsy (as
in those mutations involving the a4-subunit, which
may eventually lead to different alterations in the
properties of the ACh-gated channel) or myasthenic
syndromes (e.g., slow-channel syndrome). The latter
abnormalities arise from delayed closure of the ion
channel, ACh receptor deficiency, and short channel
open time; these are kinetic abnormalities that lead to
high conductance or abnormal interactions of the
ligand with its receptor.
VII. SUMMARY
Cell surface receptors are signal transducers for
water-soluble extracellular signals. There are three
main classes of cell surface receptors: G-proteincoupled receptors, enzyme-coupled receptors, and
ion-channel-linked receptors. Each class of receptor
mediates the signals carried by extracellular ligands
through particular mechanisms, most of them
involving the intracellular activation of particular
protein – protein interaction cascades. G-Protein –
coupled receptors mediate their intracellular actions
through the activation of G-proteins and specific
effector enzymes, whereas enzyme-linked receptors
function directly as enzymes or through associated
enzymes that, on activation, autophosphorylate or
phosphorylate the receptor molecule, subsequently
recruiting associated proteins that act as intracellular
signal transducers. Ion-channel-linked receptors are
protein molecules that convert chemical signals into a
charge flux across the cell membrane by opening an
intrinsic pore, through which ions flow. Membrane
receptors and their associated signal transducers may
be altered in a number of diseases as a result of
adaptive or maladaptive mechanisms, including
mutations in their encoding genes.
Glossary
domain Portion of a protein that has a tertiary structure of
its own. In large proteins, each domain is connected to
other domains by flexible regions of polypeptide.
effector Molecule that performs an action in response to a
stimulus.
guanosine 50 -triphosphate Nucleoside triphosphate used in
RNA synthesis and in some energy-transfer reactions. It
also plays a special role in protein synthesis, cell
signaling, and microtubule assembly.
ligand Any molecule that binds to a specific site on another
molecule.
neurotransmitter Small signaling molecule secreted by the
presynaptic nerve cell at a chemical synapse; relays a
signal to the postsynaptic cell. A neurotransmitter can
elicit either excitatory or inhibitory responses on the
target synapse.
protein kinase Enzyme that transfers the terminal phosphate group of adenosine triphosphate to a specific
amino acid of a target protein.
protein phosphatase Enzyme that removes a phosphate
group from a protein by hydrolysis.
receptor Protein that binds a specific extracellular signaling
molecule and initiates or blocks a response in the cell.
second messenger Small molecule that is formed in or
released into the cytosol in response to an extracellular signal; helps to relay the signal to the interior
of the cell.
signaling molecule Extracellular or intracellular molecule
that cues the response of a cell to the stimulus of other
cells.
signal transduction Process whereby a cell converts an
extracellular signal into a biochemical response.
See Also the Following Articles
Heterotrimeric G-Proteins . Membrane Steroid Receptors
. Multiple G-Protein Coupling Systems . Protein Kinases
657
MEMBRANE STEROID RECEPTORS
. Receptor-Mediated Interlinked Systems, Mathematical
Modeling of . Receptor– Receptor Interactions . Signaling
Pathways, Interaction of
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Edwards, S. W., Tan, C. M., and Limbird, L. E. (2000).
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Khakh, B. S., and Henderson, G. (2000). Modulation of fast
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Labrecque, J., McNicoll, N., Marquis, M., and De Léan, A. (1999).
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Encyclopedia of Hormones. Copyright 2003, Elsevier Science (USA). All rights reserved.
Membrane Steroid Receptors
CLARA M. SZEGO *, RICHARD J. PIETRAS *,
ILKA NEMERE †
AND
p
University of California, Los Angeles, . †Utah State
University
I. INTRODUCTION
II. SUPRAMOLECULAR ORGANIZATION OF THE SURFACE
MEMBRANE AND OCCURRENCE OF STEROID RECEPTORS
III. SPECIFIC BINDING OF STEROID HORMONES TO SURFACE
MEMBRANES OF RESPONSIVE CELLS
IV. CONSEQUENCES OF RECEPTOR OCCUPANCY:
ACTIVATION OF SIGNAL TRANSDUCTION PATHWAYS
V. MEMBRANE SIGNALING AND THE CELLULAR RESPONSE
TO STEROID HORMONES
VI. SUMMARY
Mutual recognition between a responsive cell
and a hormone in the extracellular fluid takes
place at their dynamic boundary, the cell
surface membrane. This fundamental process,
applicable to agonists of diverse structure, lipid
as well as peptide, leads to a chain of secondary
mechanisms that amplify the impact of selective
interception of hormone by receptor. It is
now possible to integrate this primary step in
the coordinated events that constitute the
cellular response.
I. INTRODUCTION
It seems axiomatic that mutual recognition between
an agonist in the extracellular fluid and a responsive
cell must take place at the cell surface membrane. As
first envisioned in the immunologic context by Paul
Ehrlich (Fig. 1), extracellular hormones of varied
structure, lipid as well as peptide, are now understood
to interact with receptors at the outer cell membrane.
Examples of the lines of evidence that support this
concept, and the criteria for identifying the selectivity,
specificity, and affinity of such interaction between
the several steroid classes and the specialized protein
components of the target cell surface, are presented in
this article.