Bioscience Reports, Vol. 15, No. 5, 1995
REVIEW
Luminal Calcium Regulation of Calcium
Release from Sarcoplasmic Reticulum
Cecilia H i d a l g o la and Paulina D o n o s o 1
Received September 14, 1995
This article discusses how changes in luminal calcium concentration affect calcium release rates from
triad-enriched sarcoplasmic reticulum vesicles, as well as single channel opening probability of the
ryanodine receptor/calcium release channels incorporated in bilayers. The possible participation of
calsequestrin, or of other luminal proteins of sarcoplasmic reticulum in this regulation is addressed. A
comparison with the regulation by luminal calcium of calcium release mediated by the inositol
1,4,5-trisphosphate receptor/calcium channel is presented as well.
KEY WORDS: Calcium; Ca2+-channel; inosital phosphate; ryanodine; sarcoplasmic reticulum.
CALCIUM RELEASE FROM SARCOPLASMIC RETICULUM
General Considerations
Calcium ions control a variety of cellular functions. Increases in cytoplasmic
calcium concentration trigger cellular events such as neuronal excitation, muscle
contraction, secretion, cell division, apoptosis and immune responses. Cellular
activation in these systems, acting through different mechanisms, leads to opening
of intracellular calcium channels, allowing fast calcium release to the cytoplasm.
The free calcium concentration inside living cells, -<10-7M, is much lower
than the total cellular calcium content. Most of the cellular calcium is either
bound to cytosolic sites or is stored within intracellular compartments, where its
concentration can reach the mM range (for a comprehensive review, see Pozzan
et al., 1994). In most cells calcium is stored inside the endoplasmic reticulum
(ER), or in specialized functional domains of the ER, the calciosomes. The
calcium storage compartment of muscle cells is the sarcoplasmic reticulum (SR).
Both calcium storage compartments, the E R and the SR, have essentially
1 Departamento de Fisologfa y Biofisica, Facultad de Medicina, Universidad de Chile, Casilla 70005,
Santiago 7, Chile, and Centro de Estudios Cientfficos de Santiago, Casilla 16443, Santiago 9, Chile.
2 To whom correspondence should be addressed.
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0144-8463/95/1000-0387507.50/09 1995PlenumPublishingCorporation
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Hidalgo and Donoso
three classes of protein with three different functions: A calcium pump protein
that accumulates calcium inside the storage against a very large chemical gradient
(in the order of 104). A calcium storage protein that binds inside the compartment
with large capacity and low affinity. And a calcium channel protein, that allows
the fast and massive release of calcium from the stores.
The calcium pumps present in ER or SR are Ca2+-ATPases that actively
transport calcium to the lumen of the compartment, coupled to the hydrolysis of
ATP. They are referred to as SERCA ATPases (sarco/endoplasmic reticulum
calcium ATPases) that share many molecular and biochemical properties (Pozzan
et al., 1994).
Two main calcium storage proteins have been described, calsequestrin in the
SR (Ikemoto et al., 1974); Ostwald et al., 1974), and calreticulin in the ER (Van
Delden et al., 1992; Enyedi et al., 1993). Both proteins allow large amounts of
calcium to be accumulated inside the stores, due to their large calcium binding
acapacity, and at the same time, they allow the bound calcium to be released
expediently due to their low calcium binding affinity. Both proteins present
several similarities (Pozzan et al., 1994). However, only calsequestrin undergoes a
change in hydrophobicity following calcium binding (Ikemoto et al., 1974; Cala
and Jones, 1983; Slupsky et al., 1987; He et al., 1993) indicating molecular
differences between both proteins that many have physiological relevance.
The ER contains inositol 1,4,5-trisphosphate (IP3) receptors, that function as
agonistgated calcium channels originating IP3-induced calcium release upon IP3
binding. Muscle SR has ryanodine receptor-calcium release channels located in
the terminal cisternae regions (Coronado et al., 1994; Meissner, 1994) that are
sensitive to caffeine. The physiological mechanisms responsible for channel
opening are not well known in all muscle types. In cardiac muscle, the ryanodine
receptors are gated by entry of extracellular calcium, giving rise to calciuminduced calcium release (Meissner, 1994). In skeletal muscle, the channels open in
response to voltage-induced conformational changes of the transverse tubules
voltage sensors (Rios et al., 1992), by a mechanism not yet defined in molecular
terms.
Recent studies have established that non-muscle cells also contain ryanodine
receptors (Coronado et al., 1994), and an outstanding problem in calcium
signalling is to establish whether and how the two calcium releasing systems
connect functionally. Furthermore, cyclic ADP-ribose has been proposed to act as
an agonist of ER ryanodine receptors (Galione, 1993; Lee, 1991 and 1993).
Activation by cyclic ADP-ribose of muscle ryanodine receptors is still a matter of
controversy, and may depend on luminal calcium content, as discussed below.
The IP3 receptor and the ryanodine receptor share many structural features.
Both are very large tetrameric proteins that present a significant degree of
homology near the carboxy terminal region, in the membrane spanning segment
that presumably forms the calcium channel (for a review, see Pozzan et al., 1994).
A large mass of both proteins protrudes into the cytoplasm, and only a very
limited portion of both receptor proteins is exposed to the luminal side.
Molecular studies have revealed heterogeneity of the IP3 receptor due to gene
multiplicity and gene splicing. Likewise, two types of ryanodine receptor with
Calcium releasefrom SR
389
66% homology have been characterized, one expressed in mammalian skeletal
muscle and the other in cardiac muscle. An additional ryanodine receptor, the
type 3 ryanodine receptor, has been found, that is sensitive to ryanodine but
insensitive to caffeine (for reviews, see Coronado et al., 1994; Meissner et al.,
1994; Pozzan et al., 1994).
Properties of Calcium Release from SR
Calcium release from the SR terminal cisternae is the physiological response
whereby muscle cells respond to transverse tubule depolarization, leading to
muscle contraction (Rios et al., 1992).
The SR ryanodine receptors-calcium release channels have been studied at
the single channel level, after fusion of SR vesicles isolated from rabbit (Smith et
al., 1985), frog (Su~irez-Isla et al., 1988), pig (Fill et al., 1990), fish (O'Brien et al.,
1995), avian (Percival et al., 1994) and human (Fill et al., 1991) skeletal muscle
with planar lipid bilayers.
All these channels share similar properties (Coronado et al., 1994; Meissner,
1994): they are activated by cytosolic addition of millimolar ATP and micromolar
calcium, and are blocked by millimolar Mg2§ or micromolar Ruthenium Red.
Ryanodine in the nanomolar range increases channel fractional open time (Po)
without changing channel conductance (Buck et al., 1992; Bull et al., 1989); higher
ryanodine concentrations locks the channel in a low conductance state with P0
close to unity (Buck et al., 1992; Bull et al., 1989; Rousseau et al., 1987; Perceival
et al., 1994).
Cytosolic calcium has different effects on the single channels of SR vesicles
isolated from various types of muscle. Release channels of SR from mammalian
skeletal muscle are activated by micromolar cytosolic free calcium and blocked in
the millimolar range (Fill et al., 1990, 1991; Smith et al., 1986), whereas channels
present in SR isolated from dog hearts are activated by lower calcium concentrations with no blocking effect at 500 micromolar calcium (Chu et aL, 1993;
Rousseau et al., 1986). Channels of SR isolated from amphibian and fish skeletal
muscle exhibit both types of calcium dependence (Bull and Marengo, 1993;
O'Brien et al., 1995), whereas channels in SR from avian skeletal muscle present
a complex regulation by cytosolic calcium (Percival et al., 1994).
The immunophilin FKBP12 is a protein that is physiologically associated with
the ryanodine receptor-calcium release channels of skeletal muscle (Jayaraman et
al., 1992). This protein stabilizes the channel in its full conductance state.
Following FKBP12 removal from the receptors, the calcium channels display
mutiple subconductance states (Brillantes et al., 1994).
The kinetic properties of calcium release from heavy SR or triad vesicles
isolated from mammalian (rabbit) or amphibian (frog) skeletal muscle have been
studied by several groups (E1-Hayek et al., 1995; Ikemoto et al., 1984; Meissner et
al., 1986; and Moutin and Dupont, 1988; Donoso and Hidalgo, 1993; Donoso et
al., 1995). As found in single channel studies, vesicular release rates are
stimulated in vitro by cytosolic micromolar calcium and millimolar ATP, and are
inhibited by cytosolic millimolar Mg 2§ and micromolar Ruthenium Red.
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Hidalgo and Donoso
Cytosolic (extravesicular) pH has a marked effect on calcium release kinetics
in vesicles isolated either from rabbit or from frog skeletal muscle (Meissner,
1990; Dettbarn and Palade, 1991; Donoso and Hidalgo, 1993). Cytosolic pH <--6.5
produces complete inhibition of calcium channel activity (Ma et al., 1988;
Rousseau and Pinkos, 1990) and of vesicular calcium release (Meissner, 1990;
Donoso and Hidalgo, 1993), whereas cytosolic alkaline pH stimulates vesicular
calcium release (Meissner, 1990; Dettbarn and Palade, 1991).
LUMINAL R E G U L A T I O N OF CALCIUM RELEASE FROM SR
The luminal regulation of SR calcium release has been less studied than the
cytoplasmic regulation of release. Using different experimental approaches, only a
few studies have been carried out to study luminal calcium regulation of calcium
release.
In skinned skeletal fibers, a critical level of calcium load in SR is required to
observe calcium induced calcium release (Endo, 1977). Experiments with intact
isolated ferret ventricular myocytes (Bassani et aL, 1995) indicate that increasing
SR calcium load produces a marked increase in fractional SR calcium release
during a twitch; SR calcium release is almost abolished when SR calcium content
is reduced to 60% of the maximum.
Experiments have been done as well in SR vesicles isolated from skeletal
muscle (Ikemoto et aL, 1989; Nelson and Nelson, 1990; Donoso et aL, 1995), and
in single calcium channels of skeletal and cardiac SR incorporated in planar lipid
bilayers (Ma et aL, 1988; Fill et al., 1990; Hermann-Frank, 1993; Sitsapesan and
Williams, 1994; Tripathy and Meissner, 1994). All these studies indicate that
luminal calcium regulates calcium release from skeletal and cardiac muscle SR.
However, there are some discrepancies, arising from single channel experiments,
as to whether increasing luminal calcium stimulates or inhibits calcium channel
activity, as discussed below.
Effects of Luminal Calcium on Vesicular Calcium Release Rates
Fast release kinetics studies of caffeine-triggered calcium release, carried out
in heavy SR vesicles isolated from rabbit skeletal muscle, indicate that rate
constants change markedly on raising luminal [Ca2+] (Ikemoto et aL, 1989).
Furthermore, heavy SR vesicles isolated from porcine skeletal muscle, actively
loaded with calcium in the presence of ATP, release calcium only after reaching a
threshold value of luminal [Ca2+] (Nelson and Nelson, 1990), suggesting the
presence of intraluminal regulatory sites that must be occupied by calcium to
allow effective calcium release.
We have found that luminal [Ca2§ controls ATP-induced calcium release
kinetics in triads isolated from frog and rabbit skeletal muscle (Donoso et al.,
Calcium release from SR
391
1995). In both systems, the rate constants of calcium release induced by ATP
increase markedly in response to increases in luminal calcium concentration,
albeit the two vesicular preparations show some significant differences in their
responses. The initial rates of release vary differently with luminal calcium as
well; they increase in a hyperbolic fashion with increasing luminal [Ca 2§ in triads
from rabbit, and in sigmoidal fashion in triads from frog.
Our findings indicate that triads from frog and rabbit respond differently to
changes in luminal [Ca2§ It is known that SR calcium release channels from frog
display two types of calcium dependence to changes in cis calcium concentration
(Bull and Marengo, 1993), and that the two calcium channel isoforms isolated
from frog skeletal muscle SR and reconstituted in lipid bilayers behave differently
to changes in cis [Ca 2§ (Murayama and Ogawa, 1992). Hence, it is conceivable
that the two isoforms present in SR from frog (Olivares et al., 1991; Lai et al.,
1992) may also respond differently to changes in luminal [Ca2§ Studies with the
isolated isoforms are needed to test this point.
We attributed the changes in release rate constants produced by luminal
calcium to channel opening probability (P0) changes (Donoso et aL, 1995); with
this assumption, we were able to generate theoretical curves that predict the
experimental changes of rate constants with luminal [Ca2+]. From this theoretical
analysis, we proposed that the properties of the calcium release channels present
in the vesicles can account solely for the observed experimental behavior of the
rate constants.
Luminal calcium may control directly the properties of the channels by
calcium binding to channel luminal sites, since the calcium channel protein has
luminal regions (Grundwald and Meissner, 1995). Alternatively, the effects of
luminal calcium may be mediated by calsequestrin, since calsequestrin addition to
the luminal side increases SR calcium channel open probability (Kawasaki and
Kasai, 1994). A further discussion of this latter possibility is presented below.
Effects of Luminal Calcium on Single Calcium Channel Properties
An increase in SR calcium channel opening by increasing luminal [Ca 2+]
would be consistent with the results obtained in vesicular release experiments.
Studies of the effect of luminal (trans) calcium channels incorporated in bilayers
have produced contradictory results. Increasing trans calcium from the/xM to the
mM range decreases Po in calcium channels purified from rabbit skeletal muscle
(Ma et al., 1988) and produces a permanent closure of porcine skeletal muscle SR
channels (Fill et al., 1990). Contrary to these findings, a 60% increase in P0 on
increasing trans calcium from 50/xM to 10mM for the purified ryanodine
receptors from rabbit reconstituted in liposomes and fused with lipid bilayers was
described (Tripathy and Meissner, 1994).
The effects of luminal on P0 may be due to calcium binding to luminal
regulatory sites of the channel protein, as discussed above. They may depend also
on the mechanism of channel activation, as indicated by studies with channels of
skeletal (Hermann-Frank, 1993) and cardiac SR (Sitsapesan and Williams, 1994).
Furthermore, cyclic ADP-ribose activation of skeletal SR channels requires high
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Hidalgo and Donoso
luminal [Ca2+] (Sitsapesan and Williams, 1995), a finding that may be relevant for
physiological channel activation by cyclic ADP-ribose and cytosolic [Ca2+].
Is Calsequestrin, or Other Luminal Protein, Involved in the Luminal
Regulation of Calcium Release?
A role of calsequestrin in regulating calcium release has been proposed
(Ikemoto et al., 1989, 1991; Gilchrist et al., 1992). Furthermore, SR calcium
channel open probability increases after trans addition of calsequestrin with trans
mM [Ca2+] (Kawasaki and Kasi, 1994).
The rate constants of caffeine-induced calcium release change markedly in
the calcium concentration range where calsequestin binds calcium (Ikemoto et al.,
1989). Conformational changes of the channel ptotein occur following calcium
binding to calsequestrin and are reversibly abolished by dissociation of the
calsequestrin-calcium channel complex (Ikemoto et al., 1989). Transient increases
in intravesicular [Ca2§ precede calcium release (Ikemoto et al., 1991) suggesting
that conformational changes of the channel protein induced by releasing agents
are transmitted to calsequestrin and cause dissociation of its bound calcium.
Furthermore, the action of ryanodine upon calcium release from heavy SR is
highly sensitive to the filling of an intraluminal calcium compartment, presumably
calsequestrin, supporting the hypothesis that the calcium release channel and
calsequestrin are mutually coupled (Gilchrist et al., 1992).
Our results (Donoso et al., 1995) concur with those of Ikemoto et al. (1988)
in showing that release rate constants increase in the luminal calcium concentration range that leads to calsequestfin saturation with calcium. Whether this
increase is due to calcium-induced calsequestfin conformational changes or to a
direct effect of luminal [Ca 2+] on the channel protein itself remains to be
estabilshed.
The results of Ikemoto et al. (1989) and our own results (Donoso et al., 1995)
clearly show that in the range of luminal [Ca2+] where marked changes in release
rate constants occur, most of the calcium present in the vesicles must first
dissociate from calsequestrin before being released. We have reported preliminary results indicating that calcium dissociates from calsequestfin in solution in
the microsecond time range (Prieto et al., 1994), much faster than the millisecond
time range of the calcium release responses. Following calcium binding calsequestfin experiences extensive conformational changes (Ikemoto et al., 1974;
Ostwald et al., 1974) that cause changes in its intrinsic fluorescence, and
undergoes aggregation (He et al., 1993). We have determined the time course of
calcium association and dissociation from calsequestrin by measuring its intrinsic
fluorescence in a stopped-flow system after mixing calcium-saturated calsequestrin
with calcium-flee solutions, or after mixing calcium-free calsequestrin with
calcium-containing solutions. We found that the change in intrinsic fluorescence
that occurs concomitantly with calcium dissociation or association to calsequestfin
(Ikemoto et al., 1974) takes place in less than 1 ms, the resolution time of the
stopped-flow system (Prieto et al., 1994).
It remains to be established whether in vivo most of the calcium that is
Calcium releasefrom SR
393
released from the SR lumen is either free (Volpe and Simon, 1991) or bound to
calsequestrin, and whether calcium dissociation from calsequestrin in vivo is as
fast as in solution.
Other SR proteins have been implicated in the physiological regulation of the
calcium release channels. Annexin VI, a 67 KDa protein, modifies the gating
behavior of single calcium channels, increasing opening probability and channel
mean open time, without changing channel conductance (Dfaz-Mufioz et al.,
1990). The effect of annexin VI, that was specific to the calcium release channels,
was observed when this protein was added to the trans side of the bilayers, and
some annexin VI was found in the lumen of SR vesicles isolated by several
different ~procedures (Diaz-Mufioz et al., 1990), consistent with a possible
physiological role of this protein on calcium release.
It has also been proposed that a 30 KDa protein regulates the calcium release
channels of SR (Yamaguchi et aL, 1995). Furthermore, this protein also interacts
with calsequestrin, raising interesting possibilities for calcium channel regulation
(Yamaguchi et al., 1995).
COMPARISON WITH THE EFFECTS OF LUMINAL CALCIUM
ON CALCIUM RELEASE FROM IP3 SENSITIVE STORES
The IP3-sensitive calcium release channel shares many features with the
ryanodine receptor/calcium release channel (Ehrlich, 1995). Both are modulated
by cytosolic calcium and ATP, and inhibited by cytosolic Mgz+. The immunophilin FK506 binding protein, that associates with the ryanodine receptor,
also modulates calcium flux through the IP3 receptor (Cameron et al., 1995).
Several reports indicate that IP3 stimulates calcium release from skeletal SR,
although this issue remains controversial (Hidalgo and Jaimovich, 1989). However, there are pharmacological differences between both channels, such as the
effects of heparin and caffeine (Palade et aL, 1989; Ehrlich et aL, 1994).
"Quantal" calcium release, first described for IP3 sensitive stores by
Muallem et al. (1989), is a term that was coined to describe the anomalous
response of these stores to submaximal concentrations of IP3 (see Bootman, 1994,
for a review). The all-or-none model attributes "quantal" release to the presence
of stores with different sensitivities to IP3 (Muallem et al., 1989). Irvine (1990)
formulated on alternative mechanism, that "quantal" release is due to inhbition
of release caused by depletion of luminal calcium from IP3 sensitive stores. This
proposal forms the basis of the steady-state model of calcium release. "Quantal"
release has been described for ryanodine receptors as well (Cheek et aL, 1993;
Dettbarn et aL, 1994).
To understand the nature of "quantal" calcium release, it is important to
characterize the effect of luminal calcium on release. In contrast with the general
agreement that luminal calcium regulates release from SR, the situation is less
clear for IP3-induced calcium release. Thus, it has been reported that luminal
calcium controls calcium release in many cell types (Missiaen et al., 1991,
1992a, b, 1994, 1995; Nunn and Taylor, 1992; Oldershaw and Taylor, 1993; Parys
394
Hidalgo and Donoso
et al., 1993). These reports are in agreement with the steady-state model of
calcium release (Irvine, 1990).
However, lack of effect of luminal calcium on calcium release has been
reported in a variety of cellular systems (Combettes et al., 1992; Hirose and Iino,
1994; Loomis-Husselbee and Dawson, 1993; Sayers et al., 1993; Shuttleworth,
1992; van de Put et al., 1994). The reasons underlying these discrepancies are a
subject of active current debate (Shuttleworth, 1995; Missiaen et al., 1995; Mezna
and Michelangeli, 1995; Hirose and Iino, 1995).
PHYSIOLOGICAL IMPLICATIONS OF LUMINAL CONTROL
OF CALCIUM RELEASE BY CALCIUM
If in intact skeletal muscle release rate constants vary with luminal [Ca 2+] as
they do in isolated vesicles, the luminal calcium regulation of release rates would
represent a physiological regulatory mechanism. The stores would be prevented
from complete emptying during sustained muscle activation due to the luminal
inhibition of the release channel. This mechanism would also account for the
"quantal" release described for muscle ryanodine receptors (Dettbarn et al.,
1994). Furthermore, models of calcium efflux from SR in whole muscle should
take this feature into account if the physiological conditions are to be reproduced.
ACKNOWLEDGEMENTS
The authors were supported by Fondo Nacional de Investigaci6n Cientifica y
Tecnol6gica (FONDECYT) grants 1930776 and 1940369, and by institutional
support to the Centro de Estudios Cientfficos de Santiago provided by a group of
Chilean private companies (COPEC, CMPC, ENERSIS, IBM and XEROXChile).
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