Structure and function of ryanodine receptors

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1 Structure and function of ryanodine receptors ROBERTO CORON~O, JEFFERY MORRISSETTE, MANANA SUKHAREVA, A DONNA M. VAUGHAN Department of Physiology, University of Wisconsin School of Medicine, Madison, Wisconsin Coronado, Roberto, Jeffery Morrissette, Manana Sukhareva, and Donna M. Vaughan. Structure and function of ryanodine receptors. Am. J. ~~~s~oz. 266 (Cell ~~~s~oz. 35): C~485C~504, ~994.Membrane depolarization, neurotransmitters, and hormones evoke a release of Ca2 from intracellular Ca 2staring organelles like the endoplasmic reticulum and, in muscle, the sarcoplasmic reticulum (SR). In turn, the released Ca2 serves to trigger a variety of cellular responses. The presence of Ca2 pumps to replenish intracellular stores was described more than 20 years ago. The presence of Ca 2 channels, like the ryanodine receptor, which suddenly release the organellestored Ca2, is a more recent finding. This review describes the progress made in the last five years on the structure, function, and regulation of the ryanodine receptor. Numerous reports have described the response of ryanodine receptors to cellular ions and metabolites, kinases and other proteins, and pharmacological agents. In many cases, comparative measurements have been made using Ca2 fluxes in SR vesicles, singlechannel recordings in planar bilayers, and radioligand binding assays using [3~~ryanodine. These techniques have.helped to relate the activity of single ryanodine receptors to global changes in the SR Ca2 permeability. Molecular information on functional domains within the primary structure of the ryanodine receptor is also available. There are at least three ryanodine receptor isoforms in various tissues. Some cells, such as amphibian muscle cells, express more than a single isoform. The diversity of ligands known to modulate gating and the diversity of tissues known to express the protein suggest that the ryanodine receptor has the potential to participate in many types of cell stimulusca2release coupling mechanisms. excitationcontraction coupling; calcium ionrelease channel; sarcoplasmic reticulum OGAWA A EBASHI (47) described the Ca2releasing action of nonhydrolyzable ATP analogues in a preparation of isolated skeletal muscle sarcoplasmic reticulum (SR). This ob servation led the authors to suggest that Ca2 release was not simply the reversal of Ca2 uptake but a separate and pharmacolo~cally distinct event. The effect of ATP analogues could be demonstrated in SR passively equilibrated with 45Ca2 (27, 37, 222) and, unlike the Ca2 pump, was specifically localized to the terminal cisternae (76, 27, 37). Ca2 release stimulated by nucleotides shared many features of the Ca2 release stimulated by micromolar extravesicular Ca2, also known as Ca2induced Ca2 release. These included stimulation by caffeine (47) and inhibition by procaine (47), ruthenium red (27), and physiological concentrations of Mg2 (27). Thus the pharmacological properties of the nucleotideinduced release and the Ca2induced release suggested the presence of a single type of terminal cisternaespecific channel, which later became known as the Ca2release channel. The presence of this channel could also explain the Ca2 releasing action of a plethora of seemingly unrelated ligands (56). Direct recordings of Ca2 release channels were made by Smith et al. (83) using planar bilayer techniques. Adenine nucleotides increased the open probability and the mean open time of a Ca2 channel with many unusual properties, such as a large unit conductance and a low ionic selectivity. In addition, the channel displayed sensitivity to Ca2, ATP, Mg2, and ruthenium red that were quantitatively adequate to explain the ionic basis of Cazinduced Ca2 release (84, 85). The Ca2release channel was also sensitive to the muscleparalyzing alkaloid ryanodine (79, 70), an observation that was crucial to the identification of the ryanodine receptor as the protein that formed the channel. The development of a E3H]ryanodine binding assay led to the isolation of the ryanodinebinding protein or ryanodine receptor from homogenates of skeletal muscle (79, 8, 99). The large molecular mass of the ryanodine receptor monomer, typically in the range of 350, ,000 Da, prompted investigators to compare the mor /94 $3.00 Copyright o 994 the American Physiological Society Cl485

2 Cl486 INVITED REVIEW phological characteristics of the purified protein with the socalled feet structures seen at the junction of terminal cisternae and transverse tubular membranes (3, 58, 8). Th e purified complex consisted of a square or quatrefoilshaped particle of N 20 nm on each side with a 2nm hole in the center (8,99,23). This was the characteristic size and shape of the feet structures. Purified ryanodine receptors incorporated into planar bilayers formed Ca2 release channels with liganddependent properties similar to those described in native SR vesicles (74, 99, 87). These observations established that the ryanodine receptor, the Ca2release channel, and the foot structure are the same protein. Molecular cloning of the skeletal receptor by Takeshima et al. (20) suggested that the protein structure consisted of a large hydrophilic mass and a short carboxyterminal region of transmembrane segments. This arrangement was consistent with the foot portion formed by the hydrophylic domain and the pore region formed by the transmembrane domain (20). Heterologous expression of the ryanodine receptor cdna showed that the protein formed channels sensitive to Ca2, adenine nucleotides, and ryanodine (28). Three separate genes identified as ryr, ryr2, and ryr3 were found to encode ryanodine receptors (25). Expression of these genes did not appear to be tissue specific, but each was predominantly expressed in skeletal muscle, cardiac muscle, or brain and smooth muscle, respectively (66, 6, 53). Isoformspecific functional domains, such as the cardiacspecific phosphorylation site for Ca2 / calmodulindependent protein kinase (CaM kinase) (2 6), should be useful in determining the regulatory mechanisms of Ca2 signaling that are dominant in different tissues. It is the purpose of this review to describe the progress made in the last five years in our understanding of the structure and function of ryanodine receptors. The focus is largely on the protein rather than the signaling mechanisms in which ryanodine receptors participate. Specifically, we have excluded from this review excitationcontraction coupling events within striated muscle cells in which the ryanodine receptor plays a crucial role. In addition, we excluded the participation of ryanodine receptors in pathophysiologies, such as in the clinical syndrome malignant hyperthermia. This information has been reviewed elsewhere (45, 47, 50, 54, 5, 67, 92). Recent reviews complementary to ours, which focus on other aspects of ryanodine receptors, have also appeared (25,90). CA2 FLUXEX FROM SR Ca2 fluxes have been extensively measured in SR by numerous radioisotopic and nonisotopic techniques. Part of this information was reviewed by Martonosi (9) before the identification of the ryanodine receptor as the major contributor to the flux. Most flux measurements in SR make use of the isotopic tracer 45Ca2 in protocols consisting of a 45Ca 2leading phase followed by a 45Ca2release phase. Millimolar concentrations of 45Ca2 are loaded into the SR lumen by passive diffusion or by active uptake. During the release phase, the myoplasmic surface of the SR is exposed to a release solution consisting of micromolar concentrations of free Ca2 and/or other stimulatory or inhibitory ligands. The kinetics of Ca2 efflux have been resolved using stoppedflow, quenchedflow, or rapidfiltration techniques. In stopped flow, Ca2 release induced by a rapid mixing step is monitored continuously using Ca2 indicator dyes (85, 89, 4). In quenched flow, mixing of vesicles and a Ca2buffered release solution is followed by a sudden termination of the release with a quenching solution (27, 30). In rapid filtration, there is a complete substitution of the extravesicular solution with a release solution while the SR remains bound to a nitrocellulose filter (20, 30, 46, 39, 97). Rapid filtration differs from quenched flow in that the released Ca2 and the SR are separated instantaneously. In quenched flow, separation of the two Ca2 pools occurs after the release is terminated. Thus quenched flow relies entirely on the efficiency of the quenching solution, which in the case of SR is usually composed of micromolar concentrations of the dye ruthenium red. In skeletal muscle SR, Ca2induced Ca2 release is stimulated by adenine nucleotides and inhibited by Mg2 (Table ). The Ca2 dependence of the efflux rate forms a bellshaped curve with a maximum near pca 6 (44,90,27,30,39,4,97). Efflux rates decrease as extravesicular free Ca2 concentrations approach pca 9 or 3 (20, 90, 96, 27, 30, 39, 4, 47, 97). Similarly, the rate of Ca2 release from cardiac SR is a biphasic function of free Ca2 concentration with the maximum at 520 FM Ca 2 ( , 69). The bellshaped Ca2 dependence of release has been hypothesized to result from different Ca2binding sites, a highaffinity site that stimulates Ca2 release and a lowaffinity site that inhibits release (30,4). However, it is important to note that a decrease in Ca2 efflux rate at millimolar extravesicular Ca2 concentrations may not solely reflect a decrease in SR Ca2 permeability. It could also reflect a decrease in Ca2 driving force as the extravesicular Ca2 concentration approaches the intravesicular Ca2 concentration. The contribution of the decrease in driving force to the Ca2 efflux rate has not yet been adequately investigated. Because the estimated cellular free Mg2 is in the millimolar range (20), the inhibitory effect of Mg2 may be a significant mechanism for closing ryanodine receptors. In Ca2 flux protocols, Mg2 produces a strong inhibition of Ca2 release (20, 27, 30, 4), with a halfmaximal inhibitory concentration of 70 PM (27, 30). The mechanism of Mg2 inhibition appears to be a competitive displacement of Ca2 from the highaffinity stimulatory site (30, 4). In contrast to its effect on skeletal SR, Mg2 in the millimolar range does not completely block Ca2 release in cardiac SR (30, 3, 69). Adenine, adenosine, and adenine nucleotides (AMP, ADP, and ATP) and nonhydrolyzable ATP analogues, such as P,ymethyleneadenosine 5 triphosphate (AMP PCP), have been shown to counteract the inhibition by Mg2 (20, 27, 30, 39, 4, 97). For example, Ca2 release in the presence of 5 mm AMPPCP was inhibited by 40 PM free Mg2, which is twice the halfinhibitory

3 Table. Kinetics of Ca2 release from passively loaded sarcoplasmic reticulum of skeletal muscle Additions to Release Solution Initial Rate Rate of Ca2 Constant, Free Ca2, Adenine Free Mg2, Release, s nucleotide, nmolmgl*s* PM mm mm , , Quenched flow Rapid filtration Stopped flow INVITED REVIEW Cl487 References 0. 27, , , , , , free Mg2 concentration required in the absence of nucleotide (30). The halfmaximal stimulation of release by AMPPCP was.6 mm when the free Ca2 concentration was 4 PM and was 2 mm when the free Ca2 concentration was nm (30). This indicated that SR Ca2 release was stimulated by Ca2 or nucleotide more or less independently (30). In cardiac SR, adenine nucleotides stimulated release but not as effectively as in skeletal SR (27, 3, 69). The half time of release in cardiac SR was decreased by AMPPCP from 25 to 5 ms, and there was also a shift in the halfmaximal Ca2 concentration for Ca2induced Ca2 release from 2 to 23). At concentrations in the range of 0.00 FM ryanodine, Ca2 release was stimulated, whereas, at higher concentrations in the range of lo300 PM ryanodine, release was inhibited (63,68, 03, 28, 44). Similar concentrationdependent effects have recently been described with the ryanodine derivatives designated as ryanoid ester E and ryanoid ester F (73). The dose dependencies for stimulation of release were similar and resulted in halfmaximal values of 63 FM for ester E and 43 PM for ester F. However, the dose dependencies for inhibition of release were significantly different and resulted in halfmaximal values of,300 PM for ester E and 3,00 PM for ester F. Based on these observations, it was suggested that activation and inhibition of SR Ca2 release by ryanodine were mediated by functionally independent sites (73). An emerging number of metabolites from secondmessenger cascades have been shown to cause Ca2 release from the SR by activating ryanodine receptors (Table 2). On e example is the NAD metabolite cyclic ADP ribose (cadpr), which mobilizes Ca2 from intracellular stores but operates independently of the inositol,4,5trisphosphate pathway (6). Lee (04) showed that cadpr, like caffeine, potentiated Ca2induced Ca2 release in sea urchin eggs. This observation and the fact that cadpr increased the open probability of cardiac ryanodine receptors incorporated into planar bilayers (32) suggested that cadpr may be an endogenous ligand of the ryanodine receptor. However, in skeletal SR the mechanism of action of cadpr is less clear. Although cadpr specifically induced Ca2 release in rabbit skeletal SR, the release was not sensitive to ryanodine receptor blockers (38). Furthermore, high concentrations of cadpr (up to 50 PM) failed to increase the open probability of skeletal ryanodine receptor channels in planar bilayers. Morrissette et al. (38) suggested that a nonryanodine receptor release mechanism may be involved in the action of this novel ligand in skeletal muscle. Another group of Ca2 release agents that affect ryanodine receptors are fatty acids and their metabolites. For example, the glycolipid sphingosine had a dual effect. It induced release at high concentrations but inhibited caffeineinduced Ca2 release at low concentrations (7). Arachidonic acid, stearic acid, and the fatty acid derivatives palmitoyl carnitine and palmitoyl coenzyme A stimulated Ca2 release from skeletal or cardiac SR (24,42,46). The observation that palmitoyl carnitine increased the SR Ca2 permeability in nanomolar free Ca2 and millimolar Mg2 suggested that palmitoyl carnitine may generate a small Ca2 leak from the SR in resting muscle cells. This leak could influence the resting cytosolic Ca2 and serve to bring the Ca2release channel to a threshold for activation by voltage or other signals (46). BIING OF RYANODINE 0.8 PM (3). Depending on the concentration, ryanodine has been Analysis of ryanodine binding to its receptor site has shown to stimulate or inhibit Ca2 fluxes in skeletal or provided unique information about channel function. cardiac SR (63, 68, 73, 03, 28, 44, 45). A similar Studies of [3H]ryanodine binding to skeletal and cardiac observation has also been made in liver microsomes (, SR as well as binding to purified receptors is reviewed

4 Cl488 INVITED REVIEW here. However, it is important to mention that there are many reports describing the binding of [3H]ryanodine to microsomal preparations of other tissues, such as brain (33,54,55,230), smooth muscle (227), liver (49,80, 82), and epithelial cells (89). Binding of ryanodine is complex, in that there exist both high and lowaffinity binding sites (7, 25, 0, 22, 34, 6, 25). The ratio of high to lowaffinity binding sites was reported to be :3 (0, 6). In equilibrium binding experiments in cardiac and skeletal SR, Pessah and Zimanyi (6) described dissociation constants of K = l4 nm, K2 = 3050 nm, K3 = nm, and K4 = 24 PM for binding of up to four ryanodine molecules per tetrameric receptor. Hill coefficients < have been reported for the lowaffinity sites, leading to the suggestion that the sequential binding of one to three ryanodine molecules to initially identical sites results in a progressive decrease in the affinity of the unbound sites through allosterically coupled negative cooperativity (25, 0, 6). By definition, a decrease in binding affinity must result from a faster rate of dissociation of bound ryanodine and/or a slower rate of association of unbound ryanodine. One recent report confirmed negative cooperativity, as shown by a slowing of the rate of association of [3H]ryanodine as unlabeled ryanodine was increased (7). However, several reports tended to negate this model by demonstrating a reduction in the dissociation rate of bound [3H]ryanodine as ryanodine was increased (3, 0, 22,25). The latter observation might still be consistent with the model of negative cooperativity, since a decrease in the dissociation rate could be offset by a larger decrease in the association rate. However, a demonstration of a ryanodinedependent decrease in the association rate is technically difficult (25). The relationship between binding of ryanodine to its receptor and the transformation caused by ryanodine on the singlechannel conductance and mean open time is not entirely clear. Highaffinity binding to the first of four ryanodine binding sites has been suggested to result in opening of the channel to a lowconductance state, whereas subsequent binding to the lowaffinity sites results in channel closure (0). This dual effect of ryanodine is consistent with Ca2 release observations described above. Buck et al. (7) have recently demonstrated that ryanodine induces four separate kinetic states, depending on concentration. Ligands known to open the channel and stimulate Ca2 release, such as micromolar Ca2 or millimolar ATP, stimulated [3H]ryanodine binding to highaffinity sites. Ligands known to close the channel and inhibit Ca2 release, such as micromolar ruthenium red and millimolar Mg2, inhibited binding. Thus it became apparent that ryanodine bound preferentially to the open state of the channel (46, 72, 79, 83, 34, 59). This was an important finding, since it meant ryanodine could be used as a conformational probe to indicate the gating state of the Ca2 release channel. This correlation between ryanodine binding and the gating state has held true for many agents (see Table 2). Many studies have indicated that [3H]ryanodine binds in a strictly Ca 2dependent manner. Micromolar Ca2 increases both the affinity of the receptor for ryanodine and the apparent maximum binding capacity (B,,) (59, 60,63,75). The Hill coefficient of the Ca2dependent stimulation was 2 (7, 63, 229). Binding of ryanodine to skeletal receptors has a Ca2 threshold of 0.l FM, is optimal at lo00 PM, and is inhibited at Ca2 concentrations > mm (8, 3, 34, 59, 60, 20, 229, 230). The bellshaped Ca2 dependence of [3H]ryanodine binding, the Ca 2 dependence of SR Ca2 fluxes, and the Ca2 dependence of ryanodine receptor channel open probability (5) are similar and strongly support a model in which high and lowaffinity Ca2binding sites affect binding of ryanodine and opening of the channel (63). Binding of ryanodine to cardiac SR has a Ca2 threshold of J.JM, is optimal at 0 PM to mm, but, in contrast to skeletal receptors, shows little inhibition at high Ca2 concentrations (7, 32, 72, 34, 60, 75, 229). The Ca2 dependence of the cardiac channel open probability agreed with ryanodine binding data, in that little inhibition of channel activity was observed at millimolar Ca2 (32). Thus it was suggested that cardiac receptors have a highaffinity Ca2 activation site but not a lowaffinity Ca2 inhibition site (32). A bellshaped Ca2 dependence has been described for Ca2 fluxes in cardiac SR (32, 3). However, as indicated above, the latter could result from a loss in driving force for Ca2 efflux when the extravesicular Ca2 concentration is in the millimolar range. Millimolar Mg 2 has been shown to effectively inhibit ryanodine binding to skeletal receptors (3, 46, 34, 59, 60, 63) but has little effect on the binding to cardiac receptors (72, 34, 60, 75). The effect of Mg2 has been attributed to a decrease in both the apparent B max (34, 63) and th e affinity of the receptor for ryanodine, resulting from a slowing of the ryanodine association rate without a change in the dissociation rate (3). Mg2 inhibition of ryanodine binding was due to a direct competition between Ca2 and Mg2 for the Ca2 activation site (63) Caffeine in the millimblar range has been found to stimulate [3H]ryanodine binding to skeletal receptors (3, 46, 228, 229) and, to a lesser extent, to cardiac receptors (72,229). This effect resulted from an increase in the ryanodine association rate without a change in the dissociation rate (3). In the presence of Ca2 and Mg 2, caffeine appears to increase the affinity of the activation site for Ca2 (63). Millimolar concentrations of adenine nucleotides have been shown to stimulate ryanodine binding to skeletal receptors (8, 3,46, 34, 48, 59, 63, 229) but to have little effect on cardiac receptors (34, 229). The effect of adenine nucleotides seemed to be different from that of caffeine, in that there was little effect of nucleotides on the affinity of the Ca2 activation site for Ca2 (63). The stimulation due to adenine nucleotides resulted from an increase in the affinity of the receptor for ryanodine due to an increase in the association rate (3) and/or an increase in the apparent B,, (63). The order of potency in the stimulation of ryanodine binding closely matched that for SR Ca2 release and was AMPPCP > adenosine 3,5 cyclic monophosphate (CAMP) > ADP = adenosine (27,63).

5 Table 2. Agents that affect ryanodine receptors Agent Effective Ca2 [UH]ryanodine Single Concn Release Binding Channel Anthraquinones Dounorubicine l00 PM Digoxin l20 nm Doxorubicin l300 PM Mitoxantrone Rubidazone Polyamines Gentamicin Neomycin Polylysine Protamine Putrescine Spermidine Spermine Local anesthetics Benzocaine Chlorpromazine Dibucaine Lidocaine Procaine Tetracaine Volatile anesthetics Enflurane Halothane Isoflurane Fatty acid derivatives Longchain acyl CoA Arachidonic acid Acyl carnitines Palmitoyl carnitine Sphingosine Stearic acid Scorpion toxins Buthotus venom Imperatoxin Imperatoxin A I Ryanodine analogues Dihydroryanodine Ester E Ester F Others 4Alkylphenol BisGlO Caffeine Chlorocresol Cyclic ADP ribose Dantrolene DCCD Dithiothreitol &HCH FLA365 MBED Perchlorate Porphyrin Rose bengal Ruthenium Sulmazole Theophylline Verapamil red 50 PM 550 FM l20 PM FM l0 lg/ml kg/ml l00 mm l00 mm mm l0 mm 0..5 mm mm 0.5 mm l20 mm 0.02 mm 2% vol.5%, 2% vol 2%, 2.5% vol 50 FM l50 PM 50 PM l00 PM 3050 PM 0.0 ~JM 632 FM Iii3 lib Pii kg/ml l,000 l,000 nm nm l,000 nm l,000 nm l2 FM l,000 nm l2 FM lo25 nmol/mg 0.00 mm l00 mm 0.00 mm l7 PM l2 PM NE l2 PM 23 nm PiiD FM 0.5l mm 600 ~.LM PM 0.30 FM 800 mm l60 FM l200 nm PM 0.0 PM mm l,000 PM NE NE i!d Species and Tissue References Pig cardiac 37 Dog and pig cardiac 37,59 Dog and pig skeletal 37,59 NE NE skeletal, rat cardiac and brain Sheep cardiac skeletal, rat cardiac, dog cardiac skeletal skelatal skelatal 34 skeletal, dog 20, 34, 85, 3, and rat cardiac 3,28 skeletal 34,85 skeletal 34 skeletal 226 skeletal 226 skeletal 34,226 skeletal 8 skeletal 8 skeletal, sheep brain 8, 43, 8 skeletal, sheep brain 8,8 skeletal 27,47,8,220,224 skeletal, dog cardiac, 49, 05, 8, 3, sheep brain, rat liver 8,220 skeletal 46 skeletal, dog cardiac 24, 42, 46 skeletal 46 and pig skeletal 46 skeletal 7 skeletal 7 skeletal 24 skeletal, bovine cardiac, rat brain skeletal skeletal, bovine cardiac skeletal, dog cardiac 73 skeletal, dog cardiac 73 skeletal 73 Dog cardiac, rabbit skeletal 73 skeletal 73 Rat skeletal skeletal skeletal, dog and rat cardiac skeletal skeletal Skeletal Dog cardiac skeletal skeletal, sheep cardiac skeletal Rat cardiac skeletal, dog and rat cardiac skeletal skeletal, rabbit cardiac skeletal skeletal skeletal, dog and rat cardiac Sheep cardiac cardiac skeletal 2,229, ,05, 5, , 34, 72, 05, 3, 39, 4,63, 95,28, , ,30, 3, ,29 9, 7, 30, 74, 3, 27, , 99, 07, 0, 8,29, 229, Stimulation of Ca2release, [3H]ryanodine binding, or Ca2 release channel open probability;, inhibition of Ca2 release, [ Hlryanodine binding, or Ca2 release channel open probability;, not determined; NE, no effect. DCCD, N,N dicyclohexylcarbodiimide; &HCH, &hexachlorocyclohexane; FLA365, [2,6dichloro4dimethylaminophenyl]isopropylamine; MBED, 9methyl7bromoeudistomin D.

6 Cl490 INVITED REVIEW Nanomolar ruthenium red inhibited C3H]ryanodine binding to both skeletal (3, 46, 3, 60, 229) and cardiac receptors (72, 60, 75, 229). Zimanyi et al. (228) have shown that the removal of ruthenium red causes a persistent inhibition of ryanodine binding that can last to 48 h. However, this persistent inhibition could be reversed by the thiol reducing agent, dithiothreitol. Thus it appeared that a shift in the redox equilibrium of critical thiols plays an important role in the inhibition of ryanodine binding by ruthenium red. Thiol groups have also been implicated in the binding of ryanodine and in the gating of channels in the absence of inhibitors (4, 75). The binding of [3H]ryanodine to skeletal and cardiac SR was stimulated by increasing ph (34,2 lo), temperature (7, 8, 25, 48), or concentrations of NaCl or KC (8, 3, 34, 59, 229). Th e mechanism by which NaCl or KC stimulated binding has been proposed to be either a direct interaction of the salt with the binding site or a shielding of charges on the receptor (34). However, it was recently reported that a similar effect was produced by increasing sucrose concentrations, suggesting that osmolarity and not ionic strength was important (49). PURIFICATION The localization of ryanodine receptors specifically to the terminal cisternae of SR was supported by demonstrations that [3H]ryanodine binds to terminal cisternae but not to longitudinal SR (55,83), ryanodine affects SR Ca2 release from terminal cisternae but not from longitudinal SR (03,76), and ruthenium red enhances Ca2 loading in terminal cisternae but not longitudinal SR (55, 83, 36, 76). This enhancement of loading could be abolished by pretreatment of SR with nanomolar concentrations of ryanodine (55, 83). The preparation of welldefined terminal cisternae and the identification of a specific probe, such as [3H]ryanodine, which remains bound to the receptor in SR solubilized in the zwitterionic detergent 3[(3cholamidopropyl)dimethylammonio] propanesulfonate (CHAPS), were critical for purification of ryanodine receptors (59, 75). The detergentsolubilized skeletal ryanodine receptor was purified to homogeneity by sequential heparinagarose chromatography followed by hydroxylapatite chromatography (8), by immunoaffinity chromatography (2, 79), and by density centrifugation through a linear sucrose gradient (99,lO ). Sodium dodecyl sulfatepolyacrylamide gel electrophoresis of the ryanodine receptor yielded a single band with a molecular mass between 350,000 and 450,000 Da (2, 79, 99, 0). The actual molecular mass of the receptor, later determined by molecular cloning, was 564,000 Da (20,23). The purified receptor had an apparent sedi mentation coefficient of 3OS, indicating that it was a large tetrameric complex with an estimated molecular mass > lo6 Da (3,8,99,0). L k ewise, in gelexclusion chromatography, the purified receptor eluted as a peak corresponding to a molecular mass > lo6 Da (8). The CHAPSsolubilized cardiac ryanodine receptor was purified to homogeneity by sequential heparinagarose chromatography followed by paminobenzamidineagarose and gelpermeation chromatography (82), by density gradient centrifugation (9, 07), and by a combination of gelpermeation chromatography and density gradient centrifugation (64). Like that of skeletal ryanodine receptors, the cardiac receptor complex had a sedimentation coefficient of 30s (9). However, Inui et al. (82) found that th e cardiac receptor subunit had a slightly higher mobility on electrophoretic gels, and its molecular mass was later determined, with the use of molecular cloning, to be 565,000 Da (53). The CHAPSsolubilized brain ryanodine receptor was purified using a combination of heparinagarose chromatography, ionexchange chromatography, and density gradient centrifugation (23) and was found, with the use of molecular cloning techniques (66), to be a highmolecularmass protein of 552,000 Da. This protein was immunologically detected by a polyclonal antibody raised against the carboxy terminus of the skeletal muscle ryanodine receptor and by a polyclonal antibody against the putative CAMPdependent phosphorylation site of the cardiac ryanodine receptor (23). The purifica tion by sizeexclusion chromatography of a 280,000Da ryanodinesensitive channel protein from human neutrophils has also been reported (66). A CHAPSsolubilized 30s ryanodine receptor from aortic smooth muscle has been partially tion (69). PHOSPHORYLATION purified by density gradient centrifuga Seiler et al. (76) found that highmolecularmass proteins of junctional SR, later identified as ryanodine receptors, were phosphorylated by an endogenous CaM kinase or by the exogenous catalytic subunit of CAMP dependent protein kinase (PKA). Phosphorylation by these and other kinases was subsequently demonstrated in cardiac (93,99,200,209,26,223) and skeletal (33, 96,99,24) ryanodine receptors. Takasago et al. (99) observed that, in the presence of the exogenous catalytic subunit of PKA, guanosine 3,5 cyclic monophosphatedependent protein kinase (PKG), or CaM kinase, phos phorylation of the cardiac ryanodine receptor occurred at similarly rapid rates. In contrast, protein kinase C (PKC)dependent phosphorylation occurred at a relatively slow rate, even though the final level of 32P incorporation was similar to that seen with PKA and PKG. Additionally, the level of 32P incorporation in the presence of PKA, PKC, or PKG was comparable with the maximal level of [3H]ryanodine binding, indicating a stoichiometry of mol of phosphate per mole of ryanodine binding sites (99). Thus it appeared that mol of phosphate was incorporated per mole of tetrameric receptor, assuming only one highaffinity ryanodine binding site per tetramer. On the other hand, phosphorylation by exogenous CaM kinase was 4 times greater than that with PKA, PKG, or PKC (99), suggesting that four phosphorylation sites per tetramer were present for exogenous CaM kinase. However, Witcher et al. (26) found that phosphorylation of the

7 INVITED REVIEW Cl49 cardiac receptor by endogenous CaM kinase was about onefourth the value achieved with exogenous CaM kinase. These results indicated that the endogenous CaM kinase phosphorylated only one of the available sites, whereas exogenous CaM kinase phosphorylated all four of the receptor subunits (26). The endogenous CaM kinase activity and the cardiac ryanodine receptor corn&rated through several purification steps, indicating that the two proteins are tightly associated (209). Phosphorylation of the cardiac receptor by PKA, PKG, or PKC increased [3H]ryanodine binding by 22 t 5, 7 t 4, and 5 t 9%, respectively (99). In contrast, CaM kinasedependent phosphorylation decreased [3H]ryanodine binding by 38 t 4% (99). Because ryanodine binds preferentially to the open state of the channel, these results implicated phoshorylation in the modulation of the gating of the channel (99). Phosphoamino acid analysis revealed that PKA, PKG, and PKC presumably phosphorylated the same serine residue. However, a different serine was phosphorylated by CaM kinase (99). These results led to the important suggestion that phosphorylation of the cardiac receptor at two or more distinct sites up or downregulates the activity of the Ca2 release channel. Witcher et al. (26) found that phosphorylation by either endogenous or exogenous CaM kinase occurred at serine 2809 and produced activation of the cardiac receptor channel incorporated into planar bilayers. The same phosphorylation site for CaM kinase was found in the brain receptor (27). In isolated myocytes, Yoshida et al. (223) demonstrated that phosphorylation of the cardiac receptor can be enhanced by the padrenergic agonist isoproterenol. This stimulation was blocked by propranolol, indicating that the effect was through the padrenergic receptor. Thus CAMPdependent phosphorylation of the cardiac ryanodine receptor may be involved in the positive inotropic effect of padrenergic agonists. Phosphorylation of the skeletal receptor by endogenous (33,24) or exogenous (96) CaM kinase, by PKA (96), or by PKG (96, 99) has been demonstrated. Suko et al. (96) showed that the stoichiometry of phoshorylation to the purified receptor was 0.88 mol phosphate/m0 receptor monomer for PKA, 0.6 mol phosphate/m0 receptor monomer for PKG, or mol phosphate/m0 receptor monomer for CaM kinase. Phosphoamino acid analysis indicated that PKA, PKG, and CaM kinase phosphorylated serine residue In addition, CaM kinase phosphorylated other unidentified residues, including threonine (96). The observations using CaM kinase or PKA were disputed by a study in which the apparent phosphorylation of the skeletal receptor was due to the phosphorylation of an adventitious protein. This protein migrated with the ryanodine receptor but was unrelated to it since it did not crossreact with antibodies to the skeletal receptor (26). Other studies indicated insignificant or no phosphorylation due to CaM kinase or PKA (93,99,200). Thus the extent of skeletal receptor phosphorylation by CaM kinase or PKA remains to be fully elucidated. The functional significance of skeletal receptor phosphorylation is controversial. HerrmannFrank and Varsanyi (70) reported that endogenous phosphorylation of SR, presumably by CaM kinase, resulted in an increase in the open probability and an increase in the Ca2 and ATP sensitivities of skeletal receptor channels incorporated into planar bilayers. These effects could be reversed by phosphatase 2A. However, other studies described inactivation of the channel due to CaM kinasedependent phophorylation (24) or no effect of CaM kinasedependent phosphorylation on Ca2induced Ca2 release from junctional SR (33). IONIC SELECTIVITY A CA2DEPEENT GATING Ionic selectivity and Ca 2dependent gating of ryanodine receptors has been investigated in planar bilayers by fusion of SR (0,9,32,5,65,8385,207,224) or by incorporation of purified ryanodine receptors (74, 07, 09, 2, 87,220). In the fusion method (38, 86), a preformed planar bilayer separating cis and transsolutions is exposed to microgram amounts of SR protein added to the &solution. Ca2release channels incorporate into the bilayer with a polarity dictated by the polarity of the SR vesicle. Thus, typically, the myoplasmic end of the channel protrudes into the &solution (38). Purified channels usually incorporate in planar bilayers with the same polarity as those from the SR fusion method (07, 87). It is generally agreed that the properties of native and purified channels are qualitatively similar. Thus no distinction between the two is mentioned here. Two conductive features of ryanodine receptors uniformly described for various species and muscle types are the unusually large unit conductance and the low cationic selectivity (Table 3). There is little discrimination between Ca2 and Ba2, but divalent cations are more permeable than monovalent cations in mixed solutions. The anionic permeability seems to be nonexistent (07,87). The high conductance and low selectivity clearly set the ryanodine receptor apart from Ca2 channels of plasma membranes, which typically display low conductance and high ionic specificity. However, the ryanodine receptor shares many singlefile permeation properties of highly selective channels. The Ca2 conductance saturates with increasing luminal Ca2 concentrations, following a simple MichaelisMenten curve with the parameters maximum conductance (ymax) and dissociation constant (&) equal to 80 p S and 4 mm for the cardiac channel (07) and 72 ps and 3 mm for the skeletal channel, respectively (87). The monovalent cation conductance, measured in the absence of divalent cations, saturates at a much higher value and with a lower affinity. For example, the yrnax and & for K are ns and 47 mm for the skeletal channel, respectively (87). Thus the conductance ratio y&ca for the skeletal channel was 6. However, the permeability ratio PK/Pc,, was 0.4 (87). This discrepancy between the conductance ratio, measured in single salts and that favors monovalent cations, and the permeability ratio, measured in mixed salts and that favors divalent cations, was argued to support a conduction mechanism where multiple ionbinding sites are arranged in single file (87). Tinker et al. (205, 207) proposed a fourbarrier threebinding site model to

8 Cl492 INVITED REVIEW Table 3. Conductance and selectivity of purified ryanodine receptor channels Source Yc:, PS [cisltrunsl, mm YcB, PS [cis / trans], mm P$ /PC Reference Skeletal muscle K/250 K K/50 Ca Na/500 Na 9 25 Tris/50 Ca2 Frog Na / 60 Na 0 60 Na/50 Ca2 Cardiac Dog muscle Na/500 Na Tris/50 Ca2 Dog Tris/50 Ba2 Sheep K/20 K Tris/63 Ca2 Smooth muscle Pig aorta K /250 K K/lOO Ca2 Invertebrate muscle Lobster K/260 K K/50 Ca2 Crayfish Na / 00 Na Nematode K/250 K Brain Bovine K/250 K K/50 Ca K/250 K 7 (Ca2/K) 87 4 (Ca2/Tris) 5 (Ca /Tris) 99* 5 (Ca2/Na) 00* 8 (Ca2/Tris) 73* 4 (Ba2/Tris) 64 4 (Ca2/K) 07 5 (Ca /Tris) 4 (Ca2/K) 69 6 (Ca2/K) 7v 57 4 (Ca2/Cs) 93 6 (Ca2/K) yc and ycz, Singlethan nel conductances for monovalent and divalent cations, respectively; lcis ltrans], cis to transsol ratios at which yc and ycz were measured. *Pcz /PC, permeability ratio calculated based on reported reversal potential. ution concentration explain ion conduction in the cardiac channel. The main feature of this model is a central well that favors the binding of Ca over K by 6 RT units or 3.7 kcal/mol. The stronger binding of Ca2 in the pore explains the lower Ca2 conductance and the higher permeability of Ca2 in mixed solutions. It also explains the experimental results that Ca2 actually decreases rather than increases channel current measured in the presence of monovalent salts (87). Ion conduction in the cardiac channel has been probed with symmetrical tetraalkyl ammonium cations of the series (CnH2nl)4N (204, 206). Small organic cations of n = l3 added to both sides of the channel produced a strong block of K current at cis (myoplasmic)positive potentials but with little effect on the current at negative potentials. Analysis of the block was consistent with binding of the blocker ion at a single site in the pore located at 5090% of the electric field depending on the probe size. The affinity of block varied monotonically with the number of methyl and methylene groups in the blocker molecule, supporting the presence of a hydrophobic pocket within the pore to which the organic cations could bind (206). Larger quaternary ammonium derivatives of n = 4 and 5 (204) induced a voltagedependent subconductance state that was suggested to result from a partial occlusion of the channel by the bulky organic cation. These studies support a model in which the pore has a wide capture radius. Blocker molecules as large as tetraethylammonium can move through the pore for a distance of up to 90% of the electric field across the bilayer (206). Less hydrophobic blocker molecules of equivalent size, such as tris(hydroxymethyl)aminomethane ion with a molecular cross section of 38 A2, produce a small but discernible conductance (87). This pore cross section is consistent with the recently determined pore radius of the cardiac ryanodine receptor of 3.5 A (208). The maximum number of ions able to occupy the channel at a given time is probably one (205, 207) or two (87). Interestingly, in the ryanodine modified channel, there is a reduction of the capture radius for ion entry that explains the lower conductance of the channel as well as the lower rate of entry of quaternary ammonium blockers (209). Studies of permeation of neutral molecules measured by quenchedflow and lightscattering methods are consistent with the large pore size of the ryanodine receptor (86, 87, 28). Glucose entry into SR had the same characteristics as Ca2induced Ca2 release, in that it was stimulated by micromolar extravesicular Ca2, millimolar caffeine, or millimolar ATP and was inhibited by millimolar Mg2 or micromolar ruthenium red (86, 87, 28). These results suggested that glucose is capable of permeating the ryanodine receptor. Other nonelectrolytes such as xylose, glycine, and glycerol also permeate the channel (87). The Ca2 dependence of the open probability has been investigated by varying the free Ca2 in the cissolution while keeping a constant concentration of divalent or monovalent cation as the current carrier in the transsolution. The membrane potential did not influence the Ca2 dependence of the channel and, in most studies, was held constant near 0 mv. A bellshaped open probability vs. Ca2 curve with a maximum at l0 FM cis free Ca2 was described for an amphibian skeletal channel with Ca2 or Ba2 as the current carrier (9) and for mammalian skeletal channels (rabbit, pig, and human) with Cs as the current carrier (5, 52, 79). A sublinear (Hill coefficient < ) open probability vs. Ca2 curve that did not saturate as a function of cis free Ca2 was described for mammalian skeletal (rabbit) and cardiac (sheep) channels with Ca2 or Ba2 as the current carrier (0, 85). Finally, a sigmoidal (Hill coefficient ) open probability vs. Ca2 curve that saturated at 0 FM cis free Ca2 was described for both a mammalian cardiac (dog) channel with Cs as the current carrier (32, 65) and for an amphibian channel with Ca2 or Ba2 as the current carrier (9).

9 INVITED REVIEW Cl493 The origin of the discrepancy in the Ca2 dependence of the various Ca2 release channels is not entirely clear. In the case of mammalian skeletal channels, the current carrier plays an important role since high trans Ca2 or Ba2 was shown to reduce the opening probability of the channel activated by cis Ca2 (5, 2). Furthermore, differences in the skeletal muscle type, as in fast or slowtwitch muscle, also appeared to determine the Ca2 sensitivity of the channel (05). In addition to distorting the shape of the open probability vs. Ca2 curve, studies in the skeletal channel revealed that trans Ca2 introduced significant kinetic changes. For example, in the absence of trans Ca 2, there was a clear dependence of the mean open time on cis Ca2 (5), which was not seen when Ca2 was used as the transcurrent carrier (85). The Ca2 dependence of the cardiac channel may also be modified by trans Ca 2. Using Cs as the charge carrier in the canine cardiac channel (32), the open probability varied with cis free Ca2 in a sigmoidal fashion with a threshold for channel opening of 0. J.LM and saturation at 0 PM cis free Ca 2. However, in the sheep cardiac channel recorded using Ca2 as the current carrier (lo), no saturation was described. Although the species are different, it is highly likely that the sublinear Ca2 dependence and lack of saturation reported for the sheep channel may be due to the current carrier. When mammalian skeletal and cardiac channels were compared in the same solutions, there appeared to be a genuine difference. The Ca 2 dependence of the skeletal channel was described as a bellshaped curve, whereas that of the cardiac channel was described as a saturating curve (32). The Ca2 dependence of open and closed states of cardiac (0) and skeletal (85) channels was analyzed using 54 mm Ca2 as the current carrier in the transsolution. The cis free Ca2 threshold for opening of the skeletal channel was FM, whereas, in the cardiac channel, the threshold for opening was 0. FM free Ca2 (0, 85). In both cases, an increase in cis Ca2 resulted in an increased steadystate open probability with a sublinear dependence on Ca2 concentration. Lifetime analysis revealed two open states for each channel and either two or three closed states for the skeletal or cardiac channels, respectively (0, 85). The Ca2 dependence was traced to the three closed states of the cardiac channel or to one of the two closed states of the skeletal channel. Ashley and Williams (0) fitted the Ca2 dependence of the cardiac channel to a branched gating scheme in which binding of a single Ca2 to a closed state allowed the channel to open into either a longlived or a shortlived state. This model accounted for the observation that Ca2 increased the number of long and short openings to the same extent. Recent studies using photolysis of caged Ca2 at the surface of a planar bilayer have resolved the Ca2 dependence of the open probability of the cardiac channel into a transient component and a steadystate component (65). Delivery of micromolar free Ca2 by a flash resulted in a rapid transient opening of channels followed by a decrease in open probability toward a steadystate level occurring on a time scale of several seconds. The Ca2 dependence of the transient was 0 times more sensitive than that of the steadystate component. The timedependent decrease in Ca2 sensitivity, called adaptation, was suggested to serve as a mechanism to turn off Ca2induced Ca2 release from the SR (65). Numerous reports have indicated that the ligand dependence of the ryanodine receptor channel is ad equate to explain the ligand dependence of Ca2induced Ca2 release measured by Ca2 fluxes in SR. This close correspondence between the planar bilayer and SR flux measurements validated both approaches and is per haps the most compelling evidence that the Ca2release channel formed by the ryanodine receptor is the sole mediator of Ca2induced Ca2 release from SR. Thus recordings in planar bilayers have shown that the open probability of single Ca2 release channels increases in response to millimolar ATP or AMPPCP (9, 0, 29, 5, 74, 99, 00, 09, 65, 69, 83, 85, 87, 224), millimolar caffeine (52,05,09,68), and ryanodine concentrations < 0 FM (9, 0, 7, 8, 29, 5, 52, 74, 79, 99, 00, 07, 09, 2, 65, 70, 87, 224). Decreases in open probability occurred in response to millimolar free Mg2 (9, 29, 5, 74, 99, 00, 09, 69, 84, 85, 87, 224), micromolar ruthenium red (9, 29, 5, 74, 99, 00, 05, 07, 69, 83, 85, 87, 224), micromolar procaine or tetracaine (05, 220, 224), and ryanodine concentrations > 00 PM (9, 65). CLONING, EXPRESSION, A LOCALIZATION Three different ryanodine receptor genes have been identified in mammals and are designated here as the skeletal, cardiac, and brain ryanodine receptor genes or ryr, ryr2, and ryr3, respectively (25). In addition to the three mammalian ryanodine receptor genes, part of a homologous gene, called the dry gene, has been cloned from DrosophiZa. The dry and mammalian genes are highly conserved. The dry gene encodes an mrna of 5 kilobases and is expressed in the somatic muscles and, at a lower level, in neuronal tissues of Drosophila (67). The ge ne for the skeletal muscle ryanodine receptor was specifically localized to region 9q3., on the long arm of human chromosome 9 (4), whereas the cardiac ryanodine receptor gene was localized to human chromosome (53). The chromosomal position of the brain gene is currently unknown. Each of the three genes encodes mrna of 6 kilobases and proteins of 5,000 amino acid residues (66, 42, 53, 20, 23). The tissue distributions of the three proteins are summarized in Table 4. A number of features of the secondary structure are common to the three proteins. A motif of 00 amino acid residues is repeated four times in each case (66,42, 53, 23). An aminoterminal signal sequence is not present in any of the proteins, indicating that the amino terminus is cytoplasmic. The transmembrane (TM) structure of the proteins is somewhat controversial. In a model suggested by Takeshima et al. (20), four putative TM segments in the carboxyterminal tenth of the molecule were identified. In another model proposed by Zorzato et al. (23), 2 potential TM sequences were identified, 0 in the carboxyterminal fifth of the mol

10 Cl494 INVITED REVIEW Table 4. Localization of the ryanodine receptor gene products Mouse Sea urchin Species Location Method Reference Dog, rabbit, guinea pig, rat, hamster Mouse cow Dog, guinea pig Guinea pig Mink Mink Drosophda ryr Skeletal muscle Cloning 20 Skeletal muscle, heart, smooth muscle RNA blot 6 Skeletal muscle RNA blot 66 Fast and slowtwitch skeletal muscle RNA blot 53 Cerebellum Immunoblot and immunohistochemistry 97 Egg Immunoblot and immunocytochemistry 26 ryr2 Heart Heart ventricle Brain Heart, brain, stomach Heart, hippocampus, and forebrain Brain Brain except pituitary Brain Vascular and endocardial endothelium ryr3 Corpus striatum, thalamus, hippocampus, midbrain, pons, and medulla Aorta, esophagus, taenia coli, urinary bladder, ureter, and uterus Lung epithelial cells Skeletal muscle, stomach, spleen, lung, kidney, ileum, jejenum Muscles, neuronal tissue dry RNA blot, cloning 53 Immunoblots 80 Immunoblot and immunohistochemistry RNA blot and cloning of partial cdna sequence from brain Immunoblot, immunocytochemistry, in situ hybridization of antisense RNA probe, purification, RNA blot RNA blot RNA blot Immunoblot Immunoblot, immunohistochemistry, RNA blot RNA blot, cloning RNA blot, screened cdna library from aorta and sequenced Cloning RNase protection analysis Cloning ecule and 2 additional ones near the center of the found in the human form (23). Based on the 2TM molecule. Subsequent reports on the cardiac or brain segment model, all of them were located in regions ryanodine receptor seem to subscribe to one or the other predicted to be on the cytoplasmic side of the SR and of the two models (Table 5). The amino terminus and were therefore not expected to be glycosylated. Howcentral part of each molecule is hydrophilic and is ever, using the fourtm segment model, one of the therefore believed to form the cytoplasmic foot (20, glycosylation sites was located in the lumen of the SR 23). Putative modulatory sites have been identified in and might therefore be glycosylated (23). The rabbit the amino acid sequence for each protein (see Table 5). form contained highaffinity nucleotidebinding se Sites that have some, but not all, of the characteristics of quences and highaffinity Ca2binding domains of the a nucleotide binding site have been described. The EFhand type near the first TM segment in the preamino acid sequence GXGXXG, known as a nucleotide dicted cytoplasmic domain. However, these sites bore a binding motif, has been found in all three cases. How resemblance to but did not have all of the characteristics ever, the secondary structure surrounding each of these of the typical nucleotide binding sites or EFhands (20, motifs does not match that of highaffinity nucleotide 23). A potential lowaffinity Ca2 binding domain was binding sites, except for one sequence reported for the identified for the human form in a region of cytoplasmic cardiac protein (53). acidic residues (23 ). Skeletal Ryanodine Receptor Information regarding functional Ca2 binding sites was obtained by studying the binding of 45Ca2 or The cdna sequences of the ryanodine receptor from human (23 ) or rabbit (20,23 ) skeletal muscle demonstrated that the protein consists of 5,032 or 5,037 amino ruthenium red, an indicator of Ca2 binding sites, to acid residues with molecular masses of 563,584 or 565,223 Da (20, 23), respectively. Regions that may interact with calmodulin were identified in both forms (20, 23). Potential phosphorylation sites were found in the cytoplasmic region of the human form, just upstream from the probable channelforming sequences (23). Several possible glycosylation sites were also various sequences lying between residues 4,04 and 4,765 of the rabbit form (29). Polyclonal antibodies raised against sequence 3~2, lying between residues 4,478 and 4,52, increased the Ca2 sensitivity of ryanodine receptor channels incorporated into planar bilay ers, resulting in an increase in open probability and mean open time without altering the channel conductance. The antibodyactivated channel retained its sensitivity to known ryanodine receptor ligands, such as

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