Life Sciences, Vol . 25, pp . 1189-1200 Printed in the U.S .A .

Pergamon Press

MINIREVIEW COMPARATIVE ASPECTS OF CARDIAC AND SKELETAL MUSCLE SARCOPLASMIC RETICULUM W.B . Van Winkle and M.L . Entman Section of Cardiovascular Sciences, Department of Medicine and Biochemistry Baylor College of Medicine and The Methodist Hospital Houston, Texas 77030

Summary While differing in numerous physiological and biochemical parameters, mammalian cardiac and skeletal muscles exhibit many common ultrastructural characteristics . General subcellular organization is similar with longitudinal .disposition and organization of the myofibrils as well as subcellular organelles such as mitoSignificant differences chondria, sarcoplasmic reticuibm and transverse tubules . are more readily discerned in terms of degree, not only with respect to relative amounts of various organelles, but also in regard to membrane composition . It is these macromolecular variations in membrane components which may, at least in part, provide the basis for differences in overall functional characteristics in the muscles . In cardiac, as well as skeletal muscle, the concentration of Cat+ ions at The specific intracellular sites regulates the contractile state of the muscle . differences in mechanism and sources of Cat+ for contraction in cardiac and skele tal muscle are but a few of the unsolved areas which are now being addressed . We shall focus primarily on research advances involving cardiac and skeletal SR emphasizing the contrasting features related to their functional roles in control of contraction and metabolic events . I.

Calcium movement and Excitation-Contraction Coupling

In both cardiac and skeletal muscle, excitation is initiated by activation of a highly specific sodium channel which results in rapid depolarization . In skeletal muscle, rapid repolarization ensues as a result of a number of well characterized ionic conductance changes initiated by activation of sodium current through inactivation of the sodium channel and apparent potentiation of potassium conductance. In cardiac muscle, the sodium channel is similarly inactivated in a few milliseconds, but repolarization does not ensue immediately because of the activation of a "slow inward current" which results from activation of a channel which carries calcium as its principle ion. Presence of the "slow inward current" results in a characteristic plateau phase in the action potential in cardiac muscle and specialized conduction tissue . Beeler and Reuter (5), using voltageclamped dog ventricular trabeculae, observed that increasing the voltage of a clamp produced a change in calcium inward current on the first beat but several beats were required before an increase in steady state tension was obtained . This observation, along with estimates that the amount of calcium entering the myocardium with each beat (approximately 2 VM) is not sufficient to fully activate all troponin calcium binding sites for contraction, has been the basis for the suggestion that there is an internal pool of .activator calcium in cardiac muscle similar to that in skeletal muscle (65) (which does not require external calcium) . The source of this in skeletal muscle is clearly the SR ; in cardiac muscle the SR 0024-3205/79/141189-12$02 .00/0 Copyright (c) 1979 Pergamon Press Ltd

1190

Cardiac and Skeletal SR

Vol. 25, No . 14, 1979

and the sarcolemma and the extracellular glycocalyx have also been implicated (83,119) . Because the cardiac muscle requires external calcium for activity, several investigators have suggested that influx of a "trigger calcium" induces a calcium-induced calcium-release from either the internal surface of the sarcolemma, (83) in the SR, or both (35,47,48) that effects cardiac contraction . Similar phenomena have been described in the past by Ford and Podolsky (50) and Endo, et al (33) in skeletal muscle where a slow calcium current or influx is not promi-ne ent or required, however, Endo, et al (34) demonstrated that the phenomenon rerequired that the SR is loaded witTi calcium in an unphysiologic manner . The studies of Huxley (67) and Huxley and Taylor (68) in skeletal muscle demonstrated that the application of a depolarizing potassium solution into the T system resulted in contraction occurring only at the henisarcomeres surround the T tubule suggesting that depolarization at the triad resulted in the release of calcium and in the subsequent observation of contraction. Mechanisms of calcium release linked to depolarization have been suggested : 1) hydrogen ion efflux (106), 2) the displacement of calcium from storage sites by entering sodium (112) and 3) changes in electrical conductance secondary to electrical transmission . Relaxation of all striated muscle results from calcium accumulation by the

SR (discussed further in this review), but the mechanisms by which steady state

calcium levels (both free and sequestered) are maintained also vary both qualitatively and quantitatively according to the function of the muscle . For example, in contrast to skeletal muscle, it is well known that an external supply of calcium enters the cardiac muscle cell with each beat ; it also follows that a given quantum of calcium must leave the cardiac cell in equal amounts in ordir to maintain steady state. The mechanism by which calcium exits the cardiac cell has also not been well elucidated . No external calcium current has been observed in cardiac muscle cells and this has resulted in the suggestion that an electroneutral pump of exchange mechanism may exist for calcium exit . The principle mechanisms suggested are : 1) diffusion of calcium concentrated in the lateral 2) Calcium portions of the SR across junctional areas with the sarcolemma (82) . within the cell exchanges for sodium outside the cell so that the external to internal sodium gradient drives calcium efflux (114,118) and 3) the possibility of a calcium pump in cardiac muscle sarcolemma which would actively pump calcium from the cell (121) . II .

In Vitro Study of SR Membranes A.

Membrane Characteristics - General Physical Properties and Morphological Quantification

It is important to note that many isolated membrane preparations, especially cardiac SR, are contaminated by membranes from other sources, most notably mitochondria and the sarcolemma and/or transverse tubule system (4,85) . Utilizing the ability of the SR to precipitate calcium as oxalate or phosphate salts inside the vesicles, thereby increasing those vesicles' density on sucrose gradients, numerous workers have sought to purify SR preparations from cardiac (15,72,73,87), and skeletal muscle (6,8,53) . Electron microscopic observation of the resulting "Ca2+ -loaded" vesicles, however, reveals that only 7-10% of the cardiac and approximately 20% of the skeletal SR vesicles exhibit evidence of calcium accumulation . While not exhibiting detectable calcium accumulation, a Density broken or leaky SR vesicle may still exhibit Ca2+ ATPase activity . gradient centrifugation of crude skeletal sarcoplasmic reticulum preparations typically yields two populations, sedimenting at approximately 30% and 40% sucrose (53,84,99) which seem to be derived from the longitudinal and terminal The heavier vesicles concisternae - T tubule junction regions, respectively . tain higher concentrations of the calcium binding proteins Calsequestrin and

Vol. 25, No . 14, 1979

Cardiac and Skeletal SR

1191

M55 protein which may be localized in the flocculent material observed by electron microscopy in'the intact regions of the SR as well . Sucrose density gradients of cardiac SR usually give one band at approximately 33% (42) ; only recently has the cardiac SR been divided into two populations of vesicles (72) but the origin of these fractions is less clear than in skeletal SR . In skeletal muscle all studies have shown that fast twitch muscles have significantly more SR per cell volume (or myofibrillar volume) than does slow muscle (30,31,32,140,144) . In two separate investigations of cardiac muscle, how ever, it can be seen that the fast-contracting and relaxing rat heart (111) has the same amount of SR (1 .2 112 SR/u 3 cell volume) as does the much slower contracting dog heart (97) . Furthermore, the hamster heart (again faster contracting) has only one-third the SR as the similar rat heart (18) . While these are certain methodological problems involved (10), it is possible that these discrepancies may indicate membrane compositional differences in SR . Freeze fracture studies of SR in intact muscle as well as isolated SR have shown that membrane particles (Ca 2+ ATPase, see Ref. 89) are very dense in the membrane face in contact with the sarcoplasm and that the relative populations of SR Ca2+ ATPase particles are not significantly different in the longitudinal and terminal cisternae (13,21) . Since different functions, Ca 2+ uptake and Ca2+ release, are assigned to these two regions, this implies that protein and lipid differences may exist and/or that stimulation may effect separate functions in the two portions of the SR . Our own estimates of Ca2+ ATPase particle density in sarcoplasmic reticulum membranes in cardiac and skeletal muscle (3900 particles/u 2 vs . 5100 particles/11 2 , respectively) compared to greater differences in enzymatic activity (0 .67 11moles Pi/mg/ min vs . 4.2 Vmoles Pi/mg/min) again suggesting qualitative differences in enzyme function . B.

Sarcoplasmic Reticulum Biochemical Composition

Both cardiac and skeletal muscle SR contain three major proteins - the -100,000 dalton Ca 2+ ATPase and two high affinity Ca 2+ binding proteins of 55,000 and 43,000 . Whereas the Cad+ ATPase may constitute as much as 70-80% of the total skeletal SR protein, it is usually less in cardiac SR . Partial amino acid sequencing of the Ca + ATPase has been accomplished (1) and Tada and his co-workers (135) have found that the amino acid composition of Ca2+ ATPase of dog cardiac SR is very similar to that of rabbit skeletal SR . . Although it is now accepted that the two Ca 2+ binding proteins are internally located, their function in the overall dynamics of Ca 2+ sequestration and release remains unresolved . MacLennan, et al (90) found that they are easily removed from SR and suggested that they areloosely bound "extrinsic" proteins . Meissner (99) suggested that they are primarily confined to the terminal cisternae . The 30,000 dalton glycoprotein noted by Hidalgo and Ikemoto (63) in skeletal SR has also been observed via dansyl hydrazine staining of polyacrylamide gels of cardiac SR (Van Winkle, unpublished observations) . Considerable differences are observed in the phospholipid components of cardiac and skeletal SR (3,63,85,94,109,152) although again it is important to stress the problems associated with such estimates given the heterogeneity of mem brane vesicle preparations . While purified skeletal SR fractions from longitudinal and terminal cisternae regions exhibit identical phospholipid profiles, that of isolated transverse tubular vesicles derived from the "heavy SR" fraction is markedly different (85) . The phospholipid composition of purified skeletal SR Ca2+ ATPase is initially the same as its parent crude SR (64) ; however, this may stem from randomization of lipids attendant to detergent solubilization of the enzyme during purification . 2+ It is accepted that the major activities of the SR, Ca ATPase and Ca 2+ uptake, are greatly influenced by the surrounding phospholipid bilayer . Studies from various muscle sources, - which are subject to the problems of contamination,

119 2

Cardiac and Skeletal SR

Vol . 25, No . 14, 1979

indicate substantial differences in phospholipid composition in SR preparations (3,63,85,94,109,152) . Recent ghospholipid substitution studies by Warren and his co-workers (149) have shown that not only fatty acyl composition and saturation but head group composition as well (7,150) may greatly affect SR Cat + ATPase activities . Hesketh and co-workers (61) found a minimum of 30-35 phospholipids associated as a "lipid annulus" surrounding the Cat+ ATPase existing rather independently from the bulk lipid bilayer . Recently, Dean and Tanford (23,24) have delipidated SR Cat+ ATPase and restored full activity by addition of the non-ionic detergent dodecyloctaethylene glycol . Similar findings with Triton X-100 substitution resulted in return of function of calcium ATPase after phospholipase C treatment (95) . Thus, there is not an absolute requirement of phospholipid but rather a particular set of environmental conditions which modulate the Cat+ ATPase . Changes in skeletal SR membranes in response to changes in temperature have been studied by physical (ESR, NMR) (61,63,69) as well as enzymatic (Ca + ATPase) methods (22,63 88,92) . Discontinuities in Arrhenius plots (transition temperatures) of SR Cad + ATPase activity vs . temperature occur at approximately 17-190C . Hidalgo, et al (63) observed such "breaks" but found no changes in transition temperature fromnative SR to purified Cat' ATPase . However, employing spin labelling techniques, Hesketh, et al (61), observed breaks in the native SR and SR lipids but not in the purified Ca2_F_-ATPase . Data from x-ray diffraction, NMR (22) and differential scanning calorimetry (96) indicate that all of the SR phospholipid fatty acyl chains are in the liquid, disordered states over a broad temperature range . Several other possibilities to explain non-linear Arrhenius plots such as phase separations of boundary and free phospholipids (141), alterations in lipidprotein cluster ordering (86), lipid-protein interactions (63) or, as elaborated by Moore, et al (103), and changes associated more predominately with protein conformation (-2) . Virtually no studies such as those described above have been carried out on SR from cardiac muscle . Feher and Briggs (49) and Chiesi (16) found that cardiac SR Cat + ATPase exhibits an Arrhenius plot break at a higher temperature (22-240 C) than skeletal preparations . C.

ATP-Dependent Cat+ Transport and Release

As several recent reviews have dealt at great length with both the mechanism of calcium transport (136) and calcium release (35,47,71), these two major areas will be only briefly covered here emphasizing differences between striated muscles . Polyacrylamide gel electrophoresis of isolated skeletal and cardiac SR reveals that the Cat + ATPase is a 95-105,000 Dalton protein which, in purified active form, is observed by freeze-fracture electron microscopy as a 9 run particle in a phospholipid bilayer (89) . More recent studies involving freeze-etch of SR membranes (124), chemical crosslinking (105) and isoelectric focusing of purified Cat+ ATPase (91) suggest that the functional form of the membrane bound Cat' ATPase is a tetramer although the monomeric unit has been found to be active in isolated form (74) . Whether these subunits are identical in structure and function in each particle or in various muscle types is not known . The hydrolysis of nucleoside triphosphates, most notably ATP, is linked through a series of phosphorylation and dephosphorylation steps to the transport of externally bound Cat + into the lumen of the SR . Although the stoichiometry of this reaction is usually regarded as two calcium ions transported per phosphate released (56) recent studies indicate that this coupling ratio is less rigid and may vary considerably depending on pH, temperature and substrate concentration (23,28,120,139) . Work in our laboratory utilizing spectrophotometric methods to follow calcium accumulation (38,39,54,98,127,142,143) has shown that the rapid initial rate is significantly higher in skeletal muscle SR as is the slower phase of calcium accumulation linked to oxalate-supported calcium transport . Shigekawa,

Vol . 25, No . 14, 1979

Cardiac and Skeletal SR

119 3

et al (128), have shown that the Km for MgATP for cardiac as well as skeletal SR Ca 2"F-ATPase is approximately 180 tip and the Km for the Cat+ is higher in cardiac (4 .7 ti1M) than in skeletal (1 .3 IN) . The maximum steady state level of phosphorylated enzyme (measured at 00 or 10 0) was higher in skeletal than cardiac . Recent examination (132) of various aspects (phosp orylation, dephosphorylation, calcium dissociation) or skeletal and cardiac SR Ca + metabolism using rapid chemical quenching techniques showed similar rates of phosphoenzyme formation in the presence of Cat+; however, the dephosphorylation of both phosphoenzyme complex and the dissociation of externally bound Cat+ are much higher in skeletal than in cardiac SR . Although SR has the highest affinity for ATP in hydrolysis, phosphoenzyme formation and Cat+ transport, other nucleoside triphosphates also support each of these functions, albeit at considerably lower rates (93,136) . Whereas GTP has 2+ been shown to serve as hydrolytic substrate (29) as well as support Ca uptake in isolated skeletal SR (25,146) it has recently been shown that GTP does not support Cat+ uptake by cardiac SR nor does Cat + stimulate GTP hydrolysis over the basal rate (39,145) . Indeed the intact cardiac SR has a GTP-invoked enzyme turnover cycle not requiring Cad+ or linked to Cat+ transport . Evidence suggests that ATP and GTP compete for the same binding site on the enzyme . Release of sequestered Cat+ from isolated SR may also be effected by anion exchange-induced depolarization of the SR membrane (75) as well is numerous other less physiological agents and drugs (35) . Spontaneous calcium release occurs when ATP-dependent Cat+ transport is driven in the absence of precipitating anion (38,39,44,54) and is qualitatively re=laxant, similar in skeletal and cardiac SR except that the skeletal muscle dantrolene sodium inhibits spontaneous calcium release from skeletal muscle SR (142) and not cardiac SR which correlates with the inability of dantrolene to affect the heart while serving as a potent skeletal muscle relaxant . Katz (76) has also shown a time-dependent calcium efflux in the presence of precipitating anion which may represent the same phenomenon . Although Cat+ accumulated in isolated SR can be released back to the medium by "reversing" the Ca t+ ATPase in the presence of ADP and low external calcium (see 57 for review), the possible role of this mechanism for contraction activation is not clear (80) . In skeletal SR (29,70,107,155) as well as cardiac (128), double reciprocal plots of Cat+ ATPase activity versus by ATP concentration typically yield two Km values indicating the presence of a class of high affinity and low affinity nucleotide binding sites . Solubilization of skeletal SR results in a loss of the "negative co-operativity" (indicated by a linear double reciprocal plot (23,70) . Data of Jorgensen, et al (74), indicate that solubilization eliminates (transforms?) the low affif ATP binding site . These results suggest the possibility that a two nucleotide binding site exists (52), one possibly an allosteric site (107) or that only one site exists which undergoes trapsition (107) . Recent studies (147), using rapid chemical quenching, suggest that increased ATP results in increased enzyme turnover and may reflect interaction of two sites either on the same or neighboring polypeptides in the intact enzyme unit .

nity

III . Functional Changes in Sarcoplasmic Reti culum Changes in SR structural characteristics under pathologic, physiologic, or pharmacologic conditions have been sporadically studied (66,88,138) . They are frequently difficult to interpret because : a) isolation may result in different properties in pathologic material and b) passive calcium permeability may change . No consistent pattern to describe the etiology of these changes has been obvious . In contrast, some rather elegant data in skeletal muscle suggest that external stimuli may be very important in control of gene expression and sarcoplasmic reticulum structure. Utilizing such techniques as cross-innervation or alterations in stimulus frequency, dramatic changes in biochemical and morphologic structure and function have been delineated in skeletal muscle . It has been suggested and de-

Cardiac and Skeletal SR

1194

Vol . 25, No . 14, 1979

monstrated that actual reversible conversion of one muscle type to another can be effected with changes in the pattern of myosin light chains as well as enzymes of the SR (122,123,130,151) . In addition to these alterations in myosin components (and enzymatic activity), a change in SR composition and function is also apparent within a few days (117,130) . The appearance of a species of calcium ATPase of distinctly separate molecular weight attended the alteration in frequency (58) . The possibility exists that these changes in SR function may well emanate from changes in gene expression and that more than one gene codes for calcium ATPase within the cell may result in the expression o£ a different gene for calcium ATPase thus altering SR function through alteration of isozyme distribution . IV .

Metabolic Interrelationship

From a metabolic standpoint, the slow twitch muscles, both cardiac and skeletal, rely mainly on oxidative metabolism for generation of high energy phosphate intermediates . In contrast, fast twitch skeletal muscle relies mainly on oxida tive metabolism during rest, but becomes heavily dependent on glucose metabolism and glycolysis immediately upon the onset of contraction. Phosphorylase a activation (20,60) and ensuing glycogenolysis occurs almost immediately upon the onset of stimulation of contraction in fast twitch skeletal muscle and this contractiondependent activation of glycogenolysis is unlikely due to metabolite build-up . The work of Drummond, et al (26), demonstrated that cyclic AMP elevations were not essential for the cntraction-activated glycogenolysis although cyclic AMP-mediated function are well known to stimulate glycogenolysis in all muscle types . Since such a contraction-dependent glycogenolytic pool does not exist in cardiac muscle, and since skeletal muscle does not increase its contractility in response to cyclic AMP-mediated drugs (although it responds metabolically) in the same manner as cardiac muscle, much attention has been focused on the difference in mechanism of intermediary metabolism control and hormonal control . A.

Contraction-Dependent Glycogenolysis

Because the contraction-dependent pool of glycogenolysis was not accompanied by a rise in cyclic AMP levels, a suggestion has been made by several workers (55,57,81,100,110,131) that calcium which is the known activator of contrac tion might also be the mediator of the contraction-dependent glycogenolytic pool . It has been well demonstrated in the past that glycogenolysis effected by phosphorylase a formation is calcium-dependent (51) and that this calcium-dependence results from the calcium-dependent phosphorylase b kinase (14) . Recently it has been demonstrated by Cohen and co-workers (17) that the calcium dependence of phosphorylase kinase comes from the specific subunit, calmodulin, found in association with phosphorylase kinase as well as in association with a variety of other cellular enzymes such as light chain kinase and phosphodiesterase . Thus, the possibility of the calcium interaction with this subunit modulating metabolic steps at the same time as it modulates contraction has become even more compelling . The association of the SR and glycogenolysis was first suggested by Fischer and colleagues (54,55,59,101) who demonstrated an association of glycogen and SR in skeletal muscle which demonstrated calcium-dependent activation of phos phorylase and prompt inactivation by phosphatase in absence of calcium. In more recent years a more stable SR-glycogenolytic complex has been isolated from both cardiac and skeletal muscle (40,41,42 .44,45) which contains all the enzymes necessary for glycogenolysis activation and inactivation with the addition of ATP alone. This stable complex remains intact during a sucrose density gradient centrifugation and with dilution and contains several characteristic properties which originated from combinations of soluble enzymes . Phosphorylase, glycogen synthetase, and debrancher enzymes are commonly found in SR preparations and are regarded as extrinsic proteins (contaminants by some, see Ref . 46), which appear to be bound to glycogen which is then associated with the SR membrane (42) while the

Vol. 25, No . 14, 1979

Cardiac and Skeletal SR

1195

adenylate cyclase, protein kinase and phosphorylase kinase seem to relate to the SR membrane (19,42,153) . While the method of attachment is not known, it has been demonstrated in the past morphologically (40,102,148) . Although chaotropic intervention, such as high salt and deoxycholate can remove glycogen and phosphorylase from the SR (102), it renders it unsuitable for SR calcium transport function thereafter . Amylase digestion, however (42,45), not only removed glycogen but also uncouples phosphorylase from its activating enzymes and re-addition of exogenous glycogen to the depleted complex cannot recouple the phosphorylase indicating that the glycogen-phosphorylase particle is attached to the SR membrane and that this association represents more than chance preparative contamination . It has been suggested (45) that this SR-glycogenolytic particle represents in the in vitro counterpart of the contraction-dependent glycogenolytic pool . This mechanism of activation of glycogenolysis is in addition to the well described cyclic AMP-dependent and metabolite-dependent mechanisms observed with catecholamine stimulation and ischemia, respectively . In contrast to skeletal muscle SRglycogenolytic complex, the cardiac muscle SR-glycogenolytic complex does not self-inhibit and is not calcium-dependent (41) . This correlates with the observation that glycogen concentration in cardiac muscle is stable and absence of contraction-dependent glycogenolytic activity in cardiac muscle where glycogenolysis effected only by ischemia or severe stress . Recent work by Brautigan, et al (12), has suggested that amylase treatment of SR in skinned skeletal muscléfiFers suppresses the active calcium accumulation in this system . They also found that insulin increased calcium uptake by the SR as did the addition of glucose-6-phosphate . They suggested that feedback regulation of energy metabolism might therefore exist by regulation of calcium levels in skeletal muscle . While the mechanism of such regulation has not been delineated, considerable interest has been taken in the effects of cyclic AMP and cyclic AMP-mediated functions on SR function . These will be described below. B.

Cyclic Nucleotide Metablism in the Sarcoplasmic Reticulum

The presence of adenylate cyclase in SR fractions has been known since the 1960's when it was described in skeletal (115) and in cardiac (36) sarcoplasmic reticulum fractions . Recently, cyclic AMP has been localized by immunocyto chemical techniques in the SR of cardiac and skeletal muscle (108) . Electron microscopic cytochem,ical studies have shown hydrolytic activity attributed to the . adenylate cyclase localized along the sarcole ma and T-tubule system of cardiac cells, and in junctional regions of the SR apposing the T-system as well (125,126, 129) . Immunohistochemical observations in fast skeletal muscle (116) demonstrated activity in the terminal cisternae but little in the longitudinal SR . On the other hand, the presence of cyclic AMP phosphodiesterase has been demonstrated histochemically in the longitudinal SR, but not in the terminal cisternae (113) . Recent gradient purification studies (73), suggested the possibility that previous SR preparations contained sarcolemmal contamination and/or T-tubule contamination (84) which might result in the observed adenylate cyclase activity . Our recent work with heavy and light SR fractions from skeletal muscle shows little or no latent (detergent responsive) sodium-potassium ATPase activity or ouabain binding but reveals a high level of isoproterenol and epinephrine stimulatable adenylate cyclase activity (43) . In addition, based on differences in epinephrine stimulation, the effect of phospholipase A, rate of activation by GMP-pNp activation and stimulation by detergents, Drummond and Dunham (27), have recently proposed that the adenylate cyclase in two separate cardiac microsomal fractions may originate from the sarcolemma and SR, respectively . In addition to effects on the SR-glycogenolytic complex, cyclic AMP and cyclic AMP-mediated agents have been demonstrated to increase SR calcium accumulation . In 1969, Entman, _ et _ al (37), described a cyclic AMP-induced increase in calcium transport by cardiac SR . Subsequent work by Kirchberger, et al (77,78)

1196

Cardiac and Skeletal SR

Vol . 25, No . 14, 1979

and Tada, et al (134) linked this effect to a specific cyclic AMP-dependent protein kinase-mediated phosphorylation of a 22,000 Dalton protein (phospholamban) resulting in an increased affinity for calcium (62) and accompanied by an equal The cyclic AMP-dependent protein kinase increase in calcium ATPase (133,154) . effects in cardiac and slow skeletal muscle SR were not present in fast skeletal muscle (79), correlating well with the observed lack in fast twitch muscle of an effect of catecholamine stimulation on relaxation (11) . However, although no phosphorylated 22,000 Dalton protein was found in fast skeletal muscle preparations, increased calcium accumulation was observed coincident with phosphorylation of a 95,000 Dalton protein in fast skeletal muscle SR by phosphorylase kinase or cyclic AMP-dependent protein kinase (9,127) . Similarly, Fabiato and Fabiato (48) observed that only under conditions in which SR calcium uptake is diminished, cyclic AMP induced an increase in the relaxation rate of skinned fast skeletal muscle cells, suggesting that fast skeletal muscle SR, under normal conditions may be operating at maximal levels and that impairment of SR function may be necessary for the observation of pharmacologic stimulation by catecholamines . Although the mechanism of the relationship between the phosphorylation of the 22,000 Dalton protein in cardiac SR and increased calcium transport is not known, Tada and co-workers (137), have shown that cyclic AMP-dependent protein kinase phosphorylation of this protein results in an increased Vmax of ATP hydrolysis and the composition of the acyl phosphate intermediate of calcium ATPase in cardiac sarcoplasmic reticulum . Reaction conditions under which these studies were carried out precluded nonspecific alterations (such as permeability changes) and support the theory that phosphorylation of these SR components effects the calcium ATPase in calcium transport . However, since the 22,000 Dalton protein is absent from fast skeletal muscle, the possibility exists that alteration in the enzymatic and transport activity of fast skeletal muscle due to phosphorylation of membrane components may be mediated through a different system . Conclusion In conclusion, the specific SR complements of skeletal and cardiac muscle while both modulating contractile activity by regulation of intracellular Cat+ levels, appears to vary considerably in several important aspects . Potentially significant, morphological and compositional variations in the SR derived from these two divergent muscle sources may underlie the observed physiological and pharmacological differences found in intact muscles . Furthermore, variations at the macromolecular and biochemical level, as well as differences in metabolic interrelationships may greatly affect the role(s) of this membrane system in overall muscle function . Supported in part by HL 22,856, HL 13,870, HL 17,269 and a grant from the Muscular Dystrophy Association .

Vol. 25, No . 14, 1979

Cardiac and Skeletal SR

1197

REFERENCES 1. 2. 3. 4. 5. 6. 7. 8. 9. 10 . 11 . 12 . 13 . 14 . 15 . 16 . 17 . 18 . 19 . 20 . 21 . 22 . 23 . 24 . 25 . 26 . 27 . 28 . 29 . 30 . 31 . 32 . 33 . 34 . 35 . 36 . 37 . 38 . 39 .

G . ALLEN, Membrane Proteins, 11th Meeting of the Federation of European Biochemical Societies, p. 159-168) (1977) . K. ANZAI, Y . KIRINO, and H. SHIMIZU, J. Biochem . 84 :815-821 (1978) . H. BALZER, and A.R . KHAN, Naunyn-Schore eberg's Arch . Pharmacol . 291 :319333 (1975) . R.J . BASKIN, and D.W . DEAMER, J . Cell Biol . 43 :610-617 (1965) . G .W . BEELER, and H. REUTER, J . --P ys iol 207 :211-229 (1970) . J .P . BENNETT, K .A . MCGILL, and G.B . WARREN, Nature 274:823-825 (1978) . J .P . BENNETT, G.A . SMITH, M .D . HOUSLAY, T.R . HESKETH, J .C . METCALFE, and G .B . WARREN, Biochim. Biophys . Acta 513:310-320 (1978) . J .P . BONNOT, M. GALANTE, D . BRETHES, J .C . DEDIEU, and J . CHEVALLIER, Arch . Biochem. Bio h s . 191 :32-49 (1978) . E .P . B RNET, M.L . ENTMAN, W .B . VAN WINKLE, A . SCHWARTZ, D .C . LEHOTAY, and G .S . LEVEY, Biochim. Biophys. Acta 468 :188-193 (1977) . E .H . BOSSEN, J .R . SOMMER, and R.A . WAUGH, Tissue and Cell 10 :773-784 (1978) . W .C . BOWMAN, and E.. ZAIMIS, J . Physiol . 144 :92-107 (1958) . B .L . BRAUTIGAN, W .G .L . KERICK, and E .H . FISCHER, Fed. Proc . 38 :305 (1979) . D .F . BRAY, D.G . RAYNS, and E.B . WAGENAAR, Can J . Zool . 56 :140-145 (1978) . C .D . BROSTROM, FELIX HUNKELER, and E .G . KREBS, J. Biol . Chem . 246 :19611967 (1971) . M .E . CARSTEN, and M.K . REEDY, J. Ultrastruc . Res . 35 :554-574 (1971) . M. CHIESI, J. Mol . Cell . Cardiol . 11 :245-259 (1979) . P. COHEN, A . BURCHEL, J .G . FOULKES, and P .T .W . COHEN, FEBS Letters 92 :287293 (1979) . J.A . COLGAN, M.L . LAZAROS, and H.G . SACHS, J. Mol . Cell . Cardiol . 10 :4354 (1978) . J.D . CORBIN, P .H . SUGDEN, T.M . LINCOLN, and S .C . KEELY, J. Biol . Chem . 252 :3854-3861 (1977) . G.T . LORI, and B . ILLINGWORTH, Biochim. Bio h s . Acta 21 :105-110 (1956) . L .M . CROWE, and R .J .'BASKIN, J . Ultrastruc . Res . 62 :147-154 (1978) . D.G . DAVIS, G . INESI, and T. GULIK-KRYZWICKI, Biochim. 15 :1271-1276 (1976) . W.L . DEAN, and C . TANFORD, J . Biol . Chem . 252 :3551-3553 (1977) . W.L . DEAN, and C . TANFORD, Bioc em . 17 :1683-1690 (1978) . L. DEMEIS, and M.C .F . DEMELLO, J . Biol . Chem . 248 :3691-3701 (1973) . G.I . DRUMMOND, J .P . HARWOOD, and C .A . WEL, J. Biol . Chem . 244 :4235-4240 (1969) . G.I . DRUMMOND, and J . DUNHAM, J . Mol . Cell . Cardiol . 10 :317-331 (1978) . F . DUGGAN, J . Biol . Chem . 252 :1620-1627 (1977) . K. ECKERT, R . GROSSE, D.O . LEVITSKY, A.V . KUZMIN, V.N . SMIRNOV, and K.R .H . REPKE, Acta Biol . Mod . Germ . 36 :1-10 (1977) . B .R . EISENBERG, A.M . KUDA, and J .B . PETER, J . Cell Biol . 60 :732-754 (1974) . B.R . EISENBERG, and A.M . KUDA, J . Ultrastruc . Res. 51 :176-187 (1975) . B .R . EISENBERG, and A.M . KUDA, J . Ultrastruc . Res . 54 :76-88 (1976) . M. ENDO, M. TANAKA, and Y . OGAWA, Nature 228 :34-35 (1970) . M. ENDO, Proc . Japan Acad . 51 :467-472 1975) . M. ENDO, Physiol . Rev . 57 :71-108 (1977) . M.L . ENTMAN, G .S . LEVEY, and S.E . EPSTEIN, Circ . Res . 25 :429-438 (1969) . M.L . ENTMAN, G.S . LEVEY, and S .E . EPSTEIN, Biochem. Biophys. Res . Commun . 35 :728-733 (1969) . M.L . ENTMAN, E .P . BORNET, and A. SCHWARTZ, J . Mol . Cell . Cardiol . 4 :155170 (1972) . M.L . ENTMAN, T.R . SNOW, D . FREED, and A . SCHWARTZ, J . Biol . Chem . 248 : 7762-7772 (1973) .

T

1198

40 . 41 . 42 . 43 . 44 . 45 . 46 . 47 . 48 . 49 . 50 . 51 . 52 . 53 . 54 . 55 . 56 . 57 . 58 . 59 . 60 . 61 . 62 . 63 . 64 . 65 . 66 . 67 . 68 . 69 . 70 . 71 . 72 . 73 . 74 . 75 . 76 . 77 . 78 .

Cardiac and Skeletal SR

Vol . 25, No . 14, 1979

M.L . ENTMAN, M.A . GOLDSTEIN, and A . SCHWARTZ, Life Sci . 19 :1623-1630 (1976) . M.L . ENTMAN, K . KANIIKE, M.A . GOLDSTEIN, T .E . NELSON, E .P . BORNET, T.W . FUTCH, and A. SCHWARTZ, J. Biol . Chem . 251 :3140-3146 (1976) . M.L . ENTMAN, E .P . BORNET, W .B . VAN WINKLE, M.A . GOLDSTEIN, and A . SCHWARTZ, J . Mol . Cell . Cardiol . 9 :515-528 (1977) . M.L . ENTMAN, E .P . BORNET, A .J . GARBER, A. SCHWARTZ, G .S . LEVEY, D .C . LEHOTAY, and L .A . BRICKER, Biochim. Biophys . Acta 499 :228-237 (1978) . M.L . ENTMAN, W .B . VAN WINKLE, E .P . BORNET, and C. TATE, Biochim . Biophys . Acta 551:382-388 (1979) . M .L . ENTMAN, S .S . KESLENSKY, A. CHU, and W.B . VAN WINKLE, J . Biol . Chem . submitted (1979) . F .B . ESSIEN, A .O . JORGENSEN, U.I . KALNINS, E . ZUBRZYCA, and D .H . MACLENNON, Lab . Invest . 37 :562-568 (1977) . A. FABIATO, and F . FABIATO, Circ . Res . 40 :119-129 (1977) . A. FABIATO, and F. FABIATO, Biochim. Bio h s. Acta 539 :253-260 (1978) . J .J . FEHER, and F .N . BRIGGS, Biop ys . J . 5 :109a (1979) . L .E . FORD, and R.J . PODOLSKY, Science 167 :58-59 (1970) . A.J .D . FRIESEN, N . OLIVER, and G.'ALLEN, Amer . J . Physiol . 217 :445-450 (1969) . J .P . FROEHLICH, and E.W . TAYLOR, J. Biol . Chem . 250 :2013-2021 (1975) . M .L . GREASER, R.G . CASSENS, W .G . HOEKSTRA, an E .J . BRISKEY, J . Cell Physiol . 74 :37-50 (1969) . S . HARIGAYA, and A. SCHWARTZ, Circ . Res. 25 :781-795 (1969) . R .H . HASCHKE, L .M .G . HEILMEYER, F . MEYER, and E .H . FISCHER, J. Biol . Chem . 245 :6657-6663 (1970) . W . HASSELBACH, Frog . Bio h s . Mol . Biol . 14 :167-222 (1964) . W . HASSELBACH, Biochim . Bio s . Acta 515 :23-53 (1978) . C . HEILMANN, an D. PETTE, Eur. J . Biochem. 93 :437-446 (1979) . L .M .G . HEILMEYER, F . MEYER, R .H . HASCHKE, and E .H . FISCHER, J . Biol . Chem . 245 :6649-6656 (1970) . E . HELMREICH, and C.F . CORI, Advances in Enzyme Regulation 3:91-107 (1965) . T.R . HESKETH, G .A . SMITH, N .D . HOUSLAY, K.A . MCGILL, N.J .M . BIRDSALL, J.C . METCALFE, and G.B . WARREN, Biochem. 15 :4145-4151 (1976) . M.J . HICKS, M . SHIGEKAWA, and A .M . TZ, Circ . Res . 44 :384-391 (1979) . C .HIDALGO, N . IKEMOTO, and J . GERGELY, J . Biol . Chem . 251 :4224-4232 (1976) . C . HIDALGO, and N. IKEMOTO, J . Biol . Chem . 252 :8446-8454 (1977) . A.V . HILL, Proc . Roy . Soc . 135 :446-453 1948) . Q.-S . HSU, and G. KALDOR, Proc . Soc. Exp . Biol . Med . 138:733-737 (1969) . A .F . HUXLEY, Prog . Biophys . 7 :255-318 (1957) . A.F . HUXLEY, and R.E . TAYLOR, J . Physiol . 144 :426-460 (1958) . G . INESI, M. MILLMAN, and S . ELETR, J . Mol . Biol . 81 :483-504 (1973) . G . INESI, J.A . COHEN, and C .R . COAN, Bio 15 :5293-5298 (1976) . G . INESI, and N. MALAN, Life Sci . 18 :773-780 (1976) . L .R . JONES, and H .R . BESCH JR ., Fed . Proc . 38 :2726 (1979) . L .R . JONES, and H .R . BESCH JR ., ól J. B . -Chew . 254 :530-539 (1979) . K .E . JORGENSEN, K .E . LIND, H . ROIGAARD-PETERSEN, and J .V . MOLLER, Biochem . J. 169:489-498 (1978) . M . KASAI, and H. MIYAMOTO, J . Biochem . 79 :1053-1066 (1976) . A .M . KATZ, D.I . REPKE, G. FURY A, and M . SHIGAKAWA, J . Biol . Chem . 252 : 4210-4214 (1977) . M.A . KIRCHBERGER, M . TARA, D .I . REPKE, and A .M . KATZ, J . Mol. Cell .' Cardiol . 4:673-680 (1972) . M.A . KIRCHBERGER, M . TADA, and A .M . KATZ, J . Biol . Chem . 249 :6166-6173 (1974) .

Vol . 25, No . 14, 1979

79 . 80 . 81 .

Cardiac and Skeletal SR

1199

M. KIRCHBERGER, and M. TARA, J . Biol . Chem . 251 :725-729 (1976) . M.A . KIRCHBERGER, and D. WONG, J . Biol . Chem . 253 :6941-6945 (1978) . E .G . KREBS, J .T . STULL, P .J . ENGLAND, T .S . HUANG, C .A . BROSTROM, and J .R . VANDENREEDE, Protein Phosphorylation in Control Mechanisms , (p . 3145) Academic Press, New York (1973) . 82 . G .A . LANGER, Cardiovasc . Res . Su l . 1 :71-75 (1971) . 83 . G .A . LANGER, an J .S . FRANK, J . Cell Biol . 54 :441-455 (1972) . BRUNSC 84 . Y .H . LAU, A.H . CASWELL, and J.-P HWIG, J . Biol . Chem . 252 :5565-5574 (1977) . Y .H . LAU, A .H . CASWELL, J .-P . BRUNSCHWIG, R.J . BAERWALD, and M . GARCIA, 85 . J . Biol . Chem . 254 :540-546 (1979) . 86 . A.G . LEE, N .J .M . BIRDSALL, J .G . METCALFE, P.A . TOON, and G .B . WARREN, Biochem. 13 :3699-3705 (1974) . 87 . D .O . LEVITSKY, M.K . ALIEV, A .V . KUZMIN, T .S . LEUCHENKO, U.N . SMIRNOV, and E.I . CHAZOV, Biochem. Biophys . Acta 443 :468-484 (1976) . 88 . C .J . LIMAS, Amer . J. Physiol . 235:H745-752 (1978) . 89 . D.H . MACLENNAN, P . SEEMAN, G .H . ILES, and C .C . YIP, J . Biol . Chem . 246 : 2702-2710 (1971) . 90 . D.H . MACLENNAN, C .C . YIP, G .H . ILES, and P . SEEMAN, Cold Spring Harbor Symp . Quant . Biol . 37 :469-477 (1972) . . 91 . V.M .C . MADEIRA, Biochem. Biop}tys . Acta 464:583-588 (1977) . 92 . V.M .C . MADEIRA, and M .C . ATUNES-MADEIRA, Biochem . Biophys . Res . Commun . 65 :997-1003 (1975) . 93 . M. MAKINOSE, and R. THE, Biochem. Z. 343 :383-393 (1965) . 94 . L . MARAI, and A. KUKSIS, Can. J . Biochem. 51 :1365-1379 (1973) . 95 . A. MARTONOSI, Fed . Proc . 23 :913-921 (1964) . 96 . A. MARTONOSI, FEBS Letters 47 :327-329 (1974) . 97 . L.P . MCCALLISTER, D.C . DAIELLO, and G .F .O . TYERS, J. Mol . Cell . Cardiol . 10 :67-80 (1978) . 98 . W.B : MCCOLLUM, JR ., H .R . BESCH, JR ., M .L . ENTMAN, and A. SCHWARTZ, Amer . J. Physiol . 223:608-618 (1972) . G . MEISSNER, Biothun . Biophys . Acta 389 :51-68 (1975) . 99 . 100 . W.L . MAYER, E .H . FISCHER, and E .G . KREBS, Biochem . 3 :1033 (1964) . 101 . F. MEYER, L.M .G . HEILMEYER, R.H . HASCHKE, and E .H . FISCHER, J. Biol . Chem . 245 :6642-6648 (1970) . 102 . M. MICHALAK, M.G . SARZALA, and W. DRABIKOWSKI, Acta Biochem . Polon . 24 :105-116 (1977) . 103 . B.M . MOORE, B .R . LENTZ, and G . MEISSNER, Biochem. 17 :5248-5255 (1978) . 104 . M. MORAD, and E.L . ROLETT, J. Physiol . 224:537-558 (1972) . 105 . A.J . MURPHY, Biochem . Bio h s . Res . Commun . 70 :160-166 (1976) . 106. Y. NAKAMARU, an A. SCHWARTZ, Biochem. Biophys . Res . Commun . 41 :830-836, (1970) . 107. K.E . NEET, and N .M . GREEN, Arch . Biochem . Bio h s . 178:588-597 (1977) . 108. S.H . ONG, and A.L . STEINER, Science 195 :183-l85'(977) . 109. K. OWENS, W.B . WEGLICKI, R .C . RUTH, A.C . STAM, and E .H . SONNENBLICK, Biochem. Biophys . Acta 296 :71-78 (1973) . 110. E . OZAWA, J . Biochem . 71 :321-331 (1972) . 111 . E . PAGE, and L.P . MCCALLISTER, Amer . J . Cardiol . 31 :172-181 (1973) . 112. R.F . PALMER, and V .A . POSEY, J . Gen . P ysiol . 50 :2085-2098 (1967) . 113. G .J . PARDOS, and T .L . LENTZ, Brain Res . 107 :355-364 (1976) . 114. B.J .R . PITTS, J . Biol . Chem . in press (1979) . 115. M. RABINOWITZ, L . DESALES, J . MEISLER, and L. LORAND, Biochem . Biophys . Acta 97 :29-36 (1965) . 116. D .G . RAIBLE, L.S . CUTLER, and G .A . RODAN, FEBS Letters 85 :149-152 (1978) . 117. B .V . RAMIREZ, and D. PETTE, FEBS Letters 49 :188-190 1974) . 118. H . REUTER, Circ . Res . 34 :599-605 (1974) . 119. T .L . RICH, and G.A . LANGER, J . Mol . Cell . Cardiol . 7 :747-765 (1975) . 120. B . ROSSI, F . D-A . LEONE, C. GASHE, and M. LAZDUNSKI, J . Biol . Chem . 254 :2302-2307 (1979) .

1200

121 . 122 . 123 . 124 . 125 . 126 . 127 . 128 . 129. 130 . 131 . 132 . 133 . 134 . 135 . 136 . 137 . 138 . 139 . 140 . 141 . 142 . 143 . 144 . 145 . 146. 147 . 148 . 149 150. 151 . 152 . 153 . 154 . 155 .

Cardiac and Skeletal SR

Vol . 25, No . 14, 1979

P .J . ST . LOUIS, and P .V . SULAKHE, Can . J . Biochem . 54 :946-956 (1976) . S . SALMONS, and F . SRETER, Nature 263 :30-34 1976) . S. SALMONS, D.R . GALE, and F .A . SRETER, J. Anat . 127 :17-31 (1978) . D . SCALES, and G . INESI, Biophys. J . 16 :735-751 (1976) . W. SCHULZE, E.-G . KRAUSE, and A . WOLLENBERGER, Adv . Cyclic Nucleo . Res . 1 :249-260 (1972) . W . SCHULZE, U. HINTERBERGER, E .-G . KRAUSE, and A. WOLLENBERGER, Ergibnisse Exp . Med. 28 :215-216 (1978) . A. SCHWARTZ, M.L . ENTMAN, K . KANIIKE, L .K . LANE, W.B . VAN WINKLE, and E .P . BORNET, Biochim . Biophys . Acta 426 :57-72 (1976) . M. SHIGEKAWA, J .-A.M . FINEGAN, and A.M . KATZ, J . Biol . Chem . 251 :68946900 (1976) . J . SLEZAK, and S .A . GELLER, J . Histochem . Cytochem . 27 :774-781 (1979) . F .A . SRETER, Exp . Neurol . 29 :52-64 (1970) . J .T . STULL, and S .E . MAYER, J . Biol . Chem . 246 :5716-5723 (1971) . M . SUMIDA, T . WANG, F . MANDEL, J .P . FROEHLICH, and A. SCHWARTZ, J . Biol . Chem . 253 :8772-8777 (1979) . M . TARA, M .A . KIRCHBERGER, D .I . REPKE, and A .M . KATZ, J . Biol . Chem . 249 :6174-6180 (1974) . M . TARA, M .A . KIRCHBERGER, and A .M . KATZ, J . Biol . Chem . 250:2640-2647 (1975) . M . TADA, F. OHMORI, N . KINOSHITA, and H. ABE, Adv . Cyclic Nucleo . Res . 9 :355-369 (1977) . M. TADA, T. YAMAMOTO, and Y . TONOMURA, Physiol . Rev . 58 :1-79 (1978) . M . TADA, F . OHMORI, M . YAMADO, and H. ABE, J . Biol . Chem . 254 :319-326 (1979) . A. TAKAGI, D .L . SCHOTLAND, and L.P . ROWLAND, Arch . Neurol . 28 :380-384 (1973) . C.A . TATE, W .B . VAN WINKLE, and M .L . ENTMAN, Circ . Res . 58(II) :54 (1978) . R.J . TOMANEK, J. Ultrastruc . Res . 55 :212-227 (1§-7-6T. A. TUDOR WINN-WILLIAMS, Biochem. J . 157 :279-281 (1976) . W.B . VAN WINKLE, Science 193 :1130-1131 (1976) . W.B . VAN WINKLE, M.L . ENTMAN, E .P . BORNET, and A . SCHWARTZ, J . Cell . Physiol . 97 :121-136 (1978) . W.B . VAN WINKLE, and A. SCHWARTZ, J . Cell . Physiol . 97 :99-119 (1978) . W .B . VAN WINKLE, and M.L . ENTMAN, Fed. Proc . 38 :1516 (1979) . S . VERJOVSKI-ALMEIDA, M . KURZMACK, and G. INESI, Biochem. 17 :5006-5013 (1978) . S . VERJOVSKI-ALMEIDA, and G . INESI, J . Biol . Chem . 254 :18-21 (1979) . J .-C . WANSON, and P . DROCHMANS, J . Cell Biol . 54 :206-224 (1972) . G.B . WARREN, P .A . TOON, N .J .M . BIRDSALL, A.G . LEE, and J .C . METCALFE, Proc . Nat'l . Acad . Sci. (U .S .A .) 71 :622-626 (1974) . G .B . WARREN, and J .C . METCALFE, Biochem. Soc . Trans . 5 :517-520 (1977) . A.G . WEEDS, D .R . TRENTHAM, C .J .C . KEAN, and A.J . BULLER, Nature 247 :135139 (1974) . W.B . WEGLICKI, JR ., A.C . STAM, JR ., and E .H . SONNENBLICK, J . Mol . Cell . Cardiol . 1 :131-142 (1970) . H.L . WRAY, R .R . GRAY, and R .A . OLSSON, J . Biol . Chem . 248 :1496-1498 (1973) . H.L . WRAY, and R .R . GRAY, Biochim . Biophys . Acta 461 :441-459 (1977) . T . YAMAMOTO, and Y . TONOMURA, J . Biochem . 62 :558-578 (1967) .