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• W2023974577 abstract "The control of resting free Ca2+ in skeletal muscle is thought to be a balance of channels, pumps, and exchangers in both the sarcolemma and sarcoplasmic reticulum. We explored these mechanisms using pharmacologic and molecular perturbations of genetically engineered (dyspedic) muscle cells that constitutively lack expression of the skeletal muscle sarcoplasmic reticulum Ca2+ release channels, RyR1 and RyR3. We demonstrate here that expression of RyR1 is responsible for more than half of total resting Ca2+ concentration ([Ca2+]rest) measured in wild type cells. The elevated [Ca2+]rest in RyR1-expressing cells is not a result of active gating of the RyR1 channel but instead is accounted for by the RyR1 ryanodine-insensitive Ca2+ leak conformation. In addition, we demonstrate that basal sarcolemmal Ca2+ influx is also governed by RyR1 expression and contributes in the regulation of [Ca2+]rest in skeletal myotubes. The control of resting free Ca2+ in skeletal muscle is thought to be a balance of channels, pumps, and exchangers in both the sarcolemma and sarcoplasmic reticulum. We explored these mechanisms using pharmacologic and molecular perturbations of genetically engineered (dyspedic) muscle cells that constitutively lack expression of the skeletal muscle sarcoplasmic reticulum Ca2+ release channels, RyR1 and RyR3. We demonstrate here that expression of RyR1 is responsible for more than half of total resting Ca2+ concentration ([Ca2+]rest) measured in wild type cells. The elevated [Ca2+]rest in RyR1-expressing cells is not a result of active gating of the RyR1 channel but instead is accounted for by the RyR1 ryanodine-insensitive Ca2+ leak conformation. In addition, we demonstrate that basal sarcolemmal Ca2+ influx is also governed by RyR1 expression and contributes in the regulation of [Ca2+]rest in skeletal myotubes. IntroductionIn skeletal muscle active Ca2+ efflux from the sarcoplasmic reticulum (SR) 2The abbreviations used are: SRsarcoplasmic reticulumDHPRdihydropyridine receptorRyryanodine[Ca2+]restresting Ca2+ concentrationB5bastadin 5NullRyRRyR-nullWtwild typeSERCASR Ca2+-ATPasePMCAplasma membrane sarcolemmal Ca2+-ATPaseNCXNa+-Ca2+ exchanger. occurs fundamentally through RyR1 via an orthograde signal from DHPR. In the absence of stimuli the open probability of RyR1 is very low, and [Ca2+]rest is maintained near 100 nm in frog (1López J.R. Alamo L. Caputo C. DiPolo R. Vergara S. Biophys. J. 1983; 43: 1-4Abstract Full Text PDF PubMed Scopus (71) Google Scholar), mammalian (2López J.R. Linares N. Pessah I.N. Allen P.D. Am. J. Physiol. Cell Physiol. 2005; 288: C606-C612Crossref PubMed Scopus (28) Google Scholar), and human skeletal muscle (3López J.R. Medina P. Alamo L. Muscle Nerve. 1987; 10: 77-79Crossref PubMed Scopus (19) Google Scholar) and in mammalian skeletal myotubes (4Yang T. Esteve E. Pessah I.N. Molinski T.F. Allen P.D. López J.R. Am. J. Physiol. Cell Physiol. 2007; 292: C1591-C1598Crossref PubMed Scopus (54) Google Scholar). This stems from the fact that in the absence of depolarization, the DHPR appears to suppress spontaneous RyR1 activity (5Ward C.W. Protasi F. Castillo D. Wang Y. Chen S.R. Pessah I.N. Allen P.D. Schneider M.F. Biophys. J. 2001; 81: 3216-3230Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar, 6Ward C.W. Schneider M.F. Castillo D. Protasi F. Wang Y. Chen S.R. Allen P.D. J. Physiol. 2000; 525: 91-103Crossref PubMed Scopus (45) Google Scholar) as evidenced higher RyR1 activity in mdg myotubes that lack expression of the α1s-DHPR (7Lee E.H. Lopez J.R. Li J. Protasi F. Pessah I.N. Kim D.H. Allen P.D. Am. J. Physiol. Cell Physiol. 2004; 286: C179-C189Crossref PubMed Scopus (34) Google Scholar, 8Zhou J. Yi J. Royer L. Launikonis B.S. González A. Garcia J. Ríos E. Am. J. Physiol. Cell Physiol. 2006; 290: C539-C553Crossref PubMed Scopus (62) Google Scholar).In addition to the “classical” release pathway mediated by RyR1 activation, at rest there is ample evidence for the existence of a second less defined SR Ca2+ efflux pathway that has been referred to as ryanodine (Ry)-insensitive “Ca2+ leak” (4Yang T. Esteve E. Pessah I.N. Molinski T.F. Allen P.D. López J.R. Am. J. Physiol. Cell Physiol. 2007; 292: C1591-C1598Crossref PubMed Scopus (54) Google Scholar, 9Masuno M.N. Pessah I.N. Olmstead M.M. Molinski T.F. J. Med. Chem. 2006; 49: 4497-4511Crossref PubMed Scopus (26) Google Scholar, 10Pessah I.N. Molinski T.F. Meloy T.D. Wong P. Buck E.D. Allen P.D. Mohr F.C. Mack M.M. Am. J. Physiol. Cell Physiol. 1997; 272: C601-C614Crossref PubMed Google Scholar). This Ca2+ leak can be broadly defined as a passive efflux of Ca2+ from the SR under resting or quiescent conditions. Part if not all of the Ry-insensitive Ca2+ leak pathway has been proposed to represent a conformation of RyR1 with a low conductance that is constitutively open (PO∼1) and represents a distinct conformation from that of actively gated RyR1 channels involved in excitation contraction coupling (4Yang T. Esteve E. Pessah I.N. Molinski T.F. Allen P.D. López J.R. Am. J. Physiol. Cell Physiol. 2007; 292: C1591-C1598Crossref PubMed Scopus (54) Google Scholar, 10Pessah I.N. Molinski T.F. Meloy T.D. Wong P. Buck E.D. Allen P.D. Mohr F.C. Mack M.M. Am. J. Physiol. Cell Physiol. 1997; 272: C601-C614Crossref PubMed Google Scholar). It has been shown that Ry-insensitive Ca2+ leaks may contribute significantly to SR Ca2+ loading capacity and that they may have a significant contribution to regulation of [Ca2+]rest in skeletal muscle. If this is correct, then RyR1 leak may have relevance in physiological and pathological regulation of muscle Ca2+ homeostasis.Macrocyclic bastadins isolated from the marine sponge Lanthella basta are novel modulators of RyR1. Bastadin 5 (B5) has been shown to prolong dramatically both open and closed time constants of single RyR1 channels reconstituted in bilayer lipid membranes without changing their unitary conductance or overall open probability (11Mack M.M. Molinski T.F. Buck E.D. Pessah I.N. J. Biol. Chem. 1994; 269: 23236-23249Abstract Full Text PDF PubMed Google Scholar). Importantly, under conditions where RyR1 channels are pharmacologically blocked (with micromolar ryanodine or ruthenium red) both B5 and its related congener bastadin 10 have been shown to increase significantly the Ca2+ loading capacity in SR vesicles and increase the capacity of SR membranes to bind [3H]Ry ∼4-fold (Bmax) (10Pessah I.N. Molinski T.F. Meloy T.D. Wong P. Buck E.D. Allen P.D. Mohr F.C. Mack M.M. Am. J. Physiol. Cell Physiol. 1997; 272: C601-C614Crossref PubMed Google Scholar).We hypothesized that expression of RyR1 in RyR-null (NullRyR) myotubes would increase [Ca2+]rest and that this increase would be secondary to passive Ca2+ efflux from SR stores mediated by Ry-insensitive Ca2+ leak. As expected, expression of RyR1 in NullRyR myotubes increased [Ca2+]rest to concentrations typically found in wild type myotubes, and complete blockade of caffeine sensitive RyR1 Ca2+ release by ryanodine did not modify [Ca2+]rest levels. When B5 was added to examine the contribution of RyR1 leaks toward the [Ca2+]rest, we found that Ry+B5 in combination reduced resting [Ca2+]rest to essentially dyspedic levels in RyR1-expressing cells, but had no effect in NullRyR cells. [Ca2+]rest was further reduced when Ry+B5-pretreated NullRyR and wild type (WtRyR) myotubes were exposed to low external Ca2+ solution. Similar results were obtained in primary myotubes generated from RyR1/3-null dyspedic mice and their wild type littermates. These results show that a fraction of RyR1 within the SR membrane exists in a Ry-insensitive conformation that mediates Ca2+ leak that determines [Ca2+]rest levels in skeletal muscle. In addition, RyR1 expression also regulates basal sarcolemmal Ca2+ influx, which also contributes to [Ca2+]rest in skeletal myotubes.DISCUSSIONThe purpose of this study was to examine whether the expression of RyR1 has any effect on [Ca2+]rest, the resting Ca2+ entry, and SR Ca2+ loading in skeletal muscle. Our study demonstrates that expression of WtRyR1 is associated with a significant increase in [Ca2+]rest, in resting Ca2+ entry, with no significant change in SR Ca2+ loading compared with NullRyR myotubes. The fact that we observed the same results with RyR1-transduced 1B5 myotubes and in primary myotubes rules out the possibility that the observed difference in [Ca2+]rest was related to overexpression of RyR1 when the differentiated myotubes were transduced with virion particles containing wild type RyR1 cDNA. A significant part of this elevation in [Ca2+]rest appears to be related to the presence of RyR1 leaks because Ry+B5 was able to reduce [Ca2+]rest to levels similar to those observed in NullRyR myotubes. In addition, our results show clearly that extracellular Ca2+ also plays an important role in maintaining [Ca2+]rest at physiological levels.From these results it is clear that in addition to the control of well known intracellular Ca2+ regulatory mechanisms (PMCA, NCX, SERCA) on steady-state [Ca2+]rest in skeletal muscle a significant portion of [Ca2+]rest is also set by passive Ca2+ release, which appears to be the result of a fraction of WtRyR1s within SR that are in a Ry-insensitive Ca2+ leak conformation and by the Ca2+ influx via the sarcolemma that is modulated by the presence of RyR1. In fact, the combined effect of expression of RyR1 elevated the [Ca2+]rest by ∼2-fold. The precise mechanism underlying how RyR1 leaks and the expression of the RyR1 lead to a chronic elevation [Ca2+]rest needs further study. If RyR1 leak exceeds Ca2+ uptake by the SR and extrusion by sarcolemmal mechanisms, a new dynamic equilibrium of Ca2+ mobilization must be established that allows the higher [Ca2+]rest. If the currently proposed mechanism that Ca2+extrusion processes of the plasma membrane (PMCA, SERCA, and NCX) control [Ca2+]rest they should be stimulated by elevations in resting [Ca2+]i, and in the steady state, such as those defined by our experimental conditions, these transport mechanisms should be sufficient to compensate for the increased Ca2+ leak/sarcolemmal Ca2+ entry, resulting in a return of [Ca2+]rest toward that measured in NullRyR myotubes. Because this does not happen, then the changes in [Ca2+]rest observed with the expression of RyR1 must involve a modification of the set points of the activity of both SERCA and these sarcolemmal Ca2+ transport mechanisms and/or the amount of expression of such proteins at the SR and plasma membrane. In fact, it was found that expression of RyR1 was accompanied by an increase in the expression of PMCA and a decreased expression of NCX3 and SERCA, all of them linked to the regulation of intracellular [Ca2+]. As modeled in Fig. 8, the decreased expression of SERCA, an increased expression of PMCA, elevated resting Ca2+ entry, and an elevated cytoplasmic Ca2+ are the costs for expressing RyR1 and maintaining SR stores at levels equal to that found in dyspedic cells. One explanation is that RyR1-expressing cells down-regulate SERCA as a compensatory adaptation to limit the consumption of ATP that would be needed to offset RyR1-mediated Ca2+ leak from SR. If the level of SERCA expression was maintained in the face of a sizable Ca2+ leak, futile cycling of Ca2+ between the SR lumen and the extracellular space would come at a great energy cost. Conversely, dyspedic cells express higher levels of SERCA because without the RyR1 Ca2+ leak there is a reduced energy cost. One intriguing discovery in the present study is that RyR1 expression appears to confer significant regulation of the density of SERCA protein found in SR membranes. These results are consistent with previous findings that indicated up-regulation of SERCA levels in skeletal muscle membranes isolated from dyspedic mice compared with those isolated from wild type (Fig. 6 in Ref. 24Buck E.D. Nguyen H.T. Pessah I.N. Allen P.D. J. Biol. Chem. 1997; 272: 7360-7367Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar).Second, the higher PMCA expression could help offset decreased rates of Ca2+ transient recovery (relaxation) in light of lower SERCA capacity by removing a larger fraction of released Ca2+ during excitation to the extracellular space. Why NCX protein is down-regulated and how it contributes to maintenance of resting Ca2+ are unclear.B5, through its modulatory actions on the FKBP12·RyR1 complex, has been previously shown to increase SR Ca2+ loading capacity and concomitantly attenuate RyR1 Ca2+ leak. This property of the bastadins is the result of their ability to convert Ry-insensitive leak states (RyR1 leak) into ryanodine-sensitive channels (RyR1 Ca2+ channels) (10Pessah I.N. Molinski T.F. Meloy T.D. Wong P. Buck E.D. Allen P.D. Mohr F.C. Mack M.M. Am. J. Physiol. Cell Physiol. 1997; 272: C601-C614Crossref PubMed Google Scholar) and is demonstrated by their ability to increase Bmax of Ry binding/mg of protein (10Pessah I.N. Molinski T.F. Meloy T.D. Wong P. Buck E.D. Allen P.D. Mohr F.C. Mack M.M. Am. J. Physiol. Cell Physiol. 1997; 272: C601-C614Crossref PubMed Google Scholar). Therefore, in the present study B5 was used to examine the relationship between Ry-sensitive and Ry-insensitive Ca2+ efflux pathways that coexist in the SR of WtRyR1-expressing myotubes. We found that B5 in combination with blocking concentrations of Ry decreased [Ca2+]rest in WtRyR-expressing myotubes by 43% but had no effect in NullRyR myotubes. These data are consistent with the hypothesis that bastadins can promote the conversion of RyR1 in the Ry-insensitive Ca2+ leak conformation into Ry-sensitive RyR1 channels. B5 alone, also reduced [Ca2+]rest in WtRyR1-expressing myotubes but to a lesser degree (25%) compared with its effect in combination with Ry (43%) probably because the RyR1 leaks converted into gating channels do not have the same degree of negative control by the DHPR as normal gating channels.Another interesting result is that the resting Ca2+ entry is greater in WtRyR than NullRyR myotubes, suggesting that the magnitude of this entry is modulated by the presence of RyR1. The physiological role of this resting Ca2+ entry is poorly understood, but appears to be independent of resting membrane potential (myotubes polarized based on the Nernst equation for 23 °C) and/or the degree of SR depletion as we showed in Fig. 6, as has been postulated by Kurebayashi and Ogawa (25Kurebayashi N. Ogawa Y. J. Physiol. 2001; 533: 185-199Crossref PubMed Scopus (236) Google Scholar), since the experiments were conducted in unstimulated myotubes.The existence of a RyR1-mediated Ca2+ leak pathway in the SR may have some implications for the pathophysiology of two well characterized disorders of skeletal muscle, malignant hyperthermia and central core disease. In muscle cells from the majority of patients with either disorder, there is a global elevation of [Ca2+]rest, which can be partially reversed by treating the muscle cells with B5 in combination with blocking concentrations of Ry (4Yang T. Esteve E. Pessah I.N. Molinski T.F. Allen P.D. López J.R. Am. J. Physiol. Cell Physiol. 2007; 292: C1591-C1598Crossref PubMed Scopus (54) Google Scholar). In summary, our results demonstrate that that expression of WtRyR1 is associated with an increase in [Ca2+]rest and that in addition to traditionally proposed mechanisms involving SERCA, NCX, and PMCA, [Ca2+]rest in skeletal muscle is determined in part by passive Ca2+ leak through WtRyR1 and increased basal sarcolemmal Ca2+ entry. IntroductionIn skeletal muscle active Ca2+ efflux from the sarcoplasmic reticulum (SR) 2The abbreviations used are: SRsarcoplasmic reticulumDHPRdihydropyridine receptorRyryanodine[Ca2+]restresting Ca2+ concentrationB5bastadin 5NullRyRRyR-nullWtwild typeSERCASR Ca2+-ATPasePMCAplasma membrane sarcolemmal Ca2+-ATPaseNCXNa+-Ca2+ exchanger. occurs fundamentally through RyR1 via an orthograde signal from DHPR. In the absence of stimuli the open probability of RyR1 is very low, and [Ca2+]rest is maintained near 100 nm in frog (1López J.R. Alamo L. Caputo C. DiPolo R. Vergara S. Biophys. J. 1983; 43: 1-4Abstract Full Text PDF PubMed Scopus (71) Google Scholar), mammalian (2López J.R. Linares N. Pessah I.N. Allen P.D. Am. J. Physiol. Cell Physiol. 2005; 288: C606-C612Crossref PubMed Scopus (28) Google Scholar), and human skeletal muscle (3López J.R. Medina P. Alamo L. Muscle Nerve. 1987; 10: 77-79Crossref PubMed Scopus (19) Google Scholar) and in mammalian skeletal myotubes (4Yang T. Esteve E. Pessah I.N. Molinski T.F. Allen P.D. López J.R. Am. J. Physiol. Cell Physiol. 2007; 292: C1591-C1598Crossref PubMed Scopus (54) Google Scholar). This stems from the fact that in the absence of depolarization, the DHPR appears to suppress spontaneous RyR1 activity (5Ward C.W. Protasi F. Castillo D. Wang Y. Chen S.R. Pessah I.N. Allen P.D. Schneider M.F. Biophys. J. 2001; 81: 3216-3230Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar, 6Ward C.W. Schneider M.F. Castillo D. Protasi F. Wang Y. Chen S.R. Allen P.D. J. Physiol. 2000; 525: 91-103Crossref PubMed Scopus (45) Google Scholar) as evidenced higher RyR1 activity in mdg myotubes that lack expression of the α1s-DHPR (7Lee E.H. Lopez J.R. Li J. Protasi F. Pessah I.N. Kim D.H. Allen P.D. Am. J. Physiol. Cell Physiol. 2004; 286: C179-C189Crossref PubMed Scopus (34) Google Scholar, 8Zhou J. Yi J. Royer L. Launikonis B.S. González A. Garcia J. Ríos E. Am. J. Physiol. Cell Physiol. 2006; 290: C539-C553Crossref PubMed Scopus (62) Google Scholar).In addition to the “classical” release pathway mediated by RyR1 activation, at rest there is ample evidence for the existence of a second less defined SR Ca2+ efflux pathway that has been referred to as ryanodine (Ry)-insensitive “Ca2+ leak” (4Yang T. Esteve E. Pessah I.N. Molinski T.F. Allen P.D. López J.R. Am. J. Physiol. Cell Physiol. 2007; 292: C1591-C1598Crossref PubMed Scopus (54) Google Scholar, 9Masuno M.N. Pessah I.N. Olmstead M.M. Molinski T.F. J. Med. Chem. 2006; 49: 4497-4511Crossref PubMed Scopus (26) Google Scholar, 10Pessah I.N. Molinski T.F. Meloy T.D. Wong P. Buck E.D. Allen P.D. Mohr F.C. Mack M.M. Am. J. Physiol. Cell Physiol. 1997; 272: C601-C614Crossref PubMed Google Scholar). This Ca2+ leak can be broadly defined as a passive efflux of Ca2+ from the SR under resting or quiescent conditions. Part if not all of the Ry-insensitive Ca2+ leak pathway has been proposed to represent a conformation of RyR1 with a low conductance that is constitutively open (PO∼1) and represents a distinct conformation from that of actively gated RyR1 channels involved in excitation contraction coupling (4Yang T. Esteve E. Pessah I.N. Molinski T.F. Allen P.D. López J.R. Am. J. Physiol. Cell Physiol. 2007; 292: C1591-C1598Crossref PubMed Scopus (54) Google Scholar, 10Pessah I.N. Molinski T.F. Meloy T.D. Wong P. Buck E.D. Allen P.D. Mohr F.C. Mack M.M. Am. J. Physiol. Cell Physiol. 1997; 272: C601-C614Crossref PubMed Google Scholar). It has been shown that Ry-insensitive Ca2+ leaks may contribute significantly to SR Ca2+ loading capacity and that they may have a significant contribution to regulation of [Ca2+]rest in skeletal muscle. If this is correct, then RyR1 leak may have relevance in physiological and pathological regulation of muscle Ca2+ homeostasis.Macrocyclic bastadins isolated from the marine sponge Lanthella basta are novel modulators of RyR1. Bastadin 5 (B5) has been shown to prolong dramatically both open and closed time constants of single RyR1 channels reconstituted in bilayer lipid membranes without changing their unitary conductance or overall open probability (11Mack M.M. Molinski T.F. Buck E.D. Pessah I.N. J. Biol. Chem. 1994; 269: 23236-23249Abstract Full Text PDF PubMed Google Scholar). Importantly, under conditions where RyR1 channels are pharmacologically blocked (with micromolar ryanodine or ruthenium red) both B5 and its related congener bastadin 10 have been shown to increase significantly the Ca2+ loading capacity in SR vesicles and increase the capacity of SR membranes to bind [3H]Ry ∼4-fold (Bmax) (10Pessah I.N. Molinski T.F. Meloy T.D. Wong P. Buck E.D. Allen P.D. Mohr F.C. Mack M.M. Am. J. Physiol. Cell Physiol. 1997; 272: C601-C614Crossref PubMed Google Scholar).We hypothesized that expression of RyR1 in RyR-null (NullRyR) myotubes would increase [Ca2+]rest and that this increase would be secondary to passive Ca2+ efflux from SR stores mediated by Ry-insensitive Ca2+ leak. As expected, expression of RyR1 in NullRyR myotubes increased [Ca2+]rest to concentrations typically found in wild type myotubes, and complete blockade of caffeine sensitive RyR1 Ca2+ release by ryanodine did not modify [Ca2+]rest levels. When B5 was added to examine the contribution of RyR1 leaks toward the [Ca2+]rest, we found that Ry+B5 in combination reduced resting [Ca2+]rest to essentially dyspedic levels in RyR1-expressing cells, but had no effect in NullRyR cells. [Ca2+]rest was further reduced when Ry+B5-pretreated NullRyR and wild type (WtRyR) myotubes were exposed to low external Ca2+ solution. Similar results were obtained in primary myotubes generated from RyR1/3-null dyspedic mice and their wild type littermates. These results show that a fraction of RyR1 within the SR membrane exists in a Ry-insensitive conformation that mediates Ca2+ leak that determines [Ca2+]rest levels in skeletal muscle. In addition, RyR1 expression also regulates basal sarcolemmal Ca2+ influx, which also contributes to [Ca2+]rest in skeletal myotubes." @default.
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• W2023974577 title "RyR1-mediated Ca2+ Leak and Ca2+ Entry Determine Resting Intracellular Ca2+ in Skeletal Myotubes" @default.
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