scholarly journals Increased sensitivity of the ryanodine receptor to halothane-induced oligomerization in malignant hyperthermia-susceptible human skeletal muscle

2004 ◽  
Vol 96 (1) ◽  
pp. 11-18 ◽  
Author(s):  
Louise Glover ◽  
James J. A. Heffron ◽  
Kay Ohlendieck
Keyword(s):  
Skeletal Muscle ◽  
Sarcoplasmic Reticulum ◽  
Malignant Hyperthermia ◽  
Ryanodine Receptor ◽  
Human Skeletal Muscle ◽  
Dihydropyridine Receptor ◽  
Threshold Concentration ◽  
Release Channel ◽  
Functional Dynamics ◽  
Increased Sensitivity

Mutations in the skeletal muscle RyR1 isoform of the ryanodine receptor (RyR) Ca2+-release channel confer susceptibility to malignant hyperthermia, which may be triggered by inhalational anesthetics such as halothane. Using immunoblotting, we show here that the ryanodine receptor, calmodulin, junctin, calsequestrin, sarcalumenin, calreticulin, annexin-VI, sarco(endo)plasmic reticulum Ca2+-ATPase, and the dihydropyridine receptor exhibit no major changes in their expression level between normal human skeletal muscle and biopsies from individuals susceptible to malignant hyperthermia. In contrast, protein gel-shift studies with halothane-treated sarcoplasmic reticulum vesicles from normal and susceptible specimens showed a clear difference. Although the α2-dihydropyridine receptor and calsequestrin were not affected, clustering of the Ca2+-ATPase was induced at comparable halothane concentrations. In the concentration range of 0.014–0.35 mM halothane, anesthetic-induced oligomerization of the RyR1 complex was observed at a lower threshold concentration in the sarcoplasmic reticulum from patients with malignant hyperthermia. Thus the previously described decreased Ca2+-loading ability of the sarcoplasmic reticulum from susceptible muscle fibers is probably not due to a modified expression of Ca2+-handling elements, but more likely a feature of altered quaternary receptor structure or modified functional dynamics within the Ca2+-regulatory apparatus. Possibly increased RyR1 complex formation, in conjunction with decreased Ca2+ uptake, is of central importance to the development of a metabolic crisis in malignant hyperthermia.

Altered binding site for Ca2+ in the ryanodine receptor of human malignant hyperthermia

1991 ◽  
Vol 261 (2) ◽  
pp. C237-C245 ◽  
Author(s):  
H. H. Valdivia ◽  
K. Hogan ◽  
R. Coronado
Keyword(s):  
Skeletal Muscle ◽  
Malignant Hyperthermia ◽  
Binding Site ◽  
Ryanodine Receptor ◽  
Human Skeletal Muscle ◽  
Scatchard Analysis ◽  
Dependent Manner ◽  
Binding Properties ◽  
Release Channel ◽  
Planar Bilayers

The binding properties of [3H]ryanodine, a specific ligand of the receptor complex that forms the Ca2+ release channel of sarcoplasmic reticulum, were studied in normal (N) and malignant hyperthermia-susceptible (MH) human skeletal muscle. Integrity of the solubilized ryanodine receptor was demonstrated by single-channel recordings in planar bilayers and by the changes produced by activators and inhibitors of the Ca2+ release channel on the binding properties of [3H]ryanodine. N and MH receptors were capable of binding [3H]ryanodine in a Ca(2+)-dependent manner. Scatchard analysis showed that a single binding site for [3H]ryanodine was present in either N or MH muscle. Binding affinity was approximately the same in N and MH (Kd approximately 7 nM), when the Ca2+ concentration was greater than 30 microM. At 0.3 microM Ca2+, MH receptors displayed a higher affinity for [3H]ryanodine (Kd = 4.1 +/- 1.0 nM) than N receptors (Kd = 7.1 +/- 0.8 nM). The presence of a single Kd for [3H]ryanodine in MH muscle, distinct from that of N muscle, indicated that MH muscle does not have detectable levels of N receptors. Ca2+ dependence of [3H]ryanodine binding further suggested that MH receptors had a higher affinity for Ca2+ (Kd[Ca2+] = 120 +/- 50 nM) than N receptors (Kd[Ca2+] = 250 +/- 80 nM). Caffeine increased [3H]ryanodine binding at submicromolar [Ca2+], and the effect was larger in MH. Apparent affinity constants for caffeine were 13 +/- 1.8 mM in N and 6 +/- 0.8 mM in MH receptors. Evidently, the ryanodine receptor of MH-susceptible human skeletal muscle has an unusually high sensitivity to Ca2+ which is augmented by caffeine.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Complex interactions between skeletal muscle ryanodine receptor and dihydropyridine receptor proteins

1998 ◽  
Vol 76 (5) ◽  
pp. 681-694 ◽  
Author(s):  
Peng Leong ◽  
David H MacLennan
Keyword(s):  
Skeletal Muscle ◽  
Sarcoplasmic Reticulum ◽  
Ryanodine Receptor ◽  
Dihydropyridine Receptor ◽  
Release Channel ◽  
Excitation Contraction Coupling ◽  
Receptor Proteins ◽  
Contraction Coupling ◽  
Experimental Systems ◽  
Complex Interactions

Evidence for functional interactions between the Ca2+ release channel in the skeletal muscle sarcoplasmic reticulum (the ryanodine receptor) and the L-type Ca2+ channel in the sarcolemma (the dihydropyridine receptor), leading to excitation-contraction coupling, is reviewed and experimental systems used to identify candidate sites of interaction are outlined.Key words: sarcoplasmic reticulum, excitation-contraction coupling.

Dihydropyridine receptor-ryanodine receptor interactions in skeletal muscle excitation-contraction coupling

1995 ◽  
Vol 15 (5) ◽  
pp. 399-408 ◽  
Author(s):  
Gerhard Meissner ◽  
Xiangyang Lu
Keyword(s):  
Skeletal Muscle ◽  
Sarcoplasmic Reticulum ◽  
Ryanodine Receptor ◽  
Protein Interactions ◽  
Dihydropyridine Receptor ◽  
Coupling Mechanism ◽  
Protein Protein Interactions ◽  
Release Channel ◽  
Mechanical Coupling ◽  
Subsequent Step

Much recent progress has been made in our understanding of the mechanism of sarcoplasmic reticulum Ca2+ release in skeletal muscle. Vertebrate skeletal muscle excitation-contraction (E-C) coupling is thought to occur by a “mechanical coupling”� mechanism involving protein-protein interactions that lead to activation of the sarcoplasmic reticulum (SR) ryanodine receptor (RyR)/Ca2+ release channel by the voltage-sensing transverse (T−) tubule dihydropyridine receptor (DHPR)/Ca2+ channel. In a subsequent step, the released Ca2+ amplify SR Ca2+ release by activating release channels that are not linked to the DHPR. Experiments with mutant muscle cells have indicated that skeletal muscle specific DHPR and RyR isoforms are required for skeletal muscle E-C coupling. A direct functional and structural interaction between a DHPR-derived peptide and the RyR has been described. The interaction between the DHPR and RyR may be stabilized by other proteins such as triadin (a SR junctional protein) and modulated by phosphorylation of the DHPR.

Effects of Propofol on Calcium sup 2+ Regulation by Malignant Hyperthermia-susceptible Muscle Membranes 

1995 ◽  
Vol 82 (5) ◽  
pp. 1274-1282 ◽  
Author(s):  
Bradley R. Fruen ◽  
James R. Mickelson ◽  
Timothy J. Roghair ◽  
Lynn A. Litterer ◽  
Charles F. Louis
Keyword(s):  
Skeletal Muscle ◽  
Sarcoplasmic Reticulum ◽  
Malignant Hyperthermia ◽  
Ryanodine Receptor ◽  
Membrane Vesicles ◽  
Dihydropyridine Receptor ◽  
Muscle Membrane ◽  
Inhalation Anesthetics ◽  
Transverse Tubule ◽  
Malignant Hyperthermia Susceptible

Background The effects of inhalation anesthetics on Ca2+ regulation in malignant hyperthermia-susceptible skeletal muscle are considered to be responsible for triggering malignant hyperthermia. The intravenous anesthetic propofol does not trigger malignant hyperthermia in susceptible patients or experimental animals, suggesting that there are important differences between the effects of propofol and the effects of inhalation anesthetics on Ca2+ regulation in malignant hyperthermia-susceptible muscle. Understanding these differences may help to clarify the mechanisms responsible for triggering malignant hyperthermia. Methods To investigate the effects of propofol on Ca2+ regulation by malignant hyperthermia-susceptible skeletal muscle, we determined its effects on the membrane channels and pumps that control myoplasmic Ca2+ concentrations: the sarcoplasmic reticulum ryanodine receptor, the transverse tubule dihydropyridine receptor, and the sarcoplasmic reticulum Ca(2+)-adenosine triphosphatase (Ca(2+)-ATPase). Terminal cisternae-derived sarcoplasmic reticulum vesicles enriched in the junctional proteins of the sarcoplasmic reticulum and the transverse tubule membranes were isolated from the muscle of malignant hyperthermia-susceptible and normal pigs. Ca2+ flux, Ca(2+)-ATPase, and ligand binding measurements on these isolated vesicle preparations were performed in the presence of varying propofol concentrations. Results Propofol (10-500 microM) had no effect on ryanodine receptor-mediated Ca2+ efflux from muscle membrane vesicles. Propofol (1-100 microM) also had no effect on sarcoplasmic reticulum vesicle [3H]ryanodine binding, whereas higher concentrations (200-300 microM) slightly inhibited [3H]ryanodine binding. Binding of the dihydropyridine receptor Ca2+ channel blocker [3H]PN200-110 to these preparations was inhibited by propofol (10-300 microM). Ca(2+)-ATPase activity was stimulated by 10-100 microM propofol but was inhibited by higher concentrations. In all cases, the effects of propofol on malignant hyperthermia-susceptible and normal membrane preparations were similar. Conclusions In contrast to malignant hyperthermia-triggering inhalation anesthetics, propofol does not stimulate malignant hyperthermia-susceptible or normal ryanodine receptor channel activity, even at > 100 times clinical concentrations. Effects on dihydropyridine receptor and Ca(2+)-ATPase function, however, are similar to the effects of inhalation anesthestics and require much lower concentrations of propofol. These findings, demonstrating that propofol does not activate ryanodine receptor Ca2+ channels, suggest a plausible explanation for why propofol does not trigger malignant hyperthermia in susceptible persons.

Interaction of Bupivacaine and Tetracaine with the Sarcoplasmic Reticulum Ca2+Release Channel of Skeletal and Cardiac Muscles 

1999 ◽  
Vol 90 (3) ◽  
pp. 835-843 ◽  
Author(s):  
Hirochika Komai ◽  
Andrew J. Lokuta
Keyword(s):  
Skeletal Muscle ◽  
Sarcoplasmic Reticulum ◽  
Cardiac Muscle ◽  
Ryanodine Receptor ◽  
Local Anesthetic ◽  
Local Anesthetics ◽  
Specific Effect ◽  
Receptor Activity ◽  
Maximal Inhibition ◽  
Release Channel

Background Although various local anesthetics can cause histologic damage to skeletal muscle when injected intramuscularly, bupivacaine appears to have an exceptionally high rate of myotoxicity. Research has suggested that an effect of bupivacaine on sarcoplasmic reticulum Ca2+ release is involved in its myotoxicity, but direct evidence is lacking. Furthermore, it is not known whether the toxicity depends on the unique chemical characteristics of bupivacaine and whether the toxicity is found only in skeletal muscle. Methods The authors studied the effects of bupivacaine and the similarly lipid-soluble local anesthetic, tetracaine, on the Ca2+ release channel-ryanodine receptor of sarcoplasmic reticulum in swine skeletal and cardiac muscle. [3H]Ryanodine binding was used to measure the activity of the Ca2+ release channel-ryanodine receptors in microsomes of both muscles. Results Bupivacaine enhanced (by two times at 5 mM) and inhibited (66% inhibition at 10 mM) [3H]ryanodine binding to skeletal muscle microsomes. In contrast, only inhibitory effects were observed with cardiac microsomes (about 3 mM for half-maximal inhibition). Tetracaine, which inhibits [3H]ryanodine binding to skeletal muscle microsomes, also inhibited [3H]ryanodine binding to cardiac muscle microsomes (half-maximal inhibition at 99 microM). Conclusions Bupivacaine's ability to enhance Ca2+ release channel-ryanodine receptor activity of skeletal muscle sarcoplasmic reticulum most likely contributes to the myotoxicity of this local anesthetic. Thus, the pronounced myotoxicity of bupivacaine may be the result of this specific effect on Ca2+ release channel-ryanodine receptor superimposed on a nonspecific action on lipid bilayers to increase the Ca2+ permeability of sarcoplasmic reticulum membranes, an effect shared by all local anesthetics. The specific action of tetracaine to inhibit Ca2+ release channel-ryanodine receptor activity may in part counterbalance the nonspecific action, resulting in moderate myotoxicity.

Altered E-C coupling in triads isolated from malignant hyperthermia-susceptible porcine muscle

1995 ◽  
Vol 268 (6) ◽  
pp. C1381-C1386 ◽  
Author(s):  
R. el-Hayek ◽  
M. Yano ◽  
B. Antoniu ◽  
J. R. Mickelson ◽  
C. F. Louis ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Malignant Hyperthermia ◽  
Dihydropyridine Receptor ◽  
Normal Muscle ◽  
Direct Stimulation ◽  
Release Channel ◽  
Malignant Hyperthermia Susceptible ◽  
T Tubules ◽  
Junctional Foot Protein ◽  
Stimulation Of

Triad vesicles were isolated from normal (N) and homozygous malignant hyperthermia-susceptible (MHS) porcine skeletal muscle, and two types of sarcoplasmic reticulum Ca2+ release were investigated: 1) polylysine-induced Ca2+ release (direct stimulation of the junctional foot protein), and 2) depolarization-induced Ca2+ release (stimulation of the junctional foot protein via the dihydropyridine receptor). At submaximal concentrations of polylysine, the rates of induced Ca2+ release from the MHS triads were greater than from normal triads. The T tubules of polarized triads were depolarized by the K(+)-to-Na+ ionic replacement protocol. Higher grades of T-tubule depolarization resulted in higher rates of Ca2+ release from both MHS and normal triads but, when compared at a given grade of T-tubule depolarization, the release rate was always greater from the MHS than from normal triads. Thus the activity of the SR Ca2+ release channel is always higher in MHS than in normal muscle at a given submaximal dose of release trigger. This difference is observed when the channel is stimulated directly by polylysine or indirectly via a depolarization-induced activation of the T-tubule dihydropyridine receptor.

Sign in / Sign up

Export Citation Format

Share Document