scholarly journals Mg 2+ dependence of Ca 2+ release from the sarcoplasmic reticulum induced by sevoflurane or halothane in skeletal muscle from humans susceptible to malignant hyperthermia

2006 ◽  
Vol 97 (3) ◽  
pp. 320-328 ◽  
Author(s):  
A.M. Duke ◽  
P.M. Hopkins ◽  
P.J. Halsall ◽  
D.S. Steele
Keyword(s):  
Skeletal Muscle ◽  
Sarcoplasmic Reticulum ◽  
Malignant Hyperthermia

Caffeine sensitivity of native RyR channels from normal and malignant hyperthermic pigs: effects of a DHPR II–III loop peptide

2004 ◽  
Vol 286 (4) ◽  
pp. C821-C830 ◽  
Author(s):  
Esther M. Gallant ◽  
James Hart ◽  
Kevin Eager ◽  
Suzanne Curtis ◽  
Angela F. Dulhunty
Keyword(s):  
Skeletal Muscle ◽  
Sarcoplasmic Reticulum ◽  
Malignant Hyperthermia ◽  
Lipid Bilayers ◽  
Ryanodine Receptor ◽  
High Affinity ◽  
Enhanced Sensitivity ◽  
Skeletal Muscle Contraction ◽  
Activation Mechanisms ◽  
Standard Tests

Enhanced sensitivity to caffeine is part of the standard tests for susceptibility to malignant hyperthermia (MH) in humans and pigs. The caffeine sensitivity of skeletal muscle contraction and Ca2+ release from the sarcoplasmic reticulum is enhanced, but surprisingly, the caffeine sensitivity of purified porcine ryanodine receptor Ca2+-release channels (RyRs) is not affected by the MH mutation (Arg615Cys). In contrast, we show here that native malignant hyperthermic pig RyRs (incorporated into lipid bilayers with RyR-associated lipids and proteins) were activated by caffeine at 100- to 1,000-fold lower concentrations than native normal pig RyRs. In addition, the results show that the mutant ryanodine receptor channels were less sensitive to high-affinity activation by a peptide (CS) that corresponds to a part of the II–III loop of the skeletal dihydropyridine receptor (DHPR). Furthermore, subactivating concentrations of peptide CS enhanced the response of normal pig and rabbit RyRs to caffeine. In contrast, the caffeine sensitivity of MH RyRs was not enhanced by the peptide. These novel results showed that in MH-susceptible pig muscles 1) the caffeine sensitivity of native RyRs was enhanced, 2) the sensitivity of RyRs to a skeletal II–III loop peptide was depressed, and 3) an interaction between the caffeine and peptide CS activation mechanisms seen in normal RyRs was lost.

Reduced Mg2+ inhibition of Ca2+ release in muscle fibers of pigs susceptible to malignant hyperthermia

1997 ◽  
Vol 272 (1) ◽  
pp. C203-C211 ◽  
Author(s):  
V. J. Owen ◽  
N. L. Taske ◽  
G. D. Lamb
Keyword(s):  
Skeletal Muscle ◽  
Sarcoplasmic Reticulum ◽  
Malignant Hyperthermia ◽  
Ryanodine Receptor ◽  
Muscle Fiber ◽  
Muscle Fibers ◽  
Inhibitory Effect ◽  
Fiber Bundles ◽  
Force Response ◽  
Skeletal Muscle Fibers

The inhibitory effect of myoplasmic Mg2+ on Ca2+ release from the sarcoplasmic reticulum (SR) was examined in mechanically skinned skeletal muscle fibers from pigs of different ryanodine-receptor (RyR) genotypes. In fibers from pigs homozygous for the normal RyR allele, the free Mg2+ concentration ([Mg2+]) had to be lowered from the normal resting level of 1 to approximately 0.1 mM to induce Ca2+ release and a force response. Fibers from pigs heterozygous or homozygous for the RyR allele associated with malignant hyperthermia (MH) needed only a smaller reduction in free [Mg2+] to induce Ca2+ release (reduction to 0.1-0.2 and > or = 0.2 mM, respectively). Dantrolene (20 microM) counteracted the effect of this reduced Mg2+ inhibition in MH muscle. The response of muscle fiber bundles to the caffeine-halothane contracture test in the three genotypes correlated well with the responsiveness of single fibers to reduced [Mg2+]. Thus the abnormal responsiveness of MH muscle to various stimuli may largely result from the reduced ability of myoplasmic Mg2+ to inhibit Ca2+ release from the SR.

Postulated role of interdomain interactions within the type 1 ryanodine receptor in the low gain of Ca2+-induced Ca2+ release activity of mammalian skeletal muscle sarcoplasmic reticulum

2005 ◽  
Vol 288 (6) ◽  
pp. C1222-C1230 ◽  
Author(s):  
Takashi Murayama ◽  
Toshiharu Oba ◽  
Shigeki Kobayashi ◽  
Noriaki Ikemoto ◽  
Yasuo Ogawa
Keyword(s):  
Skeletal Muscle ◽  
Sarcoplasmic Reticulum ◽  
Malignant Hyperthermia ◽  
Ryanodine Receptor ◽  
Single Channel ◽  
Common Mechanism ◽  
Mammalian Skeletal Muscle ◽  
Selective Stabilization ◽  
Interdomain Interactions

Ryanodine receptor (RyR) type 1 (RyR1) exhibits a markedly lower gain of Ca2+-induced Ca2+ release (CICR) activity than RyR type 3 (RyR3) in the sarcoplasmic reticulum (SR) of mammalian skeletal muscle (selective stabilization of the RyR1 channel), and this reduction in the gain is largely eliminated using 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonic acid (CHAPS). We have investigated whether the hypothesized interdomain interactions within RyR1 are involved in the selective stabilization of the channel using [3H]ryanodine binding, single-channel recordings, and Ca2+ release from the SR vesicles. Like CHAPS, domain peptide 4 (DP4, a synthetic peptide corresponding to the Leu2442-Pro2477 region of RyR1), which seems to destabilize the interdomain interactions, markedly stimulated RyR1 but not RyR3. Their activating effects were saturable and nonadditive. Dantrolene, a potent inhibitor of RyR1 used to treat malignant hyperthermia, reversed the effects of DP4 or CHAPS in an identical manner. These findings indicate that RyR1 is activated by DP4 and CHAPS through a common mechanism that is probably mediated by the interdomain interactions. DP4 greatly increased [3H]ryanodine binding to RyR1 with only minor alterations in the sensitivity to endogenous CICR modulators (Ca2+, Mg2+, and adenine nucleotide). However, DP4 sensitized RyR1 four- to six-fold to caffeine in the caffeine-induced Ca2+ release. Thus the gain of CICR activity critically determines the magnitude and threshold of Ca2+ release by drugs such as caffeine. These findings suggest that the low CICR gain of RyR1 is important in normal Ca2+ handling in skeletal muscle and that perturbation of this state may result in muscle diseases such as malignant hyperthermia.

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