Brief reviewAltered Ryanodine Receptor Function in Central Core Disease: Leaky or Uncoupled Ca2+ Release Channels?☆
Section snippets
Excitation–Contraction Coupling and Central Core Disease
Excitation–contraction (EC) coupling in skeletal muscle involves a mechanical interaction between sarcolemmal dihydropyridine receptors (DHPRs) and the skeletal muscle isoform of the ryanodine receptor (RyR1), which is located in the terminal cisternae of the sarcoplasmic reticulum (SR). The skeletal muscle DHPR is a slowly activating L-type calcium channel (L-channel) that also undergoes rapid voltage-driven conformational changes that trigger SR Ca2+ release (orthograde coupling) (Melzer et
Functional Analysis of MH and CCD Mutant RyR1 Proteins
Functional effects attributable to the R614C MH mutation in RyR1 are the most thoroughly characterized of the different disease mutations in RyR1. SR Ca2+ release channels isolated from skeletal muscle of MH pigs (which carry the analogous R615C mutation) exhibit higher rates of Ca2+-induced Ca2+ release; an increased sensitivity to caffeine, halothane, 4-chloro-m-cresol, and t-tubule depolarization; as well as reduced inhibition by high concentrations of both Ca2+ and Mg2+ (for reviews, see
EC Uncoupling as an Alternate Mechanism for Muscle Weakness in CCD
Recently, Lynch et al. (1999) identified a novel mutation in the C-terminal region of RyR1 (I4898T) that causes an unusually severe and highly penetrant form of CCD in humans. Cotransfection of HEK-293 cells with cDNAs that encode wild-type RyR1 and the analogous mutation introduced into the rabbit RyR1 (I4897T) results in an increase in resting and a reduction in luminal Ca2+ levels, consistent with heterozygous RyR1/I4897T release channels exhibiting a leaky-channel phenotype (Lynch et al.
Two Distinct Mechanisms Contribute to Muscle Weakness in CCD
Each of the different CCD mutations in RyR1 studied thus far in dyspedic myotubes (R164C, I404M, Y523S, R2163H, R24355H, and I4897T) cause variable reductions in voltage-gated SR Ca2+ release Avila et al. 2001a, Avila and Dirksen 2001. Clearly, a decrease in voltage-gated calcium release triggered during a skeletal-muscle action potential would be expected to contribute to muscle weakness in CCD. However, the reduction in voltage-gated SR Ca2+ release caused by the different CCD mutations in
Perspectives and Future Directions
Over the past decade, much attention has focused on how mutations in the RyR1 gene that cause CCD in humans alter SR Ca2+ release-channel activity and ultimately result in skeletal muscle weakness. Functional analysis of the different CCD mutant RyR1 proteins provides compelling support for both of the mechanisms (leaky and EC-uncoupled SR Ca2+ release channels) originally proposed by Zhang et al. (1993) and Quane et al. (1993). Currently, only one CCD mutation in RyR1 (I4898T) appears to
Acknowledgements
This work was supported by grants to R.T. Dirksen from the National Institutes of Health (AR 44657), the Muscular Dystrophy Association, and the New York State Affiliate of the American Heart Association (00550884T).
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