Brief review
Altered Ryanodine Receptor Function in Central Core Disease: Leaky or Uncoupled Ca2+ Release Channels?

https://doi.org/10.1016/S1050-1738(02)00163-9Get rights and content

Abstract

Central core disease (CCD) is an autosomal-dominant human congenital myopathy that is associated with at least 22 different mutations in the skeletal muscle isoform of ryanodine receptor (RyR1). CCD mutations in RyR1 have been proposed to lead to the formation of sarcoplasmic reticulum (SR) Ca2+ release channels that are excessively leaky to Ca2+. Although some of the CCD mutations in RyR1 may indeed result in leaky SR Ca2+ release channels, the leaky-channel hypothesis may not represent the only mechanism for muscle weakness in this disorder. The presence of an alternate mechanism of muscle weakness in CCD is supported by the observation that muscle cells expressing a CCD mutation in the putative pore-forming segment of RyR1 (I4898T) exhibit a functional uncoupling of SR Ca2+ release from sarcolemmal depolarization. These observations cannot be explained by the leaky-channel hypothesis and indicate that muscle weakness in some forms of CCD arises from an alternate and completely unexpected mechanism, termed “excitation–contraction uncoupling.”

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).

References (40)

  • G. Avila et al.

    Excitation–contraction uncoupling by a human central core disease mutation in the ryanodine receptor

    Proc Natl Acad Sci USA

    (2001)
  • G. Avila et al.

    Ca2+ release through ryanodine receptors regulates skeletal muscle L-type Ca2+ channel expression

    J Biol Chem

    (2001)
  • R.L. Brown et al.

    A novel ryanodine receptor mutation and genotype-phenotype correlation in a large malignant hyperthermia New Zealand Maori Pedigree

    Hum Mol Genet

    (2000)
  • K. Censier et al.

    Intracellular calcium homeostasis in human primary muscle cells from malignant hyperthermia-susceptible and normal individuals. Effect of overexpression of recombinant wild-type and Arg163Cys mutated ryanodine receptors

    J Clin Invest

    (1998)
  • B. Dietze et al.

    Malignant hyperthermia mutation Arg615Cys in the porcine ryanodine receptor alters voltage dependence of Ca2+ release

    J Physiol (London)

    (2000)
  • G.G. Du et al.

    Functional characterization of mutants in the predicted pore region of the rabbit cardiac muscle Ca2+ release channel (ryanodine receptor isoform 2)

    J Biol Chem

    (2001)
  • E.M. Gallant et al.

    Porcine malignant hyperthermiagenotype and contractile threshold of immature muscles

    Muscle Nerve

    (1996)
  • A.M. Gomez et al.

    Heart failure after myocardial infarctionaltered excitation–contraction coupling

    Circulation

    (2001)
  • A.M. Gomez et al.

    Defective excitation–contraction coupling in experimental cardiac hypertrophy and heart failure

    Science

    (1997)
  • K. Hayashi et al.

    Central core diseaseultrastructure of the sarcoplasmic reticulum and T-tubules

    Muscle Nerve

    (1989)
  • Cited by (0)

    © 2002, Elsevier Science Inc. All rights reserved. 1050-1738/02/$-see front matter

    View full text