Altered ryanodine receptor function in central core disease: leaky or uncoupled Ca(2+) release channels?

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) Ca(2+) release channels that are excessively leaky to Ca(2+). Although some of the CCD mutations in RyR1 may indeed result in leaky SR Ca(2+) 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 Ca(2+) 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."