Clinical implications of cardiac ryanodine receptor/calcium release channel mutations linked to sudden cardiac death.

The cardiac ryanodine receptor (RyR2) is the major calcium (Ca ) release channel on the sarcoplasmic reticulum (SR) in cardiomyocytes. During excitationcontraction, coupling intracellular Ca stored in the SR is released via RyR2 to activate muscle contraction. In the heart, excitation-contraction coupling is activated by Ca influx via the L-type Ca channel that activates RyR2, a process referred to as Ca -induced Ca release.1,2 The cardiac muscle RyR2 and its homologue, the skeletal muscle RyR1, are macromolecular complexes that include four 565-kDa RyR1 or RyR2, four FKBP12 or FKBP12.6 (12-kDa peptidyl-prolyl isomerases that are required for normal gating of the channels), as well as cAMP-dependent kinase (PKA), phosphatases, and their targeting proteins.3–5 One key role for the macromolecular signaling complex is to modulate channel function in response to activation of the sympathetic nervous system (ie, the classic “fight-or-flight” stress response).5,6