Clinical Implications of Cardiac Ryanodine Receptor/Calcium Release Channel Mutations Linked to Sudden Cardiac Death

摘要: The cardiac ryanodine receptor (RyR2) is the major calcium (Ca2+) release channel on sarcoplasmic reticulum (SR) in cardiomyocytes. During excitation-contraction, coupling intracellular Ca2+ stored SR released via RyR2 to activate muscle contraction. In heart, excitation-contraction activated by influx L-type that activates RyR2, a process referred as Ca2+-induced release.1,2⇓ and its homologue, skeletal RyR1, are macromolecular complexes include four ≈565-kDa RyR1 or FKBP12 FKBP12.6 (12-kDa peptidyl-prolyl isomerases required for normal gating of channels), well cAMP-dependent kinase (PKA), phosphatases, their targeting proteins.3–5⇓⇓ One key role signaling complex modulate function response activation sympathetic nervous system (ie, classic “fight-or-flight” stress response).5,6⇓ See p 69 In past year, three groups have independently discovered at least 21 mutations (Figure) linked stress-induced sudden death.7–9⇓⇓ To date, been associated with 2 forms death (SCD): (1) catecholaminergic polymorphic ventricular tachycardia (CPVT) familial (FPVT), (2) arrhythmogenic right dysplasia type (ARVD2). Exercise-induced SCD-linked mutations. Locations SCD human compared MH/CCD regions known regulatory domains channel. Eleven reported mutations7–9⇓⇓ cluster homologous regions.30,31⇓ Common polymorphisms indicated italics. location 3 leucine/isoleucine zippers (LZ) target PP1, PP2A, PKA shown,5,6⇓ binding region,32 CaM site.33 …