Ryanodine receptor mutations in arrhythmia: The continuing mystery of channel dysfunction

• Published in: FEBS letters Vol. 584; no. 10; pp. 2153 - 2160
• Main Authors: Thomas, N. Lowri, Maxwell, Chloé, Mukherjee, Saptarshi, Williams, Alan J.
• Format: Journal Article
• Language: English
• Published: England Elsevier B.V 17.05.2010
• Subjects: 12.6 kDa FK506 binding protein; Animals; Arrhythmia; Arrhythmias, Cardiac - drug therapy; Arrhythmias, Cardiac - genetics; Arrhythmias, Cardiac - metabolism; atrial fibrillation; Ca 2+ release channel; Ca2+ release channel; Ca2+-calmodulin dependent protein kinase; calsequestrin; CaMKII; cAMP; Catecholaminergic polymorphic ventricular tachycardia; CCD; central core disease; CPVT; CSQ; cyclic adenosine monophosphate; DAD; delayed-after depolarisation; Epac; exchange protein activated by cAMP; excitation–contraction; FKBP12.6; H-89; heart failure; HEK 293; human embryonic kidney 293; Humans; I-1; ICD; implantable cardioverter defibrillator; malignant hyperthermia; Mutation; N-[2-(p-bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide dihydrochloride; open probability; P o; phosphatase inhibitor 1; Phosphorylation; PKA; Polymorphism, Genetic; PP1; protein kinase A; protein phosphatase 1; reactive oxygen species; ROS; Ryanodine receptor; Ryanodine Receptor Calcium Release Channel - chemistry; Ryanodine Receptor Calcium Release Channel - genetics; Ryanodine Receptor Calcium Release Channel - metabolism; RyR; sarcoplasmic reticulum; SCD; sudden cardiac death; Tachycardia, Ventricular - drug therapy; ventricular tachycardia; wild type; β-adrenergic receptor; β-AR; β-AR; Arrhythmia; H-89; Ryanodine receptor; RyR; cAMP; Epac; MH; WT; EC; P o; FKBP12.6; SR; CSQ; AF; CCD; DAD; PKA; ICD; I-1; PP1; CaMKII; CPVT; HEK 293; SCD; ROS; Ca 2+ release channel; Catecholaminergic polymorphic ventricular tachycardia; Mutation; HF; VT
• ISSN: 0014-5793; 1873-3468; 1873-3468
• DOI: 10.1016/j.febslet.2010.01.057

Mutations in RyR2 are causative of an inherited disorder which often results in sudden cardiac death. Dysfunctional channel behaviour has been the subject of many investigations varying from single channel analysis through to complex animal models. This review discusses recent advances in the field, describes the controversy surrounding the exact consequences of RyR2 mutation and how the disparate data may be reconciled. This heterogeneity of function with respect to the effects of polymorphisms, phosphorylation, cytosolic and luminal Ca 2+ as well as inter-domain interactions may have important implications for the recent pharmaceutical therapies which have been put forward. We surmise that a comprehensive characterisation of mutations on a case-by-case basis may be beneficial for the development of specifically targeted therapies.