Molecular, Subcellular, and Arrhythmogenic Mechanisms in Genetic RyR2 Disease

Abstract

The ryanodine receptor (RyR2) has a critical role in controlling Ca2+ release from the sarcoplasmic reticulum (SR) throughout the cardiac cycle. RyR2 protein has multiple functional domains with specific roles, and four of these RyR2 protomers are required to form the quaternary structure that comprises the functional channel. Numerous mutations in the gene encoding RyR2 protein have been identified and many are linked to a wide spectrum of arrhythmic heart disease. Gain of function mutations (GoF) result in a hyperactive channel that causes excessive spontaneous SR Ca2+ release. This is the predominant cause of the inherited syndrome catecholaminergic polymorphic ventricular tachycardia (CPVT). Recently, rare hypoactive loss of function (LoF) mutations have been identified that produce atypical effects on cardiac Ca2+ handling that has been termed calcium release deficiency syndrome (CRDS). Aberrant Ca2+ release resulting from both GoF and LoF mutations can result in arrhythmias through the Na+/Ca2+ exchange mechanism. This mini-review discusses recent findings regarding the role of RyR2 domains and endogenous regulators that influence RyR2 gating normally and with GoF/LoF mutations. The arrhythmogenic consequences of GoF/LoF mutations will then be discussed at the macromolecular and cellular level.

Defective ryanodine receptor N-terminus inter-subunit interaction is a common mechanism in neuromuscular and cardiac disorders

“…Numerous RyR1 and RyR2 mutations associated with MH and CPVT, respectively, have been functionally characterized with the vast majority resulting in gain-of-function channels ( Hernandez-Ochoa et al, 2016 ; Fowler and Zissimopoulos, 2022 ). However, how pathogenic RyR mutations function at the molecular or structural level, i.e., what is the defective RyR regulatory mechanism(s), is poorly understood.…”

“…Abnormal SR Ca 2+ release due to missense mutations in RYR1 and RYR2 results in neuromuscular (e.g., malignant hyperthermia, MH) and cardiac disease (e.g., catecholaminergic polymorphic ventricular tachycardia, CPVT), respectively ( Hernandez-Ochoa et al, 2016 ; Fowler and Zissimopoulos, 2022 ). Mutations are found throughout the RyR peptide sequence, but tend to concentrate on five structural domains, namely, the N-terminus domain (NTD), bridging solenoid B, core solenoid, transmembrane domain and C-terminus domain ( Fowler and Zissimopoulos, 2022 ). Neighboring NTDs from the four RyR subunits interact with each other to promote channel closure ( Tung et al, 2010 ; Zissimopoulos et al, 2013 ; Zissimopoulos et al, 2014 ).…”

Molecular Aspects Implicated in Dantrolene Selectivity with Respect to Ryanodine Receptor Isoforms

“…Cell-free experiments have indicated that a vast majority of tested CVPT1 mutations activate the RyR2 channel in response to elevated luminal Ca 2+ [ 181 , 182 , 183 , 184 ]. Although hypersensitivity to cytosolic Ca 2+ and hyposensitivity to cytosolic Mg 2+ could also participate [ 112 , 185 , 186 , 187 , 188 ], more frequent spontaneous Ca 2+ release under conditions of store Ca 2+ overload (SOICR) represents a common defect caused by CPVT1 mutations (comprehensively reviewed in [ 75 , 189 , 190 ]. This inappropriate RyR2 activation results in diastolic SR Ca 2+ leak, which has been suggested to trigger fatal cardiac arrhythmias [ 191 ].…”

HIV-Tat Exacerbates the Actions of Atazanavir, Efavirenz, and Ritonavir on Cardiac Ryanodine Receptor (RyR2)

“…When using Schrodinger's Prime protein-protein docking software, the more negative the binding energy, the better the fit. The most thermodynamically favored site of interaction (site 1: brown) for HIV-Tat resides in the region within the junctional solenoid region (JSOL: amino acids (AA) 1702-1963) [56,57], with 14 hydrogen bonding, 3 salt bridges, and 1 pi stack (See Table 1). Note, the numbering of the AA for HIV-Tat that is listed is derived from the crystal structure provided by Protein Data Bank (PDB id; 1TIV).…”