Molecular Changes in the Cardiac RyR2 With Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT).

Angela F Dulhunty

doi:10.3389/fphys.2022.830367

Abstract

The cardiac ryanodine receptor Ca2+ release channel (RyR2) is inserted into the membrane of intracellular sarcoplasmic reticulum (SR) myocyte Ca2+ stores, where it releases the Ca2+ essential for contraction. Mutations in proteins involved in Ca2+ signaling can lead to catecholaminergic polymorphic ventricular tachycardia (CPVT). The most common cellular phenotype in CPVT is higher than normal cytoplasmic Ca2+ concentrations during diastole due to Ca2+ leak from the SR through mutant RyR2. Arrhythmias are triggered when the surface membrane sodium calcium exchanger (NCX) lowers cytoplasmic Ca2+ by importing 3 Na+ ions to extrude one Ca2+ ion. The Na+ influx leads to delayed after depolarizations (DADs) which trigger arrhythmia when reaching action potential threshold. Present therapies use drugs developed for different purposes that serendipitously reduce RyR2 Ca2+ leak, but can adversely effect systolic Ca2+ release and other target processes. Ideal drugs would specifically reverse the effect of individual mutations, without altering normal channel function. Such drugs will depend on the location of the mutation in the 4967-residue monomer and the effect of the mutation on local structure, and downstream effects on structures along the conformational pathway to the pore. Such atomic resolution information is only now becoming available. This perspective provides a summary of known or predicted structural changes associated with a handful of CPVT mutations. Known molecular changes associated with RyR opening are discussed, as well one study where minute molecular changes with a particular mutation have been tracked from the N-terminal mutation site to gating residues in the channel pore.

Highlights

A group of inherited arrhythmogenic conditions fall under the catecholaminergic polymorphic ventricular tachycardia (CPVT) umbrella
In these conditions the heart is structurally normal, but patients are susceptible to catecholamine-mediated ventricular arrhythmias, syncope, bradycardia and sudden death with exercise or stress, as well as sudden death during sleep (Olubando et al, 2020)
Two variants characterized by diastolic Ca2+ leak inducing delayed after depolarizations (DADs) are CPVT-1 caused by gain-of-function mutations in RyR2, and CPVT-2 caused by mutations in calsequestrin (CSQ2), the Ca2+ binding protein within the cardiac sarcoplasmic reticulum (SR)

Summary

INTRODUCTION

A group of inherited arrhythmogenic conditions fall under the CPVT umbrella. In these conditions the heart is structurally normal, but patients are susceptible to catecholamine-mediated ventricular arrhythmias, syncope, bradycardia and sudden death with exercise or stress, as well as sudden death during sleep (Olubando et al, 2020). Human gain-of-function CPVT-1 mutations extend from the extreme cytoplasmic surface of RyR2 facing the T-tubule membrane through to deeper parts of the protein (Figures 1A,B; Priori et al, 2021), along intra- and inter-subunit interfaces to the central and C-terminal domains into the SR transmembrane domain and channel pore. In silico analysis of the mutation site based on WT RyR2 structure (Peng et al, 2016), revealed that Asp3638 is located near the Ca2+ activation site in a conserved central region, at a contact between alpha helices with positively charged residues on one side and negatively charged residues on the other. JTV519 is more effective with N-terminal and central domain RyR2 mutations than with C-terminal domain mutations (Tateishi et al, 2009), again showing a broad domain-specific action and providing a further example of the unzipping model in CPVT (Figure 2B). A related compound S48168 is effective in improving muscle function in a mouse model of Duchenne muscular dystrophy (Capogrosso et al, 2018) and is undergoing clinical trials (1ARDSLEY, N.Y., Dec. 17, 2019/PRNewswire/– ARMGO Pharma, Inc)

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