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

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.

FKBP12 binds to the cardiac ryanodine receptor with negative cooperativity: implications for heart muscle physiology in health and disease

“…FKBP interacts with the SPRY2 domain and α-solenoid 1 forming part of the corona [ 3 ], approximately 100 nm distant from the ion pore. Many ligands bind in this area and affect channel gating through a cascade of residue re-orientations along signalling pathways through the protein to the pore [ 37 ]. It is suggested that FKBP12 inhibits RyRs by clamping the SPRY2 and α-solenoid 1 domains and that reducing their mobility inhibits the channel [ 32 , 38 ].…”

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 ].…”

How does flecainide impact RyR2 channel function?

“…Not unexpectedly, there is evidence that gain-of-function point mutations in RyR1 and RyR2 increase channel opening through a variety of mechanisms, consistent with the complex organization of these tetrameric multidomain ion channels ( Iyer et al, 2022 ). The variety of possible mechanisms that would allow mutations in different domains to alter channel gating underlines the need for therapies targeted to mutations in particular domains of the protein ( Dulhunty, 2022 ; Dulhunty et al, 2022 ; Iyer et al, 2022 ).…”