Abnormal Ca(2+) homeostasis, atrial arrhythmogenesis, and sinus node dysfunction in murine hearts modeling RyR2 modification.

Yanmin Zhang,Ming Lei,Christopher L-H Huang,Gareth D K Matthews

doi:10.3389/fphys.2013.00150

Abstract

Ryanodine receptor type 2 (RyR2) mutations are implicated in catecholaminergic polymorphic ventricular tachycardia (CPVT) thought to result from altered myocyte Ca2+ homeostasis reflecting inappropriate “leakiness” of RyR2-Ca2+ release channels arising from increases in their basal activity, alterations in their phosphorylation, or defective interactions with other molecules or ions. The latter include calstabin, calsequestrin-2, Mg2+, and extraluminal or intraluminal Ca2+. Recent clinical studies additionally associate RyR2 abnormalities with atrial arrhythmias including atrial tachycardia (AT), fibrillation (AF), and standstill, and sinus node dysfunction (SND). Some RyR2 mutations associated with CPVT in mouse models also show such arrhythmias that similarly correlate with altered Ca2+ homeostasis. Some examples show evidence for increased Ca2+/calmodulin-dependent protein kinase II (CaMKII) phosphorylation of RyR2. A homozygotic RyR2-P2328S variant demonstrates potential arrhythmic substrate resulting from reduced conduction velocity (CV) in addition to delayed afterdepolarizations (DADs) and ectopic action potential (AP) firing. Finally, one model with an increased RyR2 activity in the sino-atrial node (SAN) shows decreased automaticity in the presence of Ca2+-dependent decreases in ICa, L and diastolic sarcoplasmic reticular (SR) Ca2+ depletion.

Highlights

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is one of the most malignant cardiac channelopathies
There are currently more than 150 known pathological allelic variants involving ryanodine receptor type 2 (RyR2) that are associated with CPVT (Priori and Chen, 2011)
This results in an inappropriate “leakiness” of RyR2-Ca2+ release channels owing to increases in their basal activity, altered phosphorylation status or defective interactions with other molecules or ions, including calstabin (FKBP12.6) (Lehnart et al, 2004b), calsequestrin type 2 gene (CASQ2), or Mg2+, or abnormal activation by extra- or intraluminal Ca2+ (Wehrens et al, 2004)

Summary

Introduction

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is one of the most malignant cardiac channelopathies. Several unrelated families showed a large deletion encompassing part of intron 2, exon 3, and part of intron 3, expected to result in an in-frame deletion of 35 amino acids (p.Asn57-Gly91) (NM-001035) (Bhuiyan et al, 2007; Marjamaa et al, 2009; Medeiros-Domingo et al, 2009).

Results

Conclusion