Caveolae, ion channels and cardiac arrhythmias

Abstract

Caveolae are specialized membrane microdomains enriched in cholesterol and sphingolipids which are present in multiple cell types including cardiomyocytes. Along with the essential scaffolding protein caveolin-3, a number of different ion channels and transporters have been localized to caveolae in cardiac myocytes including L-type Ca2+ channels (Ca(v)1.2), Na+ channels (Na(v)1.5), pacemaker channels (HCN4), Na+/Ca2+ exchanger (NCX1) and others. Closely associated with these channels are specific macromolecular signaling complexes that provide highly localized regulation of the channels. Mutations in the caveolin-3 gene (CAV3) have been linked with the congenital long QT syndrome (LQT9), and mutations in caveolar-localized ion channels may contribute to other inherited arrhythmias. Changes in the caveolar microdomain in acquired heart disease may also lead to dysregulation and dysfunction of ion channels, altering the risk of arrhythmias in conditions such as heart failure. This review highlights the existing evidence identifying and characterizing ion channels localized to caveolae in cardiomyocytes and their role in arrhythmogenesis.

Figure 1

Electron microscopic images of adult mouse ventricular tissue. Panel A, immunogold staining of caveolin-1. Staining for caveolin-1 is observed only in the caveolae (arrows) of endothelial cell. In contrast the ventricular myocyte caveolae (arrow heads) had no specific caveolin-1 staining (SL, sarcolemma; Z, z line of the myofibril). Panel B, immunogold co-localization of the Ca_v1.2 subunit of L-type Ca²⁺ channel and caveolin-3. Ca_v1.2 (large gold particles) and caveolin-3 (small gold particle) are co-localized relative to myocyte caveolae (arrow heads) in sarcolemma (SL) and not in the endothelial caveolae (arrows). Ca_v1.2 staining is also noticed in the T-tubules (Tt), where Cav3 staining is absent. Scale bar, 100 nm.

Figure 2

Schematic of CAV3 mutations associated with cardiac phenotype genetic diseases. Shown are locations of Cav-3 mutations identified in of Long QT syndrome type 9 (LQT9; red), sudden infant death syndrome (SIDS; pink) and hypertrophic cardiomyopathy (orange) patients. Mutation T78M in the membrane insertion region of the Cav3 was found to be associated with cases of both LQT9 and SIDS.