Caveolin-3 negatively regulates endocytic recycling of cardiac K channels.

Sarcolemmal ATP-sensitive potassium (K) channels play a vital role in cardioprotection. Cardiac K channels are enriched in caveolae and physically interact with the caveolae structural protein caveolin-3 (Cav3). Disrupting caveolae impairs the regulation of K channels through several signaling pathways.

The cardioprotective role of sirtuins is mediated in part by regulating K channel surface expression.

Sirtuins are NAD-dependent deacetylases with beneficial roles in conditions relevant to human health, including metabolic disease, type II diabetes, obesity, cancer, aging, neurodegenerative diseases, and cardiac ischemia. Since ATP-sensitive K (K) channels have cardioprotective roles, we investigated whether they are regulated by sirtuins. Nicotinamide mononucleotide (NMN) was used to increase cytosolic NAD levels and to activate sirtuins in cell lines, isolated rat and mouse cardiomyocytes or insulin-secreting INS-1 cells.

Rab35 GTPase positively regulates endocytic recycling of cardiac K channels.

ATP-sensitive K (K) channel couples membrane excitability to intracellular energy metabolism. Maintaining K channel surface expression is key to normal insulin secretion, blood pressure and cardioprotection. However, the molecular mechanisms regulating K channel internalization and endocytic recycling, which directly affect the surface expression of K channels, are poorly understood.