Ahnak, a new player in beta-adrenergic regulation of the cardiac L-type Ca2+ channel

Ahnak, originally identified as a giant, tumour-related phosphoprotein, has emerged as an important signalling molecule in a wide range of physiological activities. In this article, current knowledge will be reviewed that places ahnak into the context of cardiac L-type Ca2+ channel function by its interaction with the beta2 subunit. Beginning with an overview on structural and functional properties of ahnak, basic features of beta subunits are highlighted. The review characterizes multiple ahnak/beta2 subunit binding sites and focuses on recent progress in understanding their functional role in Cav1.2 channel conductance (I(CaL)). Three main aspects of ahnak function in I(CaL) of cardiomyocytes emerge from available experimental data. First, ahnak acts as repressor towards I(CaL) by beta2 subunit sequestration. Second, PKA phosphorylation relieves the inhibition imposed by the C-terminal ahnak domain, ahnak-C1. Third, this action is mimicked by ahnak-derived fragments carrying a naturally occurring missense mutation Ile5236Thr. This paradigm introduces ahnak as a player in beta-adrenergic control of I(CaL) and sheds new light upon the molecular mechanism underlying this fundamental process of Cav1.2 channel physiology.