Protein kinase A modulation of Ca v 1.4 calcium channels

Abstract

The regulation of L-type Ca2+ channels by protein kinase A (PKA) represents a crucial element within cardiac, skeletal muscle and neurological systems. Although much work has been done to understand this regulation in cardiac Ca V 1.2 Ca2+ channels, relatively little is known about the closely related Ca V 1.4 L-type Ca2+ channels, which feature prominently in the visual system. Here we find that Ca V 1.4 channels are indeed modulated by PKA phosphorylation within the inhibitor of Ca2+-dependent inactivation (ICDI) motif. Phosphorylation of this region promotes the occupancy of calmodulin on the channel, thus increasing channel open probability (P O) and Ca2+-dependent inactivation. Although this interaction seems specific to Ca V1.4 channels, introduction of ICDI 1.4 to CaV 1.3 or CaV1.2 channels endows these channels with a form of PKA modulation, previously unobserved in heterologous systems. Thus, this mechanism may not only play an important role in the visual system but may be generalizable across the L-type channel family.