Protein kinase A modulation of CaV1.4 calcium channels

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 (PO) and Ca2+-dependent inactivation. Although this interaction seems specific to Ca(V)1.4 channels, introduction of ICDI1.4 to Ca(V)1.3 or Ca(V)1.2 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.