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 CaV1.2 Ca2+ channels, relatively little is known about the closely related CaV1.4 L-type Ca2+ channels, which feature prominently in the visual system. Here we find that CaV1.4 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 CaV1.4 channels, introduction of ICDI1.4 to CaV1.3 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.
Highlights
The regulation of L-type Ca2 þ channels by protein kinase A (PKA) represents a crucial element within cardiac, skeletal muscle and neurological systems
This interaction seems specific to CaV1.4 channels, introduction of ICDI1.4 to CaV1.3 or CaV1.2 channels endows these channels with a form of PKA modulation, previously unobserved in heterologous systems
CaV1.4 channels are known to exist in retinal cells[7,8] and several other neuronal cell types[21], they are rarely studied in their native environment
Summary
The regulation of L-type Ca2 þ channels by protein kinase A (PKA) represents a crucial element within cardiac, skeletal muscle and neurological systems. We find that CaV1.4 channels are modulated by PKA phosphorylation within the inhibitor of Ca2 þ -dependent inactivation (ICDI) motif Phosphorylation of this region promotes the occupancy of calmodulin on the channel, increasing channel open probability (PO) and Ca2 þ -dependent inactivation. This interaction seems specific to CaV1.4 channels, introduction of ICDI1.4 to CaV1.3 or CaV1.2 channels endows these channels with a form of PKA modulation, previously unobserved in heterologous systems. Phosphorylation of L-type voltagegated calcium channels by protein kinase A (PKA) is essential for normal cardiac function[2], muscle contraction[3] and neurological activity[4].
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