Cav1.3 and Cav1.2 channels of adrenal chromaffin cells: Emerging views on cAMP/cGMP-mediated phosphorylation and role in pacemaking

Voltage-gated Ca2 + channels (VGCCs) are voltage sensors that convert membrane depolarizations into Ca2 + signals. In the chromaffin cells of the adrenal medulla, the Ca2 + signals driven by VGCCs regulate catecholamine secretion, vesicle retrievals, action potential shape and firing frequency. Among the VGCC-types expressed in these cells (N-, L-, P/Q-, R- and T-types), the two L-type isoforms, Cav1.2 and Cav1.3, control key activities due to their particular activation–inactivation gating and high-density of expression in rodents and humans. The two isoforms are also effectively modulated by G protein-coupled receptor pathways delimited in membrane micro-domains and by the cAMP/PKA and NO/cGMP/PKG phosphorylation pathways which induce prominent Ca2 + current changes if opposingly regulated. The two L-type isoforms shape the action potential and directly participate to vesicle exocytosis and endocytosis. The low-threshold of activation and slow rate of inactivation of Cav1.3 confer to this channel the unique property of carrying sufficient inward current at subthreshold potentials able to activate BK and SK channels which set the resting potential, the action potential shape, the cell firing mode and the degree of spike frequency adaptation during spontaneous firing or sustained depolarizations. These properties help chromaffin cells to optimally adapt when switching from normal to stress-mimicking conditions. Here, we will review past and recent findings on cAMP- and cGMP-mediated modulations of Cav1.2 and Cav1.3 and the role that these channels play in the control of chromaffin cell firing.