Direct and remote modulation of L-channels in chromaffin cells: Distinct actions on α_1C and α_1D subunits?

Understanding precisely the functioning of voltage-gated Ca²⁺ channels and their modulation by signaling molecules will help clarifying the Ca²⁺-dependent mechanisms controlling exocytosis in chromaffin cells. In recent years, we have learned more about the various pathways through which Ca²⁺ channels can be up- or down-modulated by hormones and neurotransmitters and how these changes may condition chromaffin cell activity and catecolamine release. Recently, the attention has been focused on the modulation of L-channels (Ca_v 1), which represent the major Ca ²⁺ current component in rat and human chromaffin cells. L-channels are effectively inhibited by the released content of secretory granules or by applying mixtures of exogenous ATP, opioids, and adrenaline through the activation of receptor-coupled G proteins. This unusual inhibition persists in a wide range of potentials and results from a direct (membrane-delimited) interaction of G protein subunits with the L-channels co-localized in membrane microareas. Inhibition of L-channels can be reversed when the cAMP/PKA pathway is activated by membrane permeable cAMP analog or when cells are exposed to isoprenaline (remote action), suggesting the existence of parallel and opposite effects on L-channel gating by distinctly activated membrane autoreceptors. Here, the authors review the molecular components underlying these two opposing signaling pathways and present new evidence supporting the presence of two L-channel types in rat chromaffin cells (α_1C and α_1D), which open new interesting issues concerning Ca ²⁺-channel modulation. In light of recent findings on the regulation of exocytosis by Ca²⁺-channel modulation, the authors explore the possible role of L-channels in the autocontrol of catecholamine release.