Stac2 genetic deletion alters mouse chromaffin cells' CaV channel composition, increases membrane excitability and reduces vesicle exocytosis.

Stac2 adaptor protein is expressed in neurons and endocrine cells. Stac2 overexpression in heterologous cells and hippocampal neurons has been shown to inhibit the CaV1 L-type calcium channel calcium-dependent inactivation without affecting membrane incorporation or biophysical properties of CaV2 channels. Here we show that Stac2 genetic deletion causes minimal alterations of mouse chromaffin cell (MCC) whole-cell calcium current amplitude or inactivation kinetics but induces a significant shift in calcium current voltage dependence of activation towards more negative potentials. This effect is calcium dependent, as increasing the intracellular calcium buffering reverts the current biophysical properties to control conditions. The shift in the voltage dependence of activation is not caused by altered L-type or P/Q-type current densities or biophysical properties. However Stac2 ablation causes a ∼2-fold increase in R-type current density. Functionally the altered voltage dependence of activation decreases the MCC action potential threshold and increases the induced excitability. Additionally Stac2 deletion significantly reduces the catecholamine vesicle exocytosis, an effect caused by altered functional coupling of the catecholamine vesicles to P/Q-type channels. Therefore, here we report on a novel role for endogenous Stac2 in regulating MCC excitability and catecholamine release by modulating CaV channel isoform composition. KEY POINTS: Overexpression studies in heterologous cell systems showed that Stac2 adaptor proteins primarily alter CaV1 L-type calcium channel calcium-dependent inactivation. In contrast here we show that the genetic deletion of the endogenous Stac2 isoform in mouse chromaffin cells has minimal effects on calcium current inactivation but shifts the whole-cell calcium current voltage dependence of activation leftwards and alters CaV isoform composition. The altered CaV current biophysical properties and isoform composition affect mouse chromaffin cell excitability and impair catecholamine vesicle exocytosis.