["The Journal of Physiology, EarlyView. ", "\nAbstract figure legend Stac2 adaptor protein is expressed in neurons and endocrine cells. Using a global Stac2 knockout mouse model here we investigated the role of endogenous Stac2 in adrenal gland mouse chromaffin cell (MCC) excitability and catecholamine vesicle exocytosis. Although in heterologous expression systems Stac2 modulated calcium influx calcium‐dependent inactivation, the genetic ablation of the endogenous Stac2 caused a shift in the voltage dependence of activation of calcium influx to lower membrane potentials. This shift was caused by increased R‐type current amplitude. Functionally the altered voltage dependence of activation caused an increased MCC induced excitability. Additionally Stac2 deletion reduced vesicle exocytosis due to a functional uncoupling between the P/Q‐type currents and vesicle release.\n\n\n\n\n\n\n\n\n\nAbstract\nStac2 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.\n\n\n\n\n\n\n\n\n\nKey points\n\nOverexpression studies in heterologous cell systems showed that Stac2 adaptor proteins primarily alter CaV1 L‐type calcium channel calcium‐dependent inactivation.\nIn 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.\nThe altered CaV current biophysical properties and isoform composition affect mouse chromaffin cell excitability and impair catecholamine vesicle exocytosis.\n\n\n"]