Deletion of the α2δ-1 calcium channel subunit increases excitability of mouse chromaffin cells

High voltage-gated Ca2+ channels (HVCCs) shape the electrical activity and control hormone release in most endocrine cells. HVCCs are multi-subunit protein complexes formed by the pore-forming alpha(1) and the auxiliary beta, alpha(2)delta and gamma subunits. Four genes code for the alpha(2)delta isoforms. At the mRNA level, mouse chromaffin cells (MCCs) express predominantly the CACNA2D1 gene coding for the alpha(2)delta-1 isoform. Here we show that alpha(2)delta-1 deletion led to similar to 60% reduced HVCC Ca2+ influx with slower inactivation kinetics. Pharmacological dissection showed that HVCC composition remained similar in alpha(2)delta-1(-/-) MCCs compared to wild-type (WT), demonstrating that alpha(2)delta-1 exerts similar functional effects on all HVCC isoforms. Consistent with reduced HVCC Ca2+ influx, alpha(2)delta-1(-/-) MCCs showed reduced spontaneous electrical activity with action potentials (APs) having a shorter half-maximal duration caused by faster rising and decay slopes. However, the induced electrical activity showed opposite effects with alpha(2)delta-1(-/-) MCCs displaying significantly higher AP frequency in the tonic firing mode as well as an increase in the number of cells firing AP bursts compared to WT. This gain-of-function phenotype was caused by reduced functional activation of Ca2+-dependent K+ currents. Additionally, despite the reduced HVCC Ca2+ influx, the intracellular Ca2+ transients and vesicle exocytosis or endocytosis were unaltered in alpha(2)delta-1(-/-) MCCs compared to WT during sustained stimulation. In conclusion, our study shows that alpha(2)delta-1 genetic deletion reduces Ca2+ influx in cultured MCCs but leads to a paradoxical increase in catecholamine secretion due to increased excitability.