The pancreatic islets of Langerhans secrete several hormones critical for glucose homeostasis. The β-cells, the major cellular component of the pancreatic islets, secrete insulin, the only hormone capable of lowering the plasma glucose concentration. The counter-regulatory hormone glucagon is secreted by the α-cells while δ-cells secrete somatostatin that via paracrine mechanisms regulates the α- and β-cell activity. These three peptide hormones are packed into secretory granules that are released through exocytosis following a local increase in intracellular Ca²⁺ concentration. The high voltage-gated Ca²⁺ channels (HVCCs) occupy a central role in pancreatic hormone release both as a source of Ca²⁺ required for excitation-secretion coupling as well as a scaffold for the release machinery. HVCCs are multi-protein complexes composed of the main pore-forming transmembrane α₁ and the auxiliary intracellular β, extracellular α₂δ, and transmembrane γ subunits. Here, we review the current understanding regarding the role of all HVCC subunits expressed in pancreatic β-cell on electrical activity, excitation-secretion coupling, and β-cell mass. The evidence we review was obtained from many seminal studies employing pharmacological approaches as well as genetically modified mouse models. The significance for diabetes in humans is discussed in the context of genetic variations in the genes encoding for the HVCC subunits.

In humans, type 2 diabetes mellitus shows a higher prevalence in men compared with women, a phenotype that has been attributed to a lower peripheral insulin sensitivity in men. Whether sex-specific differences in pancreatic β cell function also contribute is largely unknown. Here, we characterized the electrophysiological properties of β cells in intact male and female mouse islets. Elevation of glucose concentration above 5 mM triggered an electrical activity with a similar glucose dependence in β cells of both sexes. However, female β cells had a more depolarized membrane potential and increased firing frequency compared with males. The higher membrane depolarization in female β cells was caused by approximately 50% smaller K _v 2.1 K ⁺ currents compared with males but otherwise unchanged K _ATP , large-conductance and small-conductance Ca ²⁺ -activated K ⁺ channels, and background TASK1/TALK1 K ⁺ current densities. In female β cells, the higher depolarization caused a membrane potential–dependent inactivation of the voltage-gated Ca ²⁺ channels (Ca _V ), resulting in reduced Ca ²⁺ entry. Nevertheless, this reduced Ca ²⁺ influx was offset by a higher action potential firing frequency. Because exocytosis of insulin granules does not show a sex-specific difference, we conclude that the higher electrical activity promotes insulin release in females, improving glucose tolerance.

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 α₁ and the auxiliary β, α₂δ and γ subunits. Four genes code for the α₂δ isoforms. At the mRNA level, mouse chromaffin cells (MCCs) express predominantly the CACNA2D1 gene coding for the α₂δ‐1 isoform. Here we show that α₂δ‐1 deletion led to ∼60% reduced HVCC Ca²⁺ influx with slower inactivation kinetics. Pharmacological dissection showed that HVCC composition remained similar in α₂δ‐1^−/− MCCs compared to wild‐type (WT), demonstrating that α₂δ‐1 exerts similar functional effects on all HVCC isoforms. Consistent with reduced HVCC Ca²⁺ influx, α₂δ‐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 α₂δ‐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 α₂δ‐1^−/− MCCs compared to WT during sustained stimulation. In conclusion, our study shows that α₂δ‐1 genetic deletion reduces Ca²⁺ influx in cultured MCCs but leads to a paradoxical increase in catecholamine secretion due to increased excitability. image Key points: Deletion of the α₂δ‐1 high voltage‐gated Ca²⁺ channel (HVCC) subunit reduces mouse chromaffin cell (MCC) Ca²⁺ influx by ∼60% but causes a paradoxical increase in induced excitability. MCC intracellular Ca²⁺ transients are unaffected by the reduced HVCC Ca²⁺ influx. Deletion of α₂δ‐1 reduces the immediately releasable pool vesicle exocytosis but has no effect on catecholamine (CA) release in response to sustained stimuli. The increased electrical activity and CA release from MCCs might contribute to the previously reported cardiovascular phenotype of patients carrying α₂δ‐1 loss‐of‐function mutations.