Pancreatic β cells express several high voltage-gated Ca2+ channel (HVCC) isoforms critical for insulin release, cell differentiation, and survival. RNaseq and qPCR analyses demonstrated that CACNA1D gene encoding for CaV1.3-α1D isoform is highly expressed in pancreatic islets of both mice and men. Additionally, CACNA1D genetic polymorphisms were associated with increased susceptibility for diabetes while CaV1.3 gain-of-function mutations cause hyperinsulinemia in humans. Nevertheless, functional evidence for the role of CaV1.3 on β-cell electrical activity, insulin release, and β-cell mass is contradictory and largely unknown. Here, we show that CaV1.3 deletion led to a sixfold increase in DNA damage and a threefold decrease in proliferation markers in pancreatic β cells of 14-d-old mice, while adult mice were largely unaffected. However, β-cell mass was reduced by ∼20% in both young and old mice, resulting in a diminished sustained insulin release. Voltage-clamp recordings in β-cells of 14-d-old mice showed an ∼20% reduction in total Ca2+ influx (WT Ipeak = −19.76 ± 1.04 pA/pF; CaV1.3−/− Ipeak = −14.84 ± 0.61 pA/pF, P = 0.001) accompanied by slower inactivation and an ∼5 mV rightwards shift in the voltage dependence of activation (WT V1/2 = −7.71 ± 0.82 mV; CaV1.3−/− V1/2 = −2.32 ± 1.09 mV, P = 0.0003). Although to a lower extent, Ca2+ influx in adult CaV1.3−/− β cells was similarly affected. Moreover, current-clamp recordings showed that CaV1.3 deletion delayed the glucose-induced action potential (AP) onset, reduced AP firing frequency (e.g., at 7.5 mM glucose, WT = 4.3 Hz; CaV1.3−/− = 2.1 Hz, P = 0.001) and AP-train frequency (e.g., at 7.5 mM glucose intertrain interval, WT = 49.3 ± 9.6 s; CaV1.3−/− = 120.3 ± 25.5 s, P = 0.04) in both young and adult β cells. Therefore, our data demonstrate that the CaV1.3 channel is required for the initiation of glucose-induced β-cell electrical activity and modulates β-cell mass and insulin release in both young and old mice.
This work was supported by Austrian Science Fund (FWF) grants P31434 and DOC30-B30, and Erika-Cremer Habilitation Fellowship IBK.