Postnatal refinement of CaV channel isoform composition, electrical activity, and insulin release in mouse pancreatic β-cells.

Abstract

Pancreatic β-cell mass and glucose-stimulated insulin secretion strongly increase during postnatal development. Voltage-gated calcium channels (Ca_V) are the key determinants of pancreatic β-cell electrical activity, insulin granule exocytosis, β-cell proliferation and survival. Here we show that β-cells of 1-day-old mice have significantly smaller Ca_V currents compared to 14-day (juvenile) or 3-month-old (adult) mice, as well as a different Ca_V isoform composition. In neonates, P/Q-type channels contribute ~53% of the whole-cell current while L-type channels contribute only ~25%. The reduced L-type current is associated with a complete absence of β-cell-specific glucose-induced excitability even though the β-cells depolarize at a lower glucose threshold. By postnatal day 14, the L-type contribution increases to ~44%, reaching ~50% in adults, and P/Q-type currents decrease to ~20%. Nevertheless, the total β-cell calcium influx density is largest in juvenile mice consistent with a lower-threshold glucose dependence of the electrical activity compared to adults. Despite the larger calcium influx, the islets of 14-day-old mice show significantly reduced vesicle exocytosis, insulin release and insulin content. Our data show extensive postnatal remodeling in β-cell mass and glucose sensitivity, and an age-dependent refinement of Ca_V isoform composition, electrical activity, and insulin release. The cumulative increase in β-cell mass and insulin release causes a ~ 7-fold increase in plasma insulin levels between 14-day- and 3-month-old mice.