Role of High Voltage-Gated Ca2+ Channel Subunits in Pancreatic β-Cell Insulin Release. From Structure to Function

The pancreatic islets of Langerhans secrete several hormones critical for glucose homeostasis. The beta-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 alpha-cells while delta-cells secrete somatostatin that via paracrine mechanisms regulates the alpha- and beta-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 alpha(1) and the auxiliary intracellular beta, extracellular alpha(2)delta, and transmembrane gamma subunits. Here, we review the current understanding regarding the role of all HVCC subunits expressed in pancreatic beta-cell on electrical activity, excitation-secretion coupling, and beta-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.

Automated summary

Pancreatic islets secrete hormones critical for glucose homeostasis, with insulin from beta-cells being the main hormone for lowering blood glucose levels. Glucagon and somatostatin also play important roles in regulating hormone secretion. High voltage-gated Ca2+ channels are central in the release of pancreatic hormones and play a key role in diabetes.