The T-type calcium channel Ca3.2 regulates insulin secretion in the pancreatic β-cell.

Voltage-gated Ca (Ca) channel dysfunction leads to impaired glucose-stimulated insulin secretion in pancreatic β-cells and contributes to the development of type-2 diabetes (T2D). The role of the low-voltage gated T-type Ca channels in β-cells remains obscure. Here we have measured the global expression of T-type Ca3.2 channels in human islets and found that gene expression of CACNA1H, encoding Ca3.2, is negatively correlated with HbA1c in human donors, and positively correlated with islet insulin gene expression as well as secretion capacity in isolated human islets. Silencing or pharmacological blockade of Ca3.2 attenuates glucose-stimulated cytosolic Ca signaling, membrane potential, and insulin release. Moreover, the endoplasmic reticulum (ER) Ca store depletion is also impaired in Ca3.2-silenced β-cells. The linkage between T-type (Ca3.2) and L-type Ca channels is further identified by the finding that the intracellular Ca signaling conducted by Ca3.2 is highly dependent on the activation of L-type Ca channels. In addition, CACNA1H expression is significantly associated with the islet predominant L-type CACNA1C (Ca1.2) and CACNA1D (Ca1.3) genes in human pancreatic islets. In conclusion, our data suggest the essential functions of the T-type Ca3.2 subunit as a mediator of β-cell Ca signaling and membrane potential needed for insulin secretion, and in connection with L-type Ca channels.