The T-type calcium channel Ca_V3.2 regulates insulin secretion in the pancreatic β-cell

Voltage-gated Ca²⁺ (Ca_V) 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_V channels in β-cells remains obscure. Here we have measured the global expression of T-type Ca_V3.2 channels in human islets and found that gene expression of CACNA1H, encoding Ca_V3.2, 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 Ca_V3.2 attenuates glucose-stimulated cytosolic Ca²⁺ signaling, membrane potential, and insulin release. Moreover, the endoplasmic reticulum (ER) Ca²⁺ store depletion is also impaired in Ca_V3.2-silenced β-cells. The linkage between T-type (Ca_V3.2) and L-type Ca_V channels is further identified by the finding that the intracellular Ca²⁺ signaling conducted by Ca_V3.2 is highly dependent on the activation of L-type Ca_V channels. In addition, CACNA1H expression is significantly associated with the islet predominant L-type CACNA1C (Ca_V1.2) and CACNA1D (Ca_V1.3) genes in human pancreatic islets. In conclusion, our data suggest the essential functions of the T-type Ca_V3.2 subunit as a mediator of β-cell Ca²⁺ signaling and membrane potential needed for insulin secretion, and in connection with L-type Ca_V channels.