The T-type calcium channel CaV3.2 regulates insulin secretion in the pancreatic β-cell. (December 2022)

• Record Type: Journal Article
• Authors: Barghouth, Mohammad; Ye, Yingying; Karagiannopoulos, Alexandros; Ma, Yunhan; Cowan, Elaine; Wu, Rui; Eliasson, Lena; Renström, Erik; Luan, Cheng; Zhang, Enming
• Is Part Of: Cell calcium. Volume 108(2022)
• Publication Date: 2022-12
• Subjects: T-type CaV channel -- CaV3.2 -- CACNA1H -- Insulin secretion -- Ca2+ signaling -- Type-2 diabetes -- L-type CaV channel; Calcium -- Metabolism -- Periodicals; Vertebrates -- Physiology -- Periodicals; Calcium -- Physiological effect -- Periodicals; Cell physiology -- Periodicals; Calcium in the body -- Periodicals; 572.516
• DOI: 10.1016/j.ceca.2022.102669
• Languages: English
• ISSNs: 0143-4160

Abstract

Highlights: CACNA1H expression is negatively correlated with HbA1c in human donors. CaV 3.2 knock-down/inhibition down-regulates Ca 2+ signaling in β-cells. CaV 3.2 is essential to maintain normal insulin secretion in pancreatic β-cells. CaV 3.2 is strongly associated with L-type CaV channels. Abstract: Voltage-gated Ca 2+ (CaV ) 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 CaV channels in β-cells remains obscure. Here we have measured the global expression of T-type CaV 3.2 channels in human islets and found that gene expression of CACNA1H, encoding CaV 3.2, 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 CaV 3.2 attenuates glucose-stimulated cytosolic Ca 2+ signaling, membrane potential, and insulin release. Moreover, the endoplasmic reticulum (ER) Ca 2+ store depletion is also impaired in CaV 3.2-silenced β-cells. The linkage between T-type (CaV 3.2) and L-type CaV channels is further identified by the finding that the intracellular Ca 2+ signaling conducted by CaV 3.2 is highly dependent on the activation of L-type CaV channels. In addition, CACNA1H expression is significantly associated with the islet predominant L-type CACNA1C (CaV 1.2) and CACNA1D (CaV 1.3) genes in human pancreatic islets. In conclusion, our data suggest the essential functions of the T-type CaV 3.2 subunit as a mediator of β-cell Ca 2+ signaling and membrane potential needed for insulin secretion, and in connection with L-type CaV channels. Graphical abstract: Image, graphical abstract