High blood glucose triggers the release of insulin from pancreatic beta cells, but if chronic, causes cellular stress, partly due to impaired Ca homeostasis. Ca influx is controlled by voltage-gated calcium channels (Ca) and high density of Ca in the plasma membrane could lead to Ca overload. Trafficking of the pore-forming Caα subunit to the plasma membrane is regulated by auxiliary subunits, such as the Caβ subunit. This study investigates, using Ca imaging and immunohistochemistry, the role of palmitoylation of Caβ in maintaining Ca homeostasis and beta cell function. RNA sequencing data showed that gene expression of human CACNB2, in particular CACNB2A (Caβ), is highest in islets when compared to other tissues. Since Caβ can be regulated through palmitoylation of its two cysteines, Caβ and its mutant form were overexpressed in pancreatic beta cells. Palmitoylated Caβ tethered to the plasma membrane and colocalized with Ca1.2 while the mutant form remained in the cytosol. Interestingly, Caβ overexpression raised basal intracellular Ca and increased beta cell apoptosis. Our study shows that palmitoylation of Caβ is necessary for Caα trafficking to the plasma membrane. However, excessive number of palmitoylated Caβ leads to Ca overload and beta cell death.
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