Palmitoylation of Ca²⁺ channel subunit Ca_Vβ_2a induces pancreatic beta-cell toxicity via Ca²⁺ overload

High blood glucose triggers the release of insulin from pancreatic beta cells, but if chronic, causes cellular stress, partly due to impaired Ca²⁺ homeostasis. Ca²⁺ influx is controlled by voltage-gated calcium channels (Ca_V) and high density of Ca_V in the plasma membrane could lead to Ca²⁺ overload. Trafficking of the pore-forming Ca_Vα₁ subunit to the plasma membrane is regulated by auxiliary subunits, such as the Ca_Vβ_2a subunit. This study investigates, using Ca²⁺ imaging and immunohistochemistry, the role of palmitoylation of Ca_Vβ_2a in maintaining Ca²⁺ homeostasis and beta cell function. RNA sequencing data showed that gene expression of human CACNB2, in particular CACNB2A (Ca_Vβ_2a), is highest in islets when compared to other tissues. Since Ca_Vβ_2a can be regulated through palmitoylation of its two cysteines, Ca_Vβ_2a and its mutant form were overexpressed in pancreatic beta cells. Palmitoylated Ca_Vβ_2a tethered to the plasma membrane and colocalized with Ca_V1.2 while the mutant form remained in the cytosol. Interestingly, Ca_Vβ_2a overexpression raised basal intracellular Ca²⁺ and increased beta cell apoptosis. Our study shows that palmitoylation of Ca_Vβ_2a is necessary for Ca_Vα₁ trafficking to the plasma membrane. However, excessive number of palmitoylated Ca_Vβ_2a leads to Ca²⁺ overload and beta cell death.