Palmitoylation of Ca 2+ channel subunit Ca V β 2a induces pancreatic beta-cell toxicity via Ca 2+ overload

Biochem Biophys Res Commun. 2017 Sep 23;491(3):740-746. doi: 10.1016/j.bbrc.2017.07.117. Epub 2017 Jul 21.

Abstract

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 (CaV) and high density of CaV in the plasma membrane could lead to Ca2+ overload. Trafficking of the pore-forming CaVα1 subunit to the plasma membrane is regulated by auxiliary subunits, such as the CaVβ2a subunit. This study investigates, using Ca2+ imaging and immunohistochemistry, the role of palmitoylation of CaVβ2a in maintaining Ca2+ homeostasis and beta cell function. RNA sequencing data showed that gene expression of human CACNB2, in particular CACNB2A (CaVβ2a), is highest in islets when compared to other tissues. Since CaVβ2a can be regulated through palmitoylation of its two cysteines, CaVβ2a and its mutant form were overexpressed in pancreatic beta cells. Palmitoylated CaVβ2a tethered to the plasma membrane and colocalized with CaV1.2 while the mutant form remained in the cytosol. Interestingly, CaVβ2a overexpression raised basal intracellular Ca2+ and increased beta cell apoptosis. Our study shows that palmitoylation of CaVβ2a is necessary for CaVα1 trafficking to the plasma membrane. However, excessive number of palmitoylated CaVβ2a leads to Ca2+ overload and beta cell death.

Keywords: Apoptosis; Beta cells; Ca(V)β(2a); Palmitoylation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / physiology*
  • Binding Sites
  • Calcium / metabolism*
  • Calcium Channels, L-Type / metabolism*
  • Calcium Signaling / physiology*
  • Cell Line
  • Insulin-Secreting Cells / cytology
  • Insulin-Secreting Cells / physiology*
  • Ion Channel Gating / physiology
  • Lipoylation / physiology*
  • Protein Binding
  • Protein Subunits
  • Rats

Substances

  • Cacnb2 protein, rat
  • Calcium Channels, L-Type
  • Protein Subunits
  • Calcium