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Palmitoylation of Ca2+ channel subunit CaVβ2a induces pancreatic beta-cell toxicity via Ca2+ overload

Kazim, Abdulla S. LU ; Storm, Petter LU ; Zhang, Enming LU and Renström, Erik LU (2017) In Biochemical and Biophysical Research Communications
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... (More)

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.

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author
organization
publishing date
type
Contribution to journal
publication status
epub
subject
keywords
Apoptosis, Beta cells, Caβ, Palmitoylation
in
Biochemical and Biophysical Research Communications
publisher
Elsevier
external identifiers
  • scopus:85025598789
ISSN
0006-291X
DOI
10.1016/j.bbrc.2017.07.117
language
English
LU publication?
yes
id
0b1d8b8d-9065-4966-88a7-e8cd171d78ec
date added to LUP
2017-08-02 09:44:03
date last changed
2017-08-03 03:00:08
@article{0b1d8b8d-9065-4966-88a7-e8cd171d78ec,
  abstract     = {<p>High blood glucose triggers the release of insulin from pancreatic beta cells, but if chronic, causes cellular stress, partly due to impaired Ca<sup>2+</sup> homeostasis. Ca<sup>2+</sup> influx is controlled by voltage-gated calcium channels (Ca<sub>V</sub>) and high density of Ca<sub>V</sub> in the plasma membrane could lead to Ca<sup>2+</sup> overload. Trafficking of the pore-forming Ca<sub>V</sub>α<sub>1</sub> subunit to the plasma membrane is regulated by auxiliary subunits, such as the Ca<sub>V</sub>β<sub>2a</sub> subunit. This study investigates, using Ca<sup>2+</sup> imaging and immunohistochemistry, the role of palmitoylation of Ca<sub>V</sub>β<sub>2a</sub> in maintaining Ca<sup>2+</sup> homeostasis and beta cell function. RNA sequencing data showed that gene expression of human CACNB2, in particular CACNB2A (Ca<sub>V</sub>β<sub>2a</sub>), is highest in islets when compared to other tissues. Since Ca<sub>V</sub>β<sub>2a</sub> can be regulated through palmitoylation of its two cysteines, Ca<sub>V</sub>β<sub>2a</sub> and its mutant form were overexpressed in pancreatic beta cells. Palmitoylated Ca<sub>V</sub>β<sub>2a</sub> tethered to the plasma membrane and colocalized with Ca<sub>V</sub>1.2 while the mutant form remained in the cytosol. Interestingly, Ca<sub>V</sub>β<sub>2a</sub> overexpression raised basal intracellular Ca<sup>2+</sup> and increased beta cell apoptosis. Our study shows that palmitoylation of Ca<sub>V</sub>β<sub>2a</sub> is necessary for Ca<sub>V</sub>α<sub>1</sub> trafficking to the plasma membrane. However, excessive number of palmitoylated Ca<sub>V</sub>β<sub>2a</sub> leads to Ca<sup>2+</sup> overload and beta cell death.</p>},
  author       = {Kazim, Abdulla S. and Storm, Petter and Zhang, Enming and Renström, Erik},
  issn         = {0006-291X},
  keyword      = {Apoptosis,Beta cells,Caβ,Palmitoylation},
  language     = {eng},
  month        = {07},
  publisher    = {Elsevier},
  series       = {Biochemical and Biophysical Research Communications},
  title        = {Palmitoylation of Ca<sup>2+</sup> channel subunit Ca<sub>V</sub>β<sub>2a</sub> induces pancreatic beta-cell toxicity via Ca<sup>2+</sup> overload},
  url          = {http://dx.doi.org/10.1016/j.bbrc.2017.07.117},
  year         = {2017},
}