TY - JOUR
T1 - Palmitoylation of Ca2+ channel subunit CaVβ2a induces pancreatic beta-cell toxicity via Ca2+ overload
AU - Kazim, Abdulla S.
AU - Storm, Petter
AU - Zhang, Enming
AU - Renström, Erik
N1 - Funding Information:
This work was supported by grants from the Swedish Research Council, Diabetes Wellness foundation Sweden, Director Albert Påhlsson Foundation and Lund University to E.R. The position of E.Z. was first funded by the Integrated project BetaBat (European Union), now by the KAW foundation. Human islet data supported by grants from the Juvenile Diabetes Research Foundation, the Swedish Strategic Research area in diabetes EXODIAB and the LUDC-IRC grant by the Swedish Strategic Research Foundation SSF. This work was done using equipment financed by Exodiab and the KAW foundation.
Publisher Copyright:
© 2017 Elsevier Inc.
PY - 2017/9/23
Y1 - 2017/9/23
N2 - 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.
AB - 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.
KW - Apoptosis
KW - Beta cells
KW - Caβ
KW - Palmitoylation
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U2 - 10.1016/j.bbrc.2017.07.117
DO - 10.1016/j.bbrc.2017.07.117
M3 - Article
C2 - 28739256
AN - SCOPUS:85025598789
SN - 0006-291X
VL - 491
SP - 740
EP - 746
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
IS - 3
ER -