Research Article

Cellular and Molecular Life Sciences

, Volume 71, Issue 7, pp 1289-1303

First online:

Apolipoprotein CIII hyperactivates β cell CaV1 channels through SR-BI/β1 integrin-dependent coactivation of PKA and Src

  • Yue ShiAffiliated withThe Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet
  • , Guang YangAffiliated withThe Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska InstitutetJilin Academy of Traditional Chinese Medicine
  • , Jia YuAffiliated withThe Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet
  • , Lina YuAffiliated withThe Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet
  • , Ruth WestenbroekAffiliated withDepartment of Pharmacology, School of Medicine, University of Washington
  • , William A. CatterallAffiliated withDepartment of Pharmacology, School of Medicine, University of Washington
  • , Lisa Juntti-BerggrenAffiliated withThe Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet
  • , Per-Olof BerggrenAffiliated withThe Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet Email author 
  • , Shao-Nian YangAffiliated withThe Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet Email author 

Rent the article at a discount

Rent now

* Final gross prices may vary according to local VAT.

Get Access

Abstract

Apolipoprotein CIII (ApoCIII) not only serves as an inhibitor of triglyceride hydrolysis but also participates in diabetes-related pathological events such as hyperactivation of voltage-gated Ca2+ (CaV) channels in the pancreatic β cell. However, nothing is known about the molecular mechanisms whereby ApoCIII hyperactivates β cell CaV channels. We now demonstrate that ApoCIII increased CaV1 channel open probability and density. ApoCIII enhanced whole-cell Ca2+ currents and the CaV1 channel blocker nimodipine completely abrogated this enhancement. The effect of ApoCIII was not influenced by individual inhibition of PKA, PKC, or Src. However, combined inhibition of PKA, PKC, and Src counteracted the effect of ApoCIII, similar results obtained by coinhibition of PKA and Src. Moreover, knockdown of β1 integrin or scavenger receptor class B type I (SR-BI) prevented ApoCIII from hyperactivating β cell CaV channels. These data reveal that ApoCIII hyperactivates β cell CaV1 channels through SR-BI/β1 integrin-dependent coactivation of PKA and Src.

Keywords

Ca2+ channel Integrin Pancreatic β cell Protein kinase Scavenger receptor