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

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 whereb...

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Published in:	Cellular and molecular life sciences : CMLS 2014-04, Vol.71 (7), p.1289-1303
Main Authors:	Shi, Yue, Yang, Guang, Yu, Jia, Yu, Lina, Westenbroek, Ruth, Catterall, William A, Juntti-Berggren, Lisa, Berggren, Per-Olof, Yang, Shao-Nian
Format:	Article
Language:	eng
Subjects:	Animals Apolipoprotein C-III - metabolism Apolipoprotein C-III - pharmacology Apolipoprotein C-III - physiology Biochemistry Biomedical and Life Sciences Biomedicine calcium Calcium - metabolism Calcium Channels - metabolism cAMP-dependent protein kinase CD29 antigen CD36 Antigens - genetics CD36 Antigens - metabolism Cell Biology Cells, Cultured Cyclic AMP-Dependent Protein Kinases - metabolism Electrophysiology Female Gene Knockdown Techniques hydrolysis inhibition Insulin-Secreting Cells - metabolism Integrin beta1 - genetics Integrin beta1 - metabolism Integrin beta1 - physiology Islets of Langerhans - drug effects Islets of Langerhans - metabolism Life Sciences Male Medicin och hälsovetenskap Mice probability protein kinase C Proto-Oncogene Proteins pp60(c-src) - metabolism Research Article RNA Interference triacylglycerols Up-Regulation
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Summary:	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 CaVchannels. 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 CaVchannels. These data reveal that ApoCIII hyperactivates β cell CaV1 channels through SR-BI/β1 integrin-dependent coactivation of PKA and Src.
ISSN:	1420-682X 1420-9071 1420-9071