Journal
CELLULAR AND MOLECULAR LIFE SCIENCES
Volume 71, Issue 7, Pages 1289-1303Publisher
SPRINGER BASEL AG
DOI: 10.1007/s00018-013-1442-x
Keywords
Ca2+ channel; Integrin; Pancreatic beta cell; Protein kinase; Scavenger receptor
Categories
Funding
- Berth von Kantzow's Foundation
- Diabetes Research and Wellness Foundation
- EuroDia [FP6-518153]
- Family Erling-Persson Foundation
- Fredrik and Ingrid Thuring's Foundation
- Funds of Karolinska Institutet
- Knut and Alice Wallenberg Foundation
- Magn. Bergvall's Foundation
- Novo Nordisk Foundation
- Skandia Insurance Company, Ltd.
- Stichting af Jochnick Foundation
- Strategic Research Program in Diabetes at Karolinska Institutet
- Swedish Alzheimer Association
- Swedish Diabetes Association
- Swedish Foundation for Strategic Research
- Swedish Research Council
- Swedish Society of Medicine
- Torsten and Ragnar Soderberg Foundation
- VIBRANT [FP7-228933-2]
- Ake Wiberg's Foundation
- Novo Nordisk Fonden [NNF12OC1016557] Funding Source: researchfish
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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+ (Ca-V) channels in the pancreatic beta cell. However, nothing is known about the molecular mechanisms whereby ApoCIII hyperactivates beta cell Ca-V channels. We now demonstrate that ApoCIII increased Ca(V)1 channel open probability and density. ApoCIII enhanced whole-cell Ca2+ currents and the Ca(V)1 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 beta 1 integrin or scavenger receptor class B type I (SR-BI) prevented ApoCIII from hyperactivating beta cell Ca-V channels. These data reveal that ApoCIII hyperactivates beta cell Ca(V)1 channels through SR-BI/beta 1 integrin-dependent coactivation of PKA and Src.
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