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 Ca(2+) (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 Ca(2+) 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.
The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, SE-171 76, Stockholm, Sweden.
Yue
Y
Shi
Guang
G
Yang
Jia
J
Yu
Lina
L
Yu
Ruth
R
Westenbroek
William A
WA
Catterall
Lisa
L
Juntti-Berggren
Per-Olof
PO
Berggren
Shao-Nian
SN
Yang
D000818:Animals; D053305:Apolipoprotein C-III / Q000378:metabolism / Q000494:pharmacology* / Q000502:physiology; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000378:metabolism*; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D004594:Electrophysiology; D005260:Female; D055785:Gene Knockdown Techniques; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D019012:Integrin beta1 / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism*; D034622:RNA Interference; D015854:Up-Regulation
D053305:Apolipoprotein C-III; D018955:CD36 Antigens; D015220:Calcium Channels; D019012:Integrin beta1; D016392:Proto-Oncogene Proteins pp60(c-src); D017868:Cyclic AMP-Dependent Protein Kinases; D002118:Calcium