The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, SE-171 76, Stockholm, Sweden.
Cell Mol Life Sci. 2014 Apr;71(7):1289-303. doi: 10.1007/s00018-013-1442-x. Epub 2013 Aug 15.
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.
载脂蛋白 CIII（ApoCIII）不仅作为甘油三酯水解的抑制剂，而且还参与糖尿病相关的病理事件，如胰腺β细胞中电压门控 Ca(2+)（CaV）通道的超激活。然而，目前尚不清楚 ApoCIII 如何超激活β细胞 CaV 通道的分子机制。我们现在证明 ApoCIII 增加了 CaV1 通道的开放概率和密度。ApoCIII 增强了全细胞 Ca(2+)电流，而 CaV1 通道阻断剂尼莫地平完全阻断了这种增强。ApoCIII 的作用不受 PKA、PKC 或 Src 的单独抑制的影响。然而，PKA、PKC 和 Src 的联合抑制抵消了 ApoCIII 的作用，PKA 和 Src 的联合抑制也得到了类似的结果。此外，β1 整合素或清道夫受体 B 类 I（SR-BI）的敲低阻止了 ApoCIII 超激活β细胞 CaV 通道。这些数据表明，ApoCIII 通过 SR-BI/β1 整合素依赖性 PKA 和 Src 的共激活来超激活β细胞 CaV1 通道。
