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Eukaryotic translation initiation factor 3 subunit e controls intracellular calcium homeostasis by regulation of cav1.2 surface expression.

Authors: Buda, P  Reinbothe, T  Nagaraj, V  Mahdi, T  Luan, C  Tang, Y  Axelsson, AS  Li, D  Rosengren, AH  Renstrom, E  Zhang, E 
Citation: Buda P, etal., PLoS One. 2013 May 30;8(5):e64462. doi: 10.1371/journal.pone.0064462. Print 2013.
Pubmed: (View Article at PubMed) PMID:23737983
DOI: Full-text: DOI:10.1371/journal.pone.0064462

Inappropriate surface expression of voltage-gated Ca(2+)channels (CaV) in pancreatic ss-cells may contribute to the development of type 2 diabetes. First, failure to increase intracellular Ca(2+) concentrations at the sites of exocytosis impedes insulin release. Furthermore, excessive Ca(2+) influx may trigger cytotoxic effects. The regulation of surface expression of CaV channels in the pancreatic beta-cells remains unknown. Here, we used real-time 3D confocal and TIRFM imaging, immunocytochemistry, cellular fractionation, immunoprecipitation and electrophysiology to study trafficking of L-type CaV1.2 channels upon beta-cell stimulation. We found decreased surface expression of CaV1.2 and a corresponding reduction in L-type whole-cell Ca(2+) currents in insulin-secreting INS-1 832/13 cells upon protracted (15-30 min) stimulation. This internalization occurs by clathrin-dependent endocytosis and could be prevented by microtubule or dynamin inhibitors. eIF3e (Eukaryotic translation initiation factor 3 subunit E) is part of the protein translation initiation complex, but its effect on translation are modest and effects in ion channel trafficking have been suggested. The factor interacted with CaV1.2 and regulated CaV1.2 traffic bidirectionally. eIF3e silencing impaired CaV1.2 internalization, which resulted in an increased intracellular Ca(2+) load upon stimulation. These findings provide a mechanism for regulation of L-type CaV channel surface expression with consequences for beta-cell calcium homeostasis, which will affect pancreatic beta-cell function and insulin production.

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CRRD Object Information
CRRD ID: 10755504
Created: 2016-01-29
Species: All species
Last Modified: 2016-01-29
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.