Journal
METABOLISM-CLINICAL AND EXPERIMENTAL
Volume 63, Issue 1, Pages 120-126Publisher
W B SAUNDERS CO-ELSEVIER INC
DOI: 10.1016/j.metabol.2013.09.009
Keywords
CASK; GLP-1; PKA; Epac2
Categories
Funding
- Natural Science Foundation of Jiangsu Province [BK2012752]
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Objective. Exendin-4 (Ex-4) is an anti-diabetic drug that is a potent agonist of the glucagon-like peptide-1 (GLP-1) receptor. It has already been approved for the treatment of type 2 diabetes mellitus, but its underlying mechanisms of action are not fully understood. Calcium/calmodulin-dependent serine protein kinase (CASK), which plays a vital role in the transport and release of neurotransmitters in neurons, is expressed in pancreatic islet cells and p-cells. This study aimed to investigate whether CASK is involved in the insulin secretagogue action induced by Ex-4 in INS-1 cells. Material/Methods. A glucose-stimulated insulin secretion (GSIS) assay was performed with or without siRNA treatment against CASK. The expression level and location of CASK were evaluated by real-time PCR, western blotting and immunofluorescence. With the use of a protein kinase A (PICA) inhibitor or an exchange protein directly activated by cAMP-2 (Epac2) agonist, immunoblotting was performed to establish the signaling pathway through which Ex-4 alters CASK expression. Results. Knock-down of CASK significantly attenuated the Ex-4-enhanced insulin release, and we showed that Ex-4 could increase transcription of CASK mRNA and expression of CASK protein but did not change the cellular location of CASK. A PICA inhibitor reduced the ability of Ex-4 to stimulate CASK expression, but an Epac2 agonist had no effect suggesting that regulation was mediated by the cAMP/PkA pathway. Conclusion. Our study suggests that the stimulation of B-cell insulin secretion by Ex-4 is mediated, at least in part, by CASK via a novel signaling mechanism. (C) 2014 Elsevier Inc. All rights reserved.
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