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Glucose-dependent potentiation of mouse islet insulin secretion by Epac activator 8-pCPT-2’-O-Me-cAMP-AM

Grant G. Kelley, Oleg G. Chepurny, Frank Schwede, Hans-G. Genieser, Colin A. Leech, Michael W. Roe, Xiangquan Li, Igor Dzhura, Elvira Dzhura, Parisa Afshari and George G. Holz

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Epac2 is a cAMP-regulated guanine nucleotide exchange factor (cAMP-GEF) that is proposed to mediate stimulatory actions of the second messenger cAMP on mouse islet insulin secretion. Here we have used methods of islet perifusion to demonstrate that the acetoxymethyl ester (AM-ester) of an Epac-selective cAMP analog (ESCA) penetrates into mouse islets and is capable of potentiating both first and second phases of glucose-stimulated insulin secretion (GSIS). When used at low concentrations (1-10 μM), 8-pCPT-2’-O-Me-cAMP-AM activates Rap1 GTPase but exhibits little or no ability to activate protein kinase A (PKA), as validated in assays of in vitro PKA activity (phosphorylation of Kemptide), Ser¹³³ CREB phosphorylation status, RIP1-CRE-Luc reporter gene activity, and PKA-dependent AKAR3 biosensor activation. Since quantitative PCR demonstrates Epac2 mRNA to be expressed at levels ca. 5.3-fold greater than that of Epac1, available evidence indicates that Epac2 does in fact mediate stimulatory actions of cAMP on mouse islet GSIS.

Chepurny OG, Leech CA, Kelley GG, Dzhura I, Dzhura E, Li X, et al. Enhanced Rap1 activation and insulin secretagogue properties of an acetoxymethyl ester of an Epac-selective cyclic AMP analog in rat INS-1 cells: studies with 8-pCPT-2’-O-Me-cAMP-AM. J Biol Chem. 2009; 284:10728-36. PMID: 19244230; DOI: 10.1074/jbc.M900166200

Authors

Grant G. Kelley

Department of Medicine, State University of New York Upstate Medical University Syracuse, NY, USA

Oleg G. Chepurny

Department of Medicine, State University of New York Upstate Medical University Syracuse, NY, US

Frank Schwede

BIOLOG Life Science Institute, Bremen, Germany

Hans-G. Genieser

BIOLOG Life Science Institute, Bremen, Germany

Colin A. Leech

Department of Medicine, State University of New York Upstate Medical University Syracuse, NY, USA

Michael W. Roe

Department of Medicine, State University of New York Upstate Medical University Syracuse, NY, USA

Xiangquan Li

Department of Medicine, State University of New York Upstate Medical University Syracuse, NY, USA

Igor Dzhura

Department of Medicine, State University of New York Upstate Medical University Syracuse, NY, USA

Elvira Dzhura

Department of Medicine, State University of New York Upstate Medical University Syracuse, NY, USA

Parisa Afshari

Department of Medicine, State University of New York Upstate Medical University Syracuse, NY, USA

George G. Holz Corresponding author: holzg@upstate.edu

Department of Medicine, State University of New York Upstate Medical University Syracuse, NY, USA

This is an open-access article

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