title: Glucose-dependent potentiation of mouse islet insulin secretion by Epac activator 8-pCPT-2'-O-Me-cAMP-AM.
abstract: 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), Ser (133) 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.
authors.affiliation: Department of Medicine, State University of New York Upstate Medical University Syracuse, NY, USA.
authors.forename: Grant G
authors.initials: GG
authors.lastname: Kelley
authors.forename: Oleg G
authors.initials: OG
authors.lastname: Chepurny
authors.forename: Frank
authors.initials: F
authors.lastname: Schwede
authors.forename: Hans-G
authors.initials: HG
authors.lastname: Genieser
authors.forename: Colin A
authors.initials: CA
authors.lastname: Leech
authors.forename: Michael W
authors.initials: MW
authors.lastname: Roe
authors.forename: Xiangquan
authors.initials: X
authors.lastname: Li
authors.forename: Igor
authors.initials: I
authors.lastname: Dzhura
authors.forename: Elvira
authors.initials: E
authors.lastname: Dzhura
authors.forename: Parisa
authors.initials: P
authors.lastname: Afshari
authors.forename: George G
authors.initials: GG
authors.lastname: Holz
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D004338:Drug Combinations; D004357:Drug Synergism; D005947:Glucose / Q000008:administration & dosage / Q000494:pharmacology*; D020662:Guanine Nucleotide Exchange Factors / Q000819:agonists*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism; D051379:Mice
chemical_list: C473217:8-(4-chloro-phenylthio)-2'-O-methyladenosine-3'-5'-cyclic monophosphate; C555650:8-(4-chlorophenylthio)-2'-O-methyladenosine-3',5'-monophosphate acetoxymethyl ester; D004338:Drug Combinations; C482601:Epac protein, mouse; D020662:Guanine Nucleotide Exchange Factors; D007328:Insulin; D000242:Cyclic AMP; D005947:Glucose