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CELLULAR |
1 Department of Physiology and Neuroscience
2 Department of Pediatrics
3 Department of Cell Biology
6 Department of Pharmacology, New York University School of Medicine, New York, NY, USA
4 Department of Physiological Chemistry and Centre for Biomedical Genetics, University Medical Center Utrecht, Universiteitsweg 100, 3584CG Utrecht, The Netherlands
5 BIOLOG Life Science Institute, PO Box 107125, D-28071 Bremen, Germany
The Epac family of cAMP-regulated guanine nucleotide exchange factors (cAMPGEFs, also known as Epac1 and Epac2) mediate stimulatory actions of the second messenger cAMP on insulin secretion from pancreatic ß cells. Because Epac2 is reported to interact in vitro with the isolated nucleotide-binding fold-1 (NBF-1) of the ß-cell sulphonylurea receptor-1 (SUR1), we hypothesized that cAMP might act via Epac1 and/or Epac2 to inhibit ß-cell ATP-sensitive K+ channels (KATP channels; a hetero-octomer of SUR1 and Kir6.2). If so, Epac-mediated inhibition of KATP channels might explain prior reports that cAMP-elevating agents promote ß-cell depolarization, Ca2+ influx and insulin secretion. Here we report that Epac-selective cAMP analogues (2'-O-Me-cAMP; 8-pCPT-2'-O-Me-cAMP; 8-pMeOPT-2'-O-Me-cAMP), but not a cGMP analogue (2'-O-Me-cGMP), inhibit the function of KATP channels in human ß cells and rat INS-1 insulin-secreting cells. Inhibition of KATP channels is also observed when cAMP, itself, is administered intracellularly, whereas no such effect is observed upon administration N6-Bnz-cAMP, a cAMP analogue that activates protein kinase A (PKA) but not Epac. The inhibitory actions of Epac-selective cAMP analogues at KATP channels are mimicked by a cAMP agonist (8-Bromoadenosine-3', 5'-cyclic monophosphorothioate, Sp-isomer, Sp-8-Br-cAMPS), but not a cAMP antagonist (8-Bromoadenosine-3', 5'-cyclic monophosphorothioate, Rp-isomer, Rp-8-Br-cAMPS), and are abrogated following transfection of INS-1 cells with a dominant-negative Epac1 that fails to bind cAMP. Because both Epac1 and Epac2 coimmunoprecipitate with full-length SUR1 in HEK cell lysates, such findings delineate a novel mechanism of second messenger signal transduction in which cAMP acts via Epac to modulate ion channel function, an effect measurable as the inhibition of KATP channel activity in pancreatic ß cells.
(Received 16 March 2005;
accepted after revision 6 April 2006;
first published online 13 April 2006)
Corresponding author G. G. Holz: Medical Sciences Building Room 442, 550 First Avenue, New York, NY 10016, USA. Email: holzg01{at}popmail.med.nyu.edu
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