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Glucagon-Like Peptide-1 Inhibits Pancreatic ATP-Sensitive Potassium Channels via a Protein Kinase A- and ADP-Dependent Mechanism

Department of Pharmacology (P.E.L., J.E.M.F., M.J.R.), Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada T6G 2H7; and Department of Physiology (M.B.W.), University of Toronto, Ontario, Canada M5S 1A8

Address all correspondence and requests for reprints to: Peter E. Light, Department of Pharmacology, Faculty of Medicine and Dentistry, University of Alberta, 9-58 Medical Science Building, Alberta, Canada T6G 2H7. E-mail: peter.light{at}ualberta.ca.

Glucagon-like peptide-1 (GLP-1) elicits a glucose-dependent insulin secretory effect via elevation of cAMP and activation of protein kinase A (PKA). GLP-1-mediated closure of ATP-sensitive potassium (K_ATP) channels is involved in this process, although the mechanism of action of PKA on the K_ATP channels is not fully understood. K_ATP channel currents and membrane potentials were measured from insulin-secreting INS-1 cells and recombinant ß-cell K_ATP channels. 20 nM GLP-1 depolarized INS-1 cells significantly by 6.68 ± 1.29 mV. GLP-1 reduced recombinant K_ATP channel currents by 54.1 ± 6.9% in mammalian cells coexpressing SUR1, Kir6.2, and GLP-1 receptor clones. In the presence of 0.2 mM ATP, the catalytic subunit of PKA (cPKA, 20 nM) had no effect on SUR1/Kir6.2 activity in inside-out patches. However, the stimulatory effects of 0.2 mM ADP on SUR1/Kir6.2 currents were reduced by 26.7 ± 2.9% (P < 0.05) in the presence of cPKA. cPKA increased SUR1/Kir6.2 currents by 201.2 ± 20.8% (P < 0.05) with 0.5 mM ADP present. The point mutation S1448A in the ADP-sensing region of SUR1 removed the modulatory effects of cPKA. Our results indicate that PKA-mediated phosphorylation of S1448 in the SUR1 subunit leads to K_ATP channel closure via an ADP-dependent mechanism. The marked alteration of the PKA-mediated effects at different ADP levels may provide a cellular mechanism for the glucose-sensitivity of GLP-1.

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