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This version published online on June 20, 2002
Molecular Endocrinology, doi:10.1210/me.2002-0084
Molecular Endocrinology Vol. 0, No. 2002 200200841-
doi:10.1210/me.2002-0084
Copyright © 2002 by the Endocrine Society.
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Submitted on February 26, 2002
Accepted on June 3, 2002

Glucagon-like peptide-1 inhibits pancreatic ATP-sensitive potassium channels via a protein kinase A and adenosine diphosphate-dependent mechanism

Peter E. Light1*, Jocelyn E. Manning Fox1, Michael J. Riedel1, and Michael B. Wheeler1

1 Department of Pharmacology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada, T6G 2H7. Department of Physiology, University of Toronto, Ontario, Canada.

* To whom correspondence should be addressed. 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 (KATP) channels is involved in this process, although the mechanism of action of PKA on the KATP channels is not fully understood. KATP channel currents and membrane potentials were measured from the insulin secreting INS-1 cells and recombinant ß-cell KATP channels. 20 nM GLP-1 depolarized INS-1 cells significantly by 6.68 ± 1.29 mV. GLP-1 reduced recombinant KATP channel currents by 54.1 ± 6.9% in mammalian cells co-expressing 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) 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 KATP 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.
Key words: ATP-sensitive potassium channels • KATP channels • Glucagon-like peptide-1 • patch-clamp • diabetes




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