期刊
MOLECULAR ENDOCRINOLOGY
卷 16, 期 9, 页码 2135-2144出版社
OXFORD UNIV PRESS INC
DOI: 10.1210/me.2002-0084
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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 beta-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 S1448A 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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