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Glibenclamide opens ATP-sensitive potassium channels in Xenopus oocyte follicular cells during metabolic stress

E Guillemare, M Lazdunski and E Honore

Institut de Pharmacologie Moleculaire et Cellulaire, Valbonne, France.

Follicular cells from Xenopus oocytes offer a particularly interesting system to study ATP-sensitive K+ channels (KATP channels). In these cells, as in many other cell types, glibenclamide is a classical blocker of KATP channels. Metabolic inhibition with dinitrophenol (DNP) converts this inhibitory effect into an activation. Follicular cells treated with DNP keep their sensitivity to the KATP channel opener P1060, but this opening effect becomes insensitive to glibenclamide inhibition. Glibenclamide activation of KATP channels in DNP-treated follicular cells occurs with an EC50 of 3 microM. Glibenclamide activation is antagonized by blockers of KATP channels that do not belong to the sulfonylurea family, such as U-37883A, tedisamil, and LH 35. Other sulfonylureas display the same activating behavior as does glibenclamide in DNP-treated cells. Two of the properties of KATP channels in follicular cells are activation by cAMP through protein kinase A and inhibition by muscarinic effectors through protein kinase C activation. The stimulating effects of cAMP and glibenclamide in DNP- treated cells seem to be synergistic as are the cAMP and P1060 effects in control follicular cells. Glibenclamide-activated KATP channels in DNP-treated cells (conductance of 15 pS) are also inhibited by acetylcholine and by phorbol esters. The internal acidosis produced by metabolic exhaustion with DNP appears to be the key element in the conversion of glibenclamide from a blocker to an activator of KATP channels.

Volume 47, Issue 3, pp. 588-594, 03/01/1995
Copyright © 1995 by American Society for Pharmacology and Experimental Therapeutics




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