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1 Biophysique Moléculaire & Cellulaire, CNRS UMR5090, CEA/DRDC, 17 rue des Martyrs, 38054 Grenoble, France
2 Department de Biologie Cellulaire & Morphologie (IBCM), Université de Lausanne, 9 rue du Bugnon, 1005 Lausanne, Switzerland
3 Biologie des Neurones Endocrines, CNRS UMR5101, CCIPE, 141 rue de la Cardonille, 34094 Montpellier, France
Extracellular Zn2+ has been identified as an activator of pancreatic KATP channels. We further examined the action of Zn2+ on recombinant KATP channels formed with the inward rectifier K+ channel subunit Kir6.2 associated with either the pancreatic/neuronal sulphonylurea receptor 1 (SUR1) subunit or the cardiac SUR2A subunit. Zn2+, applied at either the extracellular or intracellular side of the membrane appeared as a potent, reversible activator of KATP channels. External Zn2+, at micromolar concentrations, activated SUR1/Kir6.2 but induced a small inhibition of SUR2A/Kir6.2 channels. Cytosolic Zn2+ dose-dependently stimulated both SUR1/Kir6.2 and SUR2A/Kir6.2 channels, with half-maximal effects at 1.8 and 60 µM, respectively, but it did not affect the Kir6.2 subunit expressed alone. These observations point to an action of both external and internal Zn2+ on the SUR subunit. Effects of internal Zn2+ were not due to Zn2+ leaking out, since they were unaffected by the presence of a Zn2+ chelator on the external side. Similarly, internal chelators did not affect activation by external Zn2+. Therefore, Zn2+ is an endogenous KATP channel opener being active on both sides of the membrane, with potentially distinct sites of action located on the SUR subunit. These findings uncover a novel regulatory pathway targeting KATP channels, and suggest a new role for Zn2+ as an intracellular signalling molecule.
(Received 22 March 2004;
accepted after revision 21 June 2004;
first published online 24 June 2004)
Corresponding author M. Vivaudou: Biophysique Moléculaire & Cellulaire, CNRS UMR5090, CEA/DRDC, 17 rue des Martyrs, 38054 Grenoble, France. Email: vivaudou{at}cea.fr
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