Zinc is both an intracellular and extracellular regulator of KATP channel function.
Extracellular Zn(2+) has been identified as an activator of pancreatic K(ATP) channels. We further examined the action of Zn(2+) on recombinant K(ATP) 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. Zn(2+), applied at either the extracellular or intracellular side of the membrane appeared as a potent, reversible activator of K(ATP) channels. External Zn(2+), at micromolar concentrations, activated SUR1/Kir6.2 but induced a small inhibition of SUR2A/Kir6.2 channels. Cytosolic Zn(2+) dose-dependently stimulated both SUR1/Kir6.2 and SUR2A/Kir6.2 channels, with half-maximal effects at 1.8 and 60 microm, respectively, but it did not affect the Kir6.2 subunit expressed alone. These observations point to an action of both external and internal Zn(2+) on the SUR subunit. Effects of internal Zn(2+) were not due to Zn(2+) leaking out, since they were unaffected by the presence of a Zn(2+) chelator on the external side. Similarly, internal chelators did not affect activation by external Zn(2+). Therefore, Zn(2+) is an endogenous K(ATP) 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 K(ATP) channels, and suggest a new role for Zn(2+) as an intracellular signalling molecule.
Prost
Anne-Lise
AL
Biophysique Moléculaire & Cellulaire, CNRS UMR5090, CEA/DRDC, 17 rue des Martyrs, 38054 Grenoble, France.
Bloc
Alain
A
Hussy
Nicolas
N
Derand
Renaud
R
Vivaudou
Michel
M
D000255:Adenosine Triphosphate / Q000737:chemistry / Q000502:physiology*; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D006224:Cricetinae; D045604:Extracellular Fluid / Q000737:chemistry / Q000502:physiology*; D005260:Female; D007424:Intracellular Fluid / Q000737:chemistry / Q000502:physiology*; D051379:Mice; D009865:Oocytes / Q000502:physiology; D024661:Potassium Channels, Inwardly Rectifying / Q000737:chemistry / Q000502:physiology*; D021122:Protein Subunits / Q000737:chemistry / Q000502:physiology; D051381:Rats; D014982:Xenopus laevis; D015032:Zinc / Q000737:chemistry*; D000099161:Kcnj11 Channel
D000255:Adenosine Triphosphate; D024661:Potassium Channels, Inwardly Rectifying; D021122:Protein Subunits; D015032:Zinc; D000099161:Kcnj11 Channel