Zinc is both an intracellular and extracellular regulator of K ATP 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 μ m , 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.