Zinc is both an intracellular and extracellular regulator of KATP channel function

J Physiol. 2004 Aug 15;559(Pt 1):157-67. doi: 10.1113/jphysiol.2004.065094. Epub 2004 Jun 24.


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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / chemistry
  • Adenosine Triphosphate / physiology*
  • Animals
  • COS Cells
  • Chlorocebus aethiops
  • Cricetinae
  • Extracellular Fluid / chemistry
  • Extracellular Fluid / physiology*
  • Female
  • Intracellular Fluid / chemistry
  • Intracellular Fluid / physiology*
  • Mice
  • Oocytes / physiology
  • Potassium Channels, Inwardly Rectifying / chemistry
  • Potassium Channels, Inwardly Rectifying / physiology*
  • Protein Subunits / chemistry
  • Protein Subunits / physiology
  • Rats
  • Xenopus laevis
  • Zinc / chemistry*


  • Kir6.2 channel
  • Potassium Channels, Inwardly Rectifying
  • Protein Subunits
  • Adenosine Triphosphate
  • Zinc