Zn2+ regulates Kv2.1 voltage-dependent gating and localization following ischemia

Eur J Neurosci. 2009 Dec;30(12):2250-7. doi: 10.1111/j.1460-9568.2009.07026.x. Epub 2009 Dec 10.

Abstract

The delayed-rectifier K(+) channel Kv2.1 exists in highly phosphorylated somatodendritic clusters. Ischemia induces rapid Kv2.1 dephosphorylation and a dispersal of these clusters, accompanied by a hyperpolarizing shift in their voltage-dependent activation kinetics. Transient modulation of Kv2.1 activity and localization following ischemia is dependent on a rise in intracellular Ca(2+)and the protein phosphatase calcineurin. Here, we show that neuronal free Zn(2+)also plays a critical role in the ischemic modulation of Kv2.1. We found that sub-lethal ischemia in cultured rat cortical neurons led to characteristic hyperpolarizing shifts in K(+) current voltage dependency and pronounced dephosphorylation of Kv2.1. Zn(2+)chelation, similar to calcineurin inhibition, attenuated ischemic induced changes in K(+) channel activation kinetics. Zn(2+)chelation during ischemia also blocked Kv2.1 declustering. Surprisingly, we found that the Zn(2+)rise following ischemia occurred in spite of calcineurin inhibition. Therefore, a calcineurin-independent rise in neuronal free Zn(2+) is critical in altering Kv2.1 channel activity and localization following ischemia. The identification of Zn(2+) in mediating ischemic modulation of Kv2.1 may lead to a better understanding of cellular adaptive responses to injury.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / physiopathology*
  • Brain Ischemia / physiopathology*
  • Calcineurin / metabolism
  • Calcineurin Inhibitors
  • Cell Membrane / physiology
  • Cells, Cultured
  • Ion Channel Gating*
  • Kinetics
  • Membrane Potentials / physiology
  • Neurons / physiology*
  • Phosphorylation
  • Potassium / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Shab Potassium Channels / metabolism*
  • Zinc / metabolism*

Substances

  • Calcineurin Inhibitors
  • Kcnb1 protein, rat
  • Shab Potassium Channels
  • Calcineurin
  • Zinc
  • Potassium