Zn2+ regulates Kv2.1 voltage-dependent gating and localization following ischemia.
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.
Aras
Mandar A
MA
Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
Saadi
Robert A
RA
Aizenman
Elias
E
D000818:Animals; D001921:Brain / Q000503:physiopathology*; D002545:Brain Ischemia / Q000503:physiopathology*; D019703:Calcineurin / Q000378:metabolism; D065095:Calcineurin Inhibitors; D002462:Cell Membrane / Q000502:physiology; D002478:Cells, Cultured; D015640:Ion Channel Gating; D007700:Kinetics; D008564:Membrane Potentials / Q000502:physiology; D009474:Neurons / Q000502:physiology*; D010766:Phosphorylation; D011188:Potassium / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D051669:Shab Potassium Channels / Q000378:metabolism*; D015032:Zinc / Q000378:metabolism*
D065095:Calcineurin Inhibitors; C496991:Kcnb1 protein, rat; D051669:Shab Potassium Channels; D019703:Calcineurin; D015032:Zinc; D011188:Potassium