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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.

Pubmed ID: 20092568 RIS Download

Mesh terms: Animals | Brain | Brain Ischemia | Calcineurin | Calcineurin Inhibitors | Cell Membrane | Cells, Cultured | Ion Channel Gating | Kinetics | Membrane Potentials | Neurons | Phosphorylation | Potassium | Rats | Rats, Sprague-Dawley | Shab Potassium Channels | Zinc

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Associated grants

  • Agency: NINDS NIH HHS, Id: R01 NS043277
  • Agency: NINDS NIH HHS, Id: R56 NS043277
  • Agency: NINDS NIH HHS, Id: R01 NS043277-07A2
  • Agency: NINDS NIH HHS, Id: R01 NS043277-10
  • Agency: NINDS NIH HHS, Id: R01 NS043277-09
  • Agency: NINDS NIH HHS, Id: NS043277
  • Agency: NINDS NIH HHS, Id: R01 NS043277-08

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NeuroMab

A national mouse monoclonal antibody generating resource for biochemical and immunohistochemical applications in mammalian brain. NeuroMabs are generated from mice immunized with synthetic and recombinant immunogens corresponding to components of the neuronal proteome as predicted from genomic and other large-scale cloning efforts. Comprehensive biochemical and immunohistochemical analyses of human, primate and non-primate mammalian brain are incorporated into the initial NeuroMab screening procedure. This yields a subset of mouse mAbs that are optimized for use in brain (i.e. NeuroMabs): for immunocytochemical-based imaging studies of protein localization in adult, developing and pathological brain samples, for biochemical analyses of subunit composition and post-translational modifications of native brain proteins, and for proteomic analyses of native brain protein networks. The NeuroMab facility was initially funded with a five-year U24 cooperative grant from NINDS and NIMH. The initial goal of the facility for this funding period is to generate a library of novel NeuroMabs against neuronal proteins, initially focusing on membrane proteins (receptors/channels/transporters), synaptic proteins, other neuronal signaling molecules, and proteins with established links to disease states. The scope of the facility was expanded with supplements from the NIH Blueprint for Neuroscience Research to include neurodevelopmental targets, the NIH Roadmap for Medical Research to include epigenetics targets, and NIH Office of Rare Diseases Research to include rare disease targets. These NeuroMabs will then be produced on a large scale and made available to the neuroscience research community on an inexpensive basis as tissue culture supernatants or purified immunoglobulin by Antibodies Inc. The UC Davis/NIH NeuroMab Facility makes NeuroMabs available directly to end users and is unable to accommodate sales to distributors for third party distribution. Note, NeuroMab antibodies are now offered through antibodiesinc.

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pClamp

Software suite for electrophysiology data acquisition and analysis by Molecular Devices. Used for the control and recording of voltage clamp, current clamp, and patch clamp experiments. The software suite consists of Clampex 11 Software for data acquisition, AxoScope 11 Software for background recording, Clampfit 11 Software for data analysis, and optional Clampfit Advanced Analysis Module for sophisticated and streamlined analysis.

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