The voltage-gated proton channel Hv1 enhances brain damage from ischemic stroke

Long Jun Wu; Gongxiong Wu; M. Reza Akhavan Sharif; Amanda Baker; Yonghui Jia; Frederic H. Fahey; Hongbo R. Luo; Edward P. Feener; David E. Clapham

doi:10.1038/nn.3059

The voltage-gated proton channel Hv1 enhances brain damage from ischemic stroke

Long Jun Wu, Gongxiong Wu, M. Reza Akhavan Sharif, Amanda Baker, Yonghui Jia, Frederic H. Fahey, Hongbo R. Luo, Edward P. Feener, David E. Clapham

Neurology

Research output: Contribution to journal › Article › peer-review

148 Scopus citations

Abstract

Phagocytic cell NADPH oxidase (NOX) generates reactive oxygen species (ROS) as part of innate immunity. Unfortunately, ischemia can also induce this pathway and inflict damage on native cells. The voltage-gated proton channel Hv1 enables NOX function by compensating cellular loss of electrons with protons. Accordingly, we investigated whether NOX-mediated brain damage in stroke can be inhibited by suppression of Hv1. We found that mouse and human brain microglia, but not neurons or astrocytes, expressed large Hv1-mediated currents. Hv1 was required for NOX-dependent ROS generation in brain microglia in situ and in vivo. Mice lacking Hv1 were protected from NOX-mediated neuronal death and brain damage 24 h after stroke. These results indicate that Hv1-dependent ROS production is responsible for a substantial fraction of brain damage at early time points after ischemic stroke and provide a rationale for Hv1 as a therapeutic target for the treatment of ischemic stroke.

Original language	English (US)
Pages (from-to)	565-573
Number of pages	9
Journal	Nature Neuroscience
Volume	15
Issue number	4
DOIs	https://doi.org/10.1038/nn.3059
State	Published - Apr 2012

ASJC Scopus subject areas

General Neuroscience

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title = "The voltage-gated proton channel Hv1 enhances brain damage from ischemic stroke",

abstract = "Phagocytic cell NADPH oxidase (NOX) generates reactive oxygen species (ROS) as part of innate immunity. Unfortunately, ischemia can also induce this pathway and inflict damage on native cells. The voltage-gated proton channel Hv1 enables NOX function by compensating cellular loss of electrons with protons. Accordingly, we investigated whether NOX-mediated brain damage in stroke can be inhibited by suppression of Hv1. We found that mouse and human brain microglia, but not neurons or astrocytes, expressed large Hv1-mediated currents. Hv1 was required for NOX-dependent ROS generation in brain microglia in situ and in vivo. Mice lacking Hv1 were protected from NOX-mediated neuronal death and brain damage 24 h after stroke. These results indicate that Hv1-dependent ROS production is responsible for a substantial fraction of brain damage at early time points after ischemic stroke and provide a rationale for Hv1 as a therapeutic target for the treatment of ischemic stroke.",

author = "Wu, {Long Jun} and Gongxiong Wu and Sharif, {M. Reza Akhavan} and Amanda Baker and Yonghui Jia and Fahey, {Frederic H.} and Luo, {Hongbo R.} and Feener, {Edward P.} and Clapham, {David E.}",

note = "Funding Information: We thank L. Silberstein, W. Yang and M. Kurtev for technical assistance, S. Doctrow (Boston University) for kindly providing us with EUK-207, Y. Kirichok (University of California, San Francisco) for Hv1 antibody, and D. Chaudhuri for critical reading of the manuscript. This work was supported by the US National Institutes of Health (R01 MH090293 to D.E.C. and R01 EY019029 to E.P.F.). L.-J.W. is supported by a Lefler postdoctoral fellowship from Harvard Medical School and a Scientist Development Grant from the American Heart Association (11SDG7340011).",

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AU - Wu, Long Jun

AU - Wu, Gongxiong

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AU - Jia, Yonghui

AU - Fahey, Frederic H.

AU - Luo, Hongbo R.

AU - Feener, Edward P.

AU - Clapham, David E.

N1 - Funding Information: We thank L. Silberstein, W. Yang and M. Kurtev for technical assistance, S. Doctrow (Boston University) for kindly providing us with EUK-207, Y. Kirichok (University of California, San Francisco) for Hv1 antibody, and D. Chaudhuri for critical reading of the manuscript. This work was supported by the US National Institutes of Health (R01 MH090293 to D.E.C. and R01 EY019029 to E.P.F.). L.-J.W. is supported by a Lefler postdoctoral fellowship from Harvard Medical School and a Scientist Development Grant from the American Heart Association (11SDG7340011).

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N2 - Phagocytic cell NADPH oxidase (NOX) generates reactive oxygen species (ROS) as part of innate immunity. Unfortunately, ischemia can also induce this pathway and inflict damage on native cells. The voltage-gated proton channel Hv1 enables NOX function by compensating cellular loss of electrons with protons. Accordingly, we investigated whether NOX-mediated brain damage in stroke can be inhibited by suppression of Hv1. We found that mouse and human brain microglia, but not neurons or astrocytes, expressed large Hv1-mediated currents. Hv1 was required for NOX-dependent ROS generation in brain microglia in situ and in vivo. Mice lacking Hv1 were protected from NOX-mediated neuronal death and brain damage 24 h after stroke. These results indicate that Hv1-dependent ROS production is responsible for a substantial fraction of brain damage at early time points after ischemic stroke and provide a rationale for Hv1 as a therapeutic target for the treatment of ischemic stroke.

AB - Phagocytic cell NADPH oxidase (NOX) generates reactive oxygen species (ROS) as part of innate immunity. Unfortunately, ischemia can also induce this pathway and inflict damage on native cells. The voltage-gated proton channel Hv1 enables NOX function by compensating cellular loss of electrons with protons. Accordingly, we investigated whether NOX-mediated brain damage in stroke can be inhibited by suppression of Hv1. We found that mouse and human brain microglia, but not neurons or astrocytes, expressed large Hv1-mediated currents. Hv1 was required for NOX-dependent ROS generation in brain microglia in situ and in vivo. Mice lacking Hv1 were protected from NOX-mediated neuronal death and brain damage 24 h after stroke. These results indicate that Hv1-dependent ROS production is responsible for a substantial fraction of brain damage at early time points after ischemic stroke and provide a rationale for Hv1 as a therapeutic target for the treatment of ischemic stroke.

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The voltage-gated proton channel Hv1 enhances brain damage from ischemic stroke

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