The Voltage–gated Proton Channel, Hv1, Enhances Brain Damage from Ischemic Stroke

Howard Hughes Medical Institute, Department of Cardiology, Children's Hospital Boston and Department of Neurobiology, Harvard Medical School, Boston, Massachusetts, USA.
Nature Neuroscience (Impact Factor: 16.1). 03/2012; 15(4):565-73. DOI: 10.1038/nn.3059
Source: PubMed


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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Article: The Voltage–gated Proton Channel, Hv1, Enhances Brain Damage from Ischemic Stroke

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    • "Whole cell patch-clamp recordings were made from dorsal horn microglia located in laminar layers I–III of freshly excised spinal cord slices. GFP-labelled microglia were studied in voltage-clamp mode (Wu et al., 2012). After establishing the whole-cell configuration , microglia were held at either À60 mV or À20 mV. "
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    • "Proton channel activity has been associated with invasive and metastatic phenotypes of different tumors such as gliomas, breast, and colorectal cancer [39] [40] [41] [42]. Additionally, H v 1 channels have been implicated in the enhancement of brain damage after an ischemic stroke [43]. Given the relevance of H v 1 in physiology and pathology, it has become a focus of active research as a potential pharmacological target [44]. "
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    • "Animals and cuprizone treatment Wild-type (WT) C57BL/6 mice, CX3CR1 GFP/+ mice, Hv1 À/À mice, and Hv1 À/À -CX3CR1 GFP/+ mice were used in the present study. All mice were purchased from Jax laboratory except Hv1 À/À mice (Wu et al. 2012; Eyo et al. 2015). Mice were used in accordance with institutional guidelines as approved by the animal care and use committee at Rutgers University. "
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