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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    • "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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    ABSTRACT: The main role of voltage-gated proton channels (Hv1) is to extrude protons from the intracellular milieu when, mediated by different cellular processes, the H(+) concentration increases. Hv1 are exquisitely selective for protons and their structure is homologous to the voltage sensing domain (VSD) of other voltage-gated ion channels like sodium, potassium, and calcium channels. In clear contrast to the classical voltage-dependent channels, Hv1 lacks a pore domain and thus permeation necessarily occurs through the voltage sensing domain. Hv1 channels are activated by depolarizing voltages and increases in internal proton concentration. It has been proposed that local conformational changes of the transmembrane segment S4, driven by depolarization, trigger the molecular rearrangements that open Hv1. However, it is still unclear how the electromechanical coupling is achieved between the VSD and the potential pore, allowing the proton from the intracellular to the extracellular side. Here we provide a revised view of voltage activation in Hv1 channels, offering a comparative scenario with other voltage sensing channels domains. Copyright © 2015. Published by Elsevier B.V.
    FEBS letters 08/2015; DOI:10.1016/j.febslet.2015.08.003 · 3.17 Impact Factor
    • ", therefore NADPH oxidase-produced reactive oxygen species may play a causative role oxidative damage in neuronal tissues during ischemia [31]. "
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    ABSTRACT: Post-stroke depression is a common neuropsychiatric affective disorder that may develop after a stroke event. In addition to abnormalities in the biogenic amine neurotransmitters and cytokine expression induced by stroke we will focus on the role of oxidative stress and hypothesize that polyphenols may be useful as therapeutics targets for the treatment of post-stroke depression. In this paper, we discuss the hypothesis that increased oxidative stress in cerebral tissues during ischemia is implicated in the pathogenesis of depressive-like symptoms following stroke. There is substantive evidence regarding the role of oxidative stress in the pathogenesis of both stroke and depression, which provides support to this hypothesis. Reactive oxygen species, generated during stroke, cause oxidative stress, lipid peroxidation, protein oxidation, and DNA damage in neural tissues. The resultant pathophysiological processes in the neural tissues could be considered a leading mechanism in the induction of post-stroke depression. Antioxidants including polyphenols therefore, may play an important role in the outcomes of ischemia and stroke, due to their ability to protect neurons against oxidative stress, to mitigate ischemic damage via inhibition of lipid peroxidation and ability to interact with the generation of nitric oxide from the vascular endothelium, and also to decrease inflammation. These data suggest that polyphenols may therefore be a useful new therapeutic target for the treatment of post-stroke depression.
    Current Medicinal Chemistry 11/2014; 22(3). DOI:10.2174/0929867321666141106122319 · 3.85 Impact Factor
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    • "This body index of gene expression (BIGE) database compares gene expression across 105 normal tissues representing all major systems of the human body. In agreement with previous reports [4], [25], we found the highest levels of Hv1 transcript in the immune system and in the testis (Fig. 2A), and low expression in brain tissues. In contrast, we found HVRP1 primarily expressed in cerebellar tissues (Fig. 2A, Table S1). "
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    ABSTRACT: The Hv1 channel and voltage-sensitive phosphatases share with voltage-gated sodium, potassium, and calcium channels the ability to detect changes in membrane potential through voltage-sensing domains (VSDs). However, they lack the pore domain typical of these other channels. NaV, KV, and CaV proteins can be found in neurons and muscles, where they play important roles in electrical excitability. In contrast, VSD-containing proteins lacking a pore domain are found in non-excitable cells and are not involved in neuronal signaling. Here, we report the identification of HVRP1, a protein related to the Hv1 channel (from which the name Hv1 Related Protein 1 is derived), which we find to be expressed primarily in the central nervous system, and particularly in the cerebellum. Within the cerebellar tissue, HVRP1 is specifically expressed in granule neurons, as determined by in situ hybridization and immunohistochemistry. Analysis of subcellular distribution via electron microscopy and immunogold labeling reveals that the protein localizes on the post-synaptic side of contacts between glutamatergic mossy fibers and the granule cells. We also find that, despite the similarities in amino acid sequence and structural organization between Hv1 and HVRP1, the two proteins have distinct functional properties. The high conservation of HVRP1 in vertebrates and its cellular and subcellular localizations suggest an important function in the nervous system.
    PLoS ONE 08/2014; 9(8):e105926. DOI:10.1371/journal.pone.0105926 · 3.23 Impact Factor
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