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

Wu, Long Jun; Wu, Guoying; Sharif, Mohammad Reza; Baker, Arthur M.; Jia, Yonghui; Fahey, Frederic H.; Luo, Hongbo; Feener, Edward P.; Clapham, David E.

doi:10.1038/nn.3059

Cited by 216 publications

(325 citation statements)

References 49 publications

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“…Thus, Hv1 knockout mice are less prone to develop neuronal death and brain damage after stroke. These indicate that, aside the cytokine and glutamate burst, ROIs are responsible for a substantial fraction of brain damage at early time points after ischemia, and rendering Hv1 with a promising therapeutic approach (Wu LJ 2012 Activated astrocytes also play a significant role in the pathogenesis of stroke. Astrocytes may not only secret many cytokines, chemokines and MMPs but also undergo astrogliosis, which is an exacerbated proliferation of astrocytes as a wound-healing like process.…”

Section: Central Nervous System Resident Cells and Strokementioning

confidence: 99%

Central Nervous System Resident Cells in Neuroinflammation: A Brave New World.

Peron¹,

Oliveira²,

Brandão³

et al. 2012

Autoimmune Diseases - Contributing Factors, Specific Cases of Autoimmune Diseases, and Stem Cell and Other Therapies

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Section: Central Nervous System Resident Cells and Strokementioning

confidence: 99%

Central Nervous System Resident Cells in Neuroinflammation: A Brave New World.

Peron¹,

Oliveira²,

Brandão³

et al. 2012

Autoimmune Diseases - Contributing Factors, Specific Cases of Autoimmune Diseases, and Stem Cell and Other Therapies

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“…Hv1 activity has been shown to exacerbate severe pathological conditions, such as ischemic brain damage (24), by facilitating the production of ROS. Furthermore, Hv1 is implicated in cancer cell survival (25)(26)(27) and is dysregulated in chronic lymphocytic leukemia (28).…”

mentioning

confidence: 99%

On the role of water density fluctuations in the inhibition of a proton channel

Gianti

Delemotte

Klein

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Hv1 is a transmembrane four-helix bundle that transports protons in a voltage-controlled manner. Its crucial role in many pathological conditions, including cancer and ischemic brain damage, makes Hv1 a promising drug target. Starting from the recently solved crystal structure of Hv1, we used structural modeling and molecular dynamics simulations to characterize the channel's most relevant conformations along the activation cycle. We then performed computational docking of known Hv1 inhibitors, 2-guanidinobenzimidazole (2GBI) and analogs. Although salt-bridge patterns and electrostatic potential profiles are well-defined and distinctive features of activated versus nonactivated states, the water distribution along the channel lumen is dynamic and reflects a conformational heterogeneity inherent to each state. In fact, pore waters assemble into intermittent hydrogen-bonded clusters that are replaced by the inhibitor moieties upon ligand binding. The entropic gain resulting from releasing these conformationally restrained waters to the bulk solvent is likely a major contributor to the binding free energy. Accordingly, we mapped the water density fluctuations inside the pore of the channel and identified the regions of maximum fluctuation within putative binding sites. Two sites appear as outstanding: One is the already known binding pocket of 2GBI, which is accessible to ligands from the intracellular side; the other is a site located at the exit of the proton permeation pathway. Our analysis of the waters confined in the hydrophobic cavities of Hv1 suggests a general strategy for drug discovery that can be applied to any ion channel.Hv1 | drug design | pore waters | binding site discovery | confined waters

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“…In addition, this channel is also found in many other cell types including neurons, sperm, and lung airway epithelia cells, where it has been implicated in acid extrusion, male fertility, and the pathology of asthma, respectively (3,4). During stroke, the activity of Hv1 channels exacerbates neuronal death (5). In 2006, two independent groups identified the genes coding for the Hv1 channel in humans (hHv1) (6) and mice and Ciona intestinalis (voltage-sensing only protein; we call it "Ci-Hv1" in this paper) (7).…”

mentioning

confidence: 99%

Hydrophobic plug functions as a gate in voltage-gated proton channels

Chamberlin

Qiu

Rebolledo

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

150

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Voltage-gated proton (Hv1) channels play important roles in the respiratory burst, in pH regulation, in spermatozoa, in apoptosis, and in cancer metastasis. Unlike other voltage-gated cation channels, the Hv1 channel lacks a centrally located pore formed by the assembly of subunits. Instead, the proton permeation pathway in the Hv1 channel is within the voltage-sensing domain of each subunit. The gating mechanism of this pathway is still unclear. Mutagenic and fluorescence studies suggest that the fourth transmembrane (TM) segment (S4) functions as a voltage sensor and that there is an outward movement of S4 during channel activation. Using thermodynamic mutant cycle analysis, we find that the conserved positively charged residues in S4 are stabilized by countercharges in the other TM segments both in the closed and open states. We constructed models of both the closed and open states of Hv1 channels that are consistent with the mutant cycle analysis. These structural models suggest that electrostatic interactions between TM segments in the closed state pull hydrophobic residues together to form a hydrophobic plug in the center of the voltage-sensing domain. Outward S4 movement during channel activation induces conformational changes that remove this hydrophobic plug and instead insert protonatable residues in the center of the channel that, together with water molecules, can form a hydrogen bond chain across the channel for proton permeation. This suggests that salt bridge networks and the hydrophobic plug function as the gate in Hv1 channels and that outward movement of S4 leads to the opening of this gate.voltage gating | mutagenesis cycle | molecular dynamics | VSOP | blocker T he best-studied function of voltage-gated proton (Hv1) channels is in the immune system, where the activity of Hv1 channels has been shown to play a key role in charge compensation for the electron extrusion by NADPH oxidase during the respiratory burst in phagocytes (1, 2). In addition, this channel is also found in many other cell types including neurons, sperm, and lung airway epithelia cells, where it has been implicated in acid extrusion, male fertility, and the pathology of asthma, respectively (3, 4). During stroke, the activity of Hv1 channels exacerbates neuronal death (5). In 2006, two independent groups identified the genes coding for the Hv1 channel in humans (hHv1) (6) and mice and Ciona intestinalis (voltage-sensing only protein; we call it "Ci-Hv1" in this paper) (7). The sequences of Hv1/(VSOP) are homologous to the sequences of the voltagesensing domain (VSD) of other voltage-gated ion channels, such as voltage-gated sodium, potassium, and calcium channels (Nav, Kv, and Cav channels), and the voltage sensor-containing phosphatase VSP (6, 7). Hydropathy analysis of the Hv1 sequence suggests the existence of four transmembrane (TM) segments (Fig. 1A), designated S1 to S4, similar to the four TM segments of the VSD of Kv channels (Fig. S1). However, Hv1 channels lack the last two TM segments of Kv channels that make up t...

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

Cited by 216 publications

References 49 publications

Central Nervous System Resident Cells in Neuroinflammation: A Brave New World.

Central Nervous System Resident Cells in Neuroinflammation: A Brave New World.

On the role of water density fluctuations in the inhibition of a proton channel

Hydrophobic plug functions as a gate in voltage-gated proton channels

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