scholarly journals Zinc modulation of proton currents in a new voltage‐gated proton channel suggests a mechanism of inhibition

FEBS Journal ◽  
2020 ◽  
Vol 287 (22) ◽  
pp. 4996-5018 ◽  
Author(s):  
Gustavo Chaves ◽  
Stefanie Bungert‐Plümke ◽  
Arne Franzen ◽  
Iryna Mahorivska ◽  
Boris Musset
Keyword(s):  
Proton Channel ◽  
Voltage Gated ◽  
Mechanism Of Inhibition ◽  
Proton Currents

scholarly journals A novel Hv1 inhibitor reveals a new mechanism of inhibition of a voltage-sensing domain

2021 ◽  
Vol 153 (9) ◽  
Author(s):  
Chang Zhao ◽  
Liang Hong ◽  
Saleh Riahi ◽  
Victoria T. Lim ◽  
Douglas J. Tobias ◽  
...  
Keyword(s):  
Md Simulations ◽  
Binding Pocket ◽  
Proton Channel ◽  
Voltage Sensing ◽  
Voltage Gated ◽  
Functional Studies ◽  
Mechanism Of Inhibition ◽  
Target Binding ◽  
Voltage Gated Ion Channels ◽  
Pore Domain

Voltage-gated sodium, potassium, and calcium channels consist of four voltage-sensing domains (VSDs) that surround a central pore domain and transition from a down state to an up state in response to membrane depolarization. While many types of drugs bind pore domains, the number of organic molecules known to bind VSDs is limited. The Hv1 voltage-gated proton channel is made of two VSDs and does not contain a pore domain, providing a simplified model for studying how small ligands interact with VSDs. Here, we describe a ligand, named HIF, that interacts with the Hv1 VSD in the up and down states. We find that HIF rapidly inhibits proton conduction in the up state by blocking the open channel, as previously described for 2-guanidinobenzimidazole and its derivatives. HIF, however, interacts with a site slowly accessible in the down state. Functional studies and MD simulations suggest that this interaction traps the compound in a narrow pocket lined with charged residues within the VSD intracellular vestibule, which results in slow recovery from inhibition. Our findings point to a “wrench in gears” mechanism whereby side chains within the binding pocket trap the compound as the teeth of interlocking gears. We propose that the use of screening strategies designed to target binding sites with slow accessibility, similar to the one identified here, could lead to the discovery of new ligands capable of interacting with VSDs of other voltage-gated ion channels in the down state.

scholarly journals Voltage-gated proton channels exist in the plasma membrane of human oocytes

2019 ◽  
Vol 34 (10) ◽  
pp. 1974-1983 ◽  
Author(s):  
R Ya Smith ◽  
D Morgan ◽  
L Sharma ◽  
V V Cherny ◽  
N Tidswell ◽  
...  
Keyword(s):  
Large Scale ◽  
Human Sperm ◽  
Proton Channel ◽  
Human Oocytes ◽  
Proton Channels ◽  
Voltage Gated ◽  
Registration Number ◽  
Heterologous Expression Systems ◽  
Competing Interest ◽  
Proton Currents

Abstract STUDY QUESTION Do human oocytes express voltage-gated proton channels? SUMMARY ANSWER Human oocytes exhibit voltage-gated proton currents. WHAT IS KNOWN ALREADY Voltage-gated proton currents have been reported in human sperm, where they contribute to capacitation and motility. No such studies of human oocytes exist. STUDY DESIGN, SIZE, DURATION Voltage-clamp studies were undertaken using entire oocytes and vesicles derived from oocytes and in excised patches of membrane from oocytes. PARTICIPANTS/MATERIALS, SETTING, METHODS Frozen, thawed human metaphase II oocytes were obtained from material donated to the gamete repository at the Rush Center for Advanced Reproductive Care. Prior to patch clamping, oocytes were warmed and equilibrated. Formation of an electrically tight seal requires exposing bare oolemma. Sections of the zona pellucida (ZP) were removed using a laser, followed by repeated pipetting, to further separate the oocyte from the ZP. Patch-clamp studies were performed using the whole-cell configuration on oocytes or vesicles derived from oocytes, and using inside-out patches of membrane, under conditions optimized to detect voltage-gated proton currents. MAIN RESULTS AND THE ROLE OF CHANCE Proton currents are present at significant levels in human oocytes where they exhibit properties similar to those reported in other human cells, as well as those in heterologous expression systems transfected with the HVCN1 gene that codes for the voltage-gated proton channel. LARGE SCALE DATA N/A LIMITATIONS, REASONS FOR CAUTION Human oocytes are large cells, which limits our ability to control the intracellular solution. Subtle effects of cryopreservation by vitrification and subsequent warming on properties of HVCN1, the HVCN1 gene product, cannot be ruled out. WIDER IMPLICATIONS OF THE FINDINGS Possible functions for voltage-gated proton channels in human oocytes may now be contemplated. STUDY FUNDING/COMPETING INTEREST(S) NIH R35GM126902 (TED), Bears Care (DM). No competing interests. TRIAL REGISTRATION NUMBER N/A.

Voltage-gated proton channel is expressed on phagosome

2009 ◽  
Vol 65 ◽  
pp. S73
Author(s):  
Yoshifumi Okochi ◽  
Mari Sasaki ◽  
Yasushi Okamura
Keyword(s):  
Proton Channel ◽  
Voltage Gated

scholarly journals Tryptophan 207 is crucial to the unique properties of the human voltage-gated proton channel, hHV1

2015 ◽  
Vol 146 (5) ◽  
pp. 343-356 ◽  
Author(s):  
Vladimir V. Cherny ◽  
Deri Morgan ◽  
Boris Musset ◽  
Gustavo Chaves ◽  
Susan M.E. Smith ◽  
...  
Keyword(s):  
Transmembrane Helix ◽  
Ph Sensor ◽  
Proton Channel ◽  
Tryptophan Residue ◽  
Ph Sensing ◽  
Ph Sensors ◽  
Voltage Gated ◽  
Karlodinium Veneficum ◽  
Channel Opening ◽  
External Ph

Part of the “signature sequence” that defines the voltage-gated proton channel (HV1) is a tryptophan residue adjacent to the second Arg in the S4 transmembrane helix: RxWRxxR, which is perfectly conserved in all high confidence HV1 genes. Replacing Trp207 in human HV1 (hHV1) with Ala, Ser, or Phe facilitated gating, accelerating channel opening by 100-fold, and closing by 30-fold. Mutant channels opened at more negative voltages than wild-type (WT) channels, indicating that in WT channels, Trp favors a closed state. The Arrhenius activation energy, Ea, for channel opening decreased to 22 kcal/mol from 30–38 kcal/mol for WT, confirming that Trp207 establishes the major energy barrier between closed and open hHV1. Cation–π interaction between Trp207 and Arg211 evidently latches the channel closed. Trp207 mutants lost proton selectivity at pHo >8.0. Finally, gating that depends on the transmembrane pH gradient (ΔpH-dependent gating), a universal feature of HV1 that is essential to its biological functions, was compromised. In the WT hHV1, ΔpH-dependent gating is shown to saturate above pHi or pHo 8, consistent with a single pH sensor with alternating access to internal and external solutions. However, saturation occurred independently of ΔpH, indicating the existence of distinct internal and external pH sensors. In Trp207 mutants, ΔpH-dependent gating saturated at lower pHo but not at lower pHi. That Trp207 mutation selectively alters pHo sensing further supports the existence of distinct internal and external pH sensors. Analogous mutations in HV1 from the unicellular species Karlodinium veneficum and Emiliania huxleyi produced generally similar consequences. Saturation of ΔpH-dependent gating occurred at the same pHo and pHi in HV1 of all three species, suggesting that the same or similar group(s) is involved in pH sensing. Therefore, Trp enables four characteristic properties: slow channel opening, highly temperature-dependent gating kinetics, proton selectivity, and ΔpH-dependent gating.

Voltage-gated proton channel is expressed on phagosomes

2009 ◽  
Vol 382 (2) ◽  
pp. 274-279 ◽  
Author(s):  
Yoshifumi Okochi ◽  
Mari Sasaki ◽  
Hirohide Iwasaki ◽  
Yasushi Okamura
Keyword(s):  
Proton Channel ◽  
Voltage Gated

Abstract T P229: Deletion of Voltage Gated Proton Channel in Microglial Cells is Neurovascular Protective After Ischemic Brain Injury

Stroke ◽  
2015 ◽  
Vol 46 (suppl_1) ◽  
Author(s):  
Weiguo Li ◽  
Becca Ward ◽  
Mohammed Abdelsaid ◽  
Tianzheng Yu ◽  
Yisang Yoon ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Ischemia Reperfusion ◽  
Hemorrhagic Transformation ◽  
Artery Occlusion ◽  
Proton Channel ◽  
Ros Generation ◽  
Vascular Integrity ◽  
Voltage Gated ◽  
Underlying Mechanisms ◽  
Cerebral Artery Occlusion

Despite the failure of antioxidant treatments in clinical trials, the undoubted role of reactive oxygen species (ROS) in neurovascular damage after ischemic stroke calls for a more targeted approach. ROS production by microglia, the primary resident immune cells in the brain, is a key event of this process in ischemic stroke. Voltage gated proton channel, Hv1, is localized primarily to microglia and sustains NADPH oxidase activity. Deletion of Hv1 is neuroprotective after permanent middle cerebral artery occlusion (MCAO). We hypothesized that Hv1-mediated microglial ROS generation is also critical for vascular integrity and contributes to reperfusion injury after transient ischemic stroke. The wildtype (WT) and Hv1 knockout (KO) rats (n=4) were subjected to permanent or 3/24 h transient MCAO. The neurological deficiency, infarct, hemorrhagic transformation, and edema ratio were assessed. We found that in both permanent and transient MCAO model, KO rats develop smaller infarct, less vascular injury, edema, and hemorrhagic transformation, resulting in better short-term functional outcome. These results suggest that deletion of microglial Hv1 channel is vasculoprotective after ischemia/reperfusion and the underlying mechanisms need to be further studied.

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