View in EDS

Molecular mechanism of Zn2+ inhibition of a voltage-gated proton channel.

Saved in:
Bibliographic Details
Title: Molecular mechanism of Zn2+ inhibition of a voltage-gated proton channel.
Authors: Feng Qiu1, Chamberlin, Adam2, Watkins, Briana M.1, Ionescu, Alina1, Perez, Marta Elena1, Barro-Soria, Rene1, González, Carlos3, Noskov, Sergei Y.2 snoskov@ucalgary.ca, Larsson, H. Peter1 plarsson@med.miami.edu
Source: Proceedings of the National Academy of Sciences of the United States of America. 10/4/2016, Vol. 113 Issue 40, pE5962-E5971. 10p.
Subjects: Zinc ions, Protons, Chemical inhibitors, Molecular models, Voltage-clamp techniques (Electrophysiology), Fluorimetry
Abstract: Voltage-gated proton (Hv1) channels are involved in many physiological processes, such as pH homeostasis and the innate immune response. Zn2+ is an important physiological inhibitor of Hv1. Sperm cells are quiescent in the male reproductive system due to Zn2+ inhibition of Hv1 channels, but become active once introduced into the low-Zn2+-concentration environment of the female reproductive tract. How Zn2+ inhibits Hv1 is not completely understood. In this study, we use the voltage clamp fluorometry technique to identify the molecular mechanism of Zn2+ inhibition of Hv1. We find that Zn2+ binds to both the activated closed and resting closed states of the Hv1 channel, thereby inhibiting both voltage sensor motion and gate opening. Mutations of some Hv1 residues affect only Zn2+ inhibition of the voltage sensor motion, whereas mutations of other residues also affect Zn2+ inhibition of gate opening. These effects are similar in monomeric and dimeric Hv1 channels, suggesting that the Zn2+-binding sites are localized within each subunit of the dimeric Hv1. We propose that Zn2+ binding has two major effects on Hv1: (i) at low concentrations, Zn2+ binds to one site and prevents the opening conformational change of the pore of Hv1, thereby inhibiting proton conduction; and (ii) at high concentrations, Zn2+, in addition, binds to a second site and inhibits the outward movement of the voltage sensor of Hv1. Elucidating the molecular mechanism of how Zn2+ inhibits Hv1 will further our understanding of Hv1 function and might provide valuable information for future drug development for Hv1 channels. [ABSTRACT FROM AUTHOR]
Copyright of Proceedings of the National Academy of Sciences of the United States of America is the property of National Academy of Sciences and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
Database: Engineering Source
FullText Text:
  Availability: 0
Header DbId: egs
DbLabel: Engineering Source
An: 118644911
AccessLevel: 6
PubType: Academic Journal
PubTypeId: academicJournal
PreciseRelevancyScore: 0
IllustrationInfo
Items – Name: Title
  Label: Title
  Group: Ti
  Data: Molecular mechanism of Zn<superscript>2+</superscript> inhibition of a voltage-gated proton channel.
– Name: Author
  Label: Authors
  Group: Au
  Data: <searchLink fieldCode="AR" term="%22Feng+Qiu%22">Feng Qiu</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Chamberlin%2C+Adam%22">Chamberlin, Adam</searchLink><relatesTo>2</relatesTo><br /><searchLink fieldCode="AR" term="%22Watkins%2C+Briana+M%2E%22">Watkins, Briana M.</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Ionescu%2C+Alina%22">Ionescu, Alina</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Perez%2C+Marta+Elena%22">Perez, Marta Elena</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Barro-Soria%2C+Rene%22">Barro-Soria, Rene</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22González%2C+Carlos%22">González, Carlos</searchLink><relatesTo>3</relatesTo><br /><searchLink fieldCode="AR" term="%22Noskov%2C+Sergei+Y%2E%22">Noskov, Sergei Y.</searchLink><relatesTo>2</relatesTo><i> snoskov@ucalgary.ca</i><br /><searchLink fieldCode="AR" term="%22Larsson%2C+H%2E+Peter%22">Larsson, H. Peter</searchLink><relatesTo>1</relatesTo><i> plarsson@med.miami.edu</i>
– Name: TitleSource
  Label: Source
  Group: Src
  Data: <searchLink fieldCode="JN" term="%22Proceedings+of+the+National+Academy+of+Sciences+of+the+United+States+of+America%22">Proceedings of the National Academy of Sciences of the United States of America</searchLink>. 10/4/2016, Vol. 113 Issue 40, pE5962-E5971. 10p.
– Name: Subject
  Label: Subjects
  Group: Su
  Data: <searchLink fieldCode="DE" term="%22Zinc+ions%22">Zinc ions</searchLink><br /><searchLink fieldCode="DE" term="%22Protons%22">Protons</searchLink><br /><searchLink fieldCode="DE" term="%22Chemical+inhibitors%22">Chemical inhibitors</searchLink><br /><searchLink fieldCode="DE" term="%22Molecular+models%22">Molecular models</searchLink><br /><searchLink fieldCode="DE" term="%22Voltage-clamp+techniques+%28Electrophysiology%29%22">Voltage-clamp techniques (Electrophysiology)</searchLink><br /><searchLink fieldCode="DE" term="%22Fluorimetry%22">Fluorimetry</searchLink>
– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: Voltage-gated proton (Hv1) channels are involved in many physiological processes, such as pH homeostasis and the innate immune response. Zn2+ is an important physiological inhibitor of Hv1. Sperm cells are quiescent in the male reproductive system due to Zn2+ inhibition of Hv1 channels, but become active once introduced into the low-Zn2+-concentration environment of the female reproductive tract. How Zn2+ inhibits Hv1 is not completely understood. In this study, we use the voltage clamp fluorometry technique to identify the molecular mechanism of Zn2+ inhibition of Hv1. We find that Zn2+ binds to both the activated closed and resting closed states of the Hv1 channel, thereby inhibiting both voltage sensor motion and gate opening. Mutations of some Hv1 residues affect only Zn2+ inhibition of the voltage sensor motion, whereas mutations of other residues also affect Zn2+ inhibition of gate opening. These effects are similar in monomeric and dimeric Hv1 channels, suggesting that the Zn2+-binding sites are localized within each subunit of the dimeric Hv1. We propose that Zn2+ binding has two major effects on Hv1: (i) at low concentrations, Zn2+ binds to one site and prevents the opening conformational change of the pore of Hv1, thereby inhibiting proton conduction; and (ii) at high concentrations, Zn2+, in addition, binds to a second site and inhibits the outward movement of the voltage sensor of Hv1. Elucidating the molecular mechanism of how Zn2+ inhibits Hv1 will further our understanding of Hv1 function and might provide valuable information for future drug development for Hv1 channels. [ABSTRACT FROM AUTHOR]
– Name: AbstractSuppliedCopyright
  Label:
  Group: Ab
  Data: <i>Copyright of Proceedings of the National Academy of Sciences of the United States of America is the property of National Academy of Sciences and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
PLink https://search.ebscohost.com/login.aspx?direct=true&site=eds-live&db=egs&AN=118644911
RecordInfo BibRecord:
  BibEntity:
    Identifiers:
      – Type: doi
        Value: 10.1073/pnas.1604082113
    Languages:
      – Code: eng
        Text: English
    PhysicalDescription:
      Pagination:
        PageCount: 10
        StartPage: E5962
    Subjects:
      – SubjectFull: Zinc ions
        Type: general
      – SubjectFull: Protons
        Type: general
      – SubjectFull: Chemical inhibitors
        Type: general
      – SubjectFull: Molecular models
        Type: general
      – SubjectFull: Voltage-clamp techniques (Electrophysiology)
        Type: general
      – SubjectFull: Fluorimetry
        Type: general
    Titles:
      – TitleFull: Molecular mechanism of Zn2+ inhibition of a voltage-gated proton channel.
        Type: main
  BibRelationships:
    HasContributorRelationships:
      – PersonEntity:
          Name:
            NameFull: Feng Qiu
      – PersonEntity:
          Name:
            NameFull: Chamberlin, Adam
      – PersonEntity:
          Name:
            NameFull: Watkins, Briana M.
      – PersonEntity:
          Name:
            NameFull: Ionescu, Alina
      – PersonEntity:
          Name:
            NameFull: Perez, Marta Elena
      – PersonEntity:
          Name:
            NameFull: Barro-Soria, Rene
      – PersonEntity:
          Name:
            NameFull: González, Carlos
      – PersonEntity:
          Name:
            NameFull: Noskov, Sergei Y.
      – PersonEntity:
          Name:
            NameFull: Larsson, H. Peter
    IsPartOfRelationships:
      – BibEntity:
          Dates:
            – D: 04
              M: 10
              Text: 10/4/2016
              Type: published
              Y: 2016
          Identifiers:
            – Type: issn-print
              Value: 00278424
          Numbering:
            – Type: volume
              Value: 113
            – Type: issue
              Value: 40
          Titles:
            – TitleFull: Proceedings of the National Academy of Sciences of the United States of America
              Type: main
ResultId 1