Direct gating of ATP-activated ion channels (P2X2 receptors) by lipophilic attachment at the outer end of the second transmembrane domain

Simon W. Rothwell; Phillip J. Stansfeld; Laricia Bragg; Alexej Verkhratsky; R. Alan North

doi:10.1074/jbc.M113.529099

Direct gating of ATP-activated ion channels (P2X2 receptors) by lipophilic attachment at the outer end of the second transmembrane domain

Simon W. Rothwell, Phillip J. Stansfeld, Laricia Bragg, Alexej Verkhratsky, R. Alan North

FBMH Faculty Office Administration (L5)

Research output: Contribution to journal › Article › peer-review

Abstract

Background: ATP-gated (P2X) receptors form pores with second transmembrane helices from each of three subunits. Results: Addition of an unbranched lipophilic group at I328C in P2X2 receptors opened the channel as effectively as ATP. Conclusion: Destabilizing the Ile328/Val48 interaction allows the Ile328 side chain to move laterally and open the pore. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

Original language	English
Pages (from-to)	618-626
Number of pages	8
Journal	Journal of Biological Chemistry
Volume	289
Issue number	2
DOIs	https://doi.org/10.1074/jbc.M113.529099
Publication status	Published - 10 Jan 2014

Keywords

Adenosine Triphosphate/chemistry/metabolism/*pharmacology
Amino Acid Substitution
Binding Sites/genetics
HEK293 Cells
Humans
Hydrophobic and Hydrophilic Interactions
Ion Channel Gating/genetics/*physiology
Ion Channels/chemistry/genetics/*physiology
Lipid Bilayers/chemistry/metabolism
Membrane Potentials/drug effects/genetics/physiology
Mesylates/chemistry/metabolism/pharmacology
Models, Molecular
Molecular Dynamics Simulation
Mutation
Patch-Clamp Techniques
Protein Structure, Tertiary
Receptors, Purinergic P2X2/chemistry/genetics/*physiology

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10.1074/jbc.M113.529099

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title = "Direct gating of ATP-activated ion channels (P2X2 receptors) by lipophilic attachment at the outer end of the second transmembrane domain",

abstract = "Background: ATP-gated (P2X) receptors form pores with second transmembrane helices from each of three subunits. Results: Addition of an unbranched lipophilic group at I328C in P2X2 receptors opened the channel as effectively as ATP. Conclusion: Destabilizing the Ile328/Val48 interaction allows the Ile328 side chain to move laterally and open the pore. {\textcopyright} 2014 by The American Society for Biochemistry and Molecular Biology, Inc.",

keywords = "Adenosine Triphosphate/chemistry/metabolism/*pharmacology, Amino Acid Substitution, Binding Sites/genetics, HEK293 Cells, Humans, Hydrophobic and Hydrophilic Interactions, Ion Channel Gating/genetics/*physiology, Ion Channels/chemistry/genetics/*physiology, Lipid Bilayers/chemistry/metabolism, Membrane Potentials/drug effects/genetics/physiology, Mesylates/chemistry/metabolism/pharmacology, Models, Molecular, Molecular Dynamics Simulation, Mutation, Patch-Clamp Techniques, Protein Structure, Tertiary, Receptors, Purinergic P2X2/chemistry/genetics/*physiology",

author = "Rothwell, {Simon W.} and Stansfeld, {Phillip J.} and Laricia Bragg and Alexej Verkhratsky and North, {R. Alan}",

note = "Rothwell, Simon W Stansfeld, Phillip J Bragg, Laricia Verkhratsky, Alexej North, R Alan 093140/Z/10/Z/Wellcome Trust/United Kingdom BB/I019855/1/Biotechnology and Biological Sciences Research Council/United Kingdom J Biol Chem. 2014 Jan 10;289(2):618-26. doi: 10.1074/jbc.M113.529099. Epub 2013 Nov 22.",

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doi = "10.1074/jbc.M113.529099",

language = "English",

volume = "289",

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journal = "Journal of Biological Chemistry",

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publisher = "American Society for Biochemistry and Molecular Biology",

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T1 - Direct gating of ATP-activated ion channels (P2X2 receptors) by lipophilic attachment at the outer end of the second transmembrane domain

AU - Rothwell, Simon W.

AU - Stansfeld, Phillip J.

AU - Bragg, Laricia

AU - Verkhratsky, Alexej

AU - North, R. Alan

N1 - Rothwell, Simon W Stansfeld, Phillip J Bragg, Laricia Verkhratsky, Alexej North, R Alan 093140/Z/10/Z/Wellcome Trust/United Kingdom BB/I019855/1/Biotechnology and Biological Sciences Research Council/United Kingdom J Biol Chem. 2014 Jan 10;289(2):618-26. doi: 10.1074/jbc.M113.529099. Epub 2013 Nov 22.

PY - 2014/1/10

Y1 - 2014/1/10

N2 - Background: ATP-gated (P2X) receptors form pores with second transmembrane helices from each of three subunits. Results: Addition of an unbranched lipophilic group at I328C in P2X2 receptors opened the channel as effectively as ATP. Conclusion: Destabilizing the Ile328/Val48 interaction allows the Ile328 side chain to move laterally and open the pore. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

AB - Background: ATP-gated (P2X) receptors form pores with second transmembrane helices from each of three subunits. Results: Addition of an unbranched lipophilic group at I328C in P2X2 receptors opened the channel as effectively as ATP. Conclusion: Destabilizing the Ile328/Val48 interaction allows the Ile328 side chain to move laterally and open the pore. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

KW - Adenosine Triphosphate/chemistry/metabolism/pharmacology

KW - Amino Acid Substitution

KW - Binding Sites/genetics

KW - HEK293 Cells

KW - Humans

KW - Hydrophobic and Hydrophilic Interactions

KW - Ion Channel Gating/genetics/physiology

KW - Ion Channels/chemistry/genetics/physiology

KW - Lipid Bilayers/chemistry/metabolism

KW - Membrane Potentials/drug effects/genetics/physiology

KW - Mesylates/chemistry/metabolism/pharmacology

KW - Models, Molecular

KW - Molecular Dynamics Simulation

KW - Mutation

KW - Patch-Clamp Techniques

KW - Protein Structure, Tertiary

KW - Receptors, Purinergic P2X2/chemistry/genetics/physiology

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DO - 10.1074/jbc.M113.529099

M3 - Article

VL - 289

SP - 618

EP - 626

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 2

ER -

Direct gating of ATP-activated ion channels (P2X2 receptors) by lipophilic attachment at the outer end of the second transmembrane domain

Abstract

Keywords

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