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Molecular Pharmacology

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Research ArticleArticle

Helix 8 of the M1 Muscarinic Acetylcholine Receptor: Scanning Mutagenesis Delineates a G Protein Recognition Site

Robert G. Kaye, José W. Saldanha, Zhi-Liang Lu and Edward C. Hulme
Molecular Pharmacology April 2011, 79 (4) 701-709; DOI: https://doi.org/10.1124/mol.110.070177
Robert G. Kaye
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José W. Saldanha
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Zhi-Liang Lu
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Edward C. Hulme
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Abstract

We have used alanine-scanning mutagenesis followed by functional expression and molecular modeling to analyze the roles of the 14 residues, Asn422 to Cys435, C-terminal to transmembrane (TM) helix 7 of the M1 muscarinic acetylcholine receptor. The results suggest that they form an eighth (H8) helix, associated with the cytoplasmic surface of the cell membrane in the active state of the receptor. We suggest that the amide side chain of Asn422 may act as a cap to the C terminus of TM7, stabilizing its junction with H8, whereas the side chain of Phe429 may restrict the relative movements of H8 and the C terminus of TM7 in the inactive ground state of the receptor. We have identified four residues, Phe425, Arg426, Thr428, and Leu432, which are important for G protein binding and signaling. These may form a docking site for the C-terminal helix of the G protein α subunit, and collaborate with G protein recognition residues elsewhere in the cytoplasmic domain of the receptor to form a coherent surface for G protein binding in the activated state of the receptor.

Footnotes

  • ↵Embedded Image The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.

  • This work was funded by the Medical Research Council, United Kingdom [Grants U117532184, U117581331]. R.K. received a Medical Research Council Sandwich Student Placement for 2009–2010.

  • Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.

    doi:10.1124/mol.110.070177.

  • ABBREVIATIONS:

    ICL
    intracellular loop
    mAChR
    muscarinic acetylcholine receptor
    ACh
    acetylcholine
    Pilo
    pilocarpine
    TM
    transmembrane domain
    ECL
    extracellular loop
    H8
    helix 8
    NMS
    (−)-N-methyl scopolamine
    PI
    phosphoinositide
    PDB
    Protein Data Bank
    GPCR
    G protein-coupled receptor
    WT
    wild type.

  • Received November 26, 2010.
  • Accepted January 19, 2011.
  • Copyright © 2011 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 79 (4)
Molecular Pharmacology
Vol. 79, Issue 4
1 Apr 2011
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Research ArticleArticle

Helix 8 of the M1 Muscarinic Acetylcholine Receptor: Scanning Mutagenesis Delineates a G Protein Recognition Site

Robert G. Kaye, José W. Saldanha, Zhi-Liang Lu and Edward C. Hulme
Molecular Pharmacology April 1, 2011, 79 (4) 701-709; DOI: https://doi.org/10.1124/mol.110.070177

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Research ArticleArticle

Helix 8 of the M1 Muscarinic Acetylcholine Receptor: Scanning Mutagenesis Delineates a G Protein Recognition Site

Robert G. Kaye, José W. Saldanha, Zhi-Liang Lu and Edward C. Hulme
Molecular Pharmacology April 1, 2011, 79 (4) 701-709; DOI: https://doi.org/10.1124/mol.110.070177
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