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Molecular Pharmacology

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Research ArticleArticle

Evidence that Interaction between Conserved Residues in Transmembrane Helices 2, 3, and 7 Are Crucial for Human VPAC1 Receptor Activation

Anton O. Chugunov, John Simms, David R. Poyner, Yves Dehouck, Marianne Rooman, Dimitri Gilis and Ingrid Langer
Molecular Pharmacology September 2010, 78 (3) 394-401; DOI: https://doi.org/10.1124/mol.110.063578
Anton O. Chugunov
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John Simms
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David R. Poyner
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Yves Dehouck
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Marianne Rooman
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Dimitri Gilis
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Ingrid Langer
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Abstract

The VPAC1 receptor belongs to family B of G protein-coupled receptors (GPCR-B) and is activated upon binding of the vasoactive intestinal peptide (VIP). Despite the recent determination of the structure of the N terminus of several members of this receptor family, little is known about the structure of the transmembrane (TM) region and about the molecular mechanisms leading to activation. In the present study, we designed a new structural model of the TM domain and combined it with experimental mutagenesis experiments to investigate the interaction network that governs ligand binding and receptor activation. Our results suggest that this network involves the cluster of residues Arg188 in TM2, Gln380 in TM7, and Asn229 in TM3. This cluster is expected to be altered upon VIP binding, because Arg188 has been shown previously to interact with Asp3 of VIP. Several point mutations at positions 188, 229, and 380 were experimentally characterized and were shown to severely affect VIP binding and/or VIP-mediated cAMP production. Double mutants built from reciprocal residue exchanges exhibit strong cooperative or anticooperative effects, thereby indicating the spatial proximity of residues Arg188, Gln380, and Asn229. Because these residues are highly conserved in the GPCR-B family, they can moreover be expected to have a general role in mediating function.

Footnotes

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

  • This work was supported by the Brussels Region TheraVip project; the Belgian State Science Policy Office through an Interuniversity Attraction Poles Programme (DYSCO); the Belgian Fund for Scientific Research [Grant 3.4553.06]; and the President of Russian Federation [Grant MK-125.2008.4].

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

    doi:10.1124/mol.110.063578.

  • ABBREVIATIONS:

    GPCR
    G protein-coupled receptor
    3D
    three dimensional
    Aln
    alignment
    MD
    molecular dynamics
    OPSD
    bovine visual rhodopsin
    TM
    transmembrane
    VIP
    vasoactive intestinal peptide
    wt
    wild type
    PTH
    parathyroid hormone.

  • Received January 13, 2010.
  • Accepted June 23, 2010.
  • Copyright © 2010 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 78 (3)
Molecular Pharmacology
Vol. 78, Issue 3
1 Sep 2010
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Research ArticleArticle

Evidence that Interaction between Conserved Residues in Transmembrane Helices 2, 3, and 7 Are Crucial for Human VPAC1 Receptor Activation

Anton O. Chugunov, John Simms, David R. Poyner, Yves Dehouck, Marianne Rooman, Dimitri Gilis and Ingrid Langer
Molecular Pharmacology September 1, 2010, 78 (3) 394-401; DOI: https://doi.org/10.1124/mol.110.063578

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Research ArticleArticle

Evidence that Interaction between Conserved Residues in Transmembrane Helices 2, 3, and 7 Are Crucial for Human VPAC1 Receptor Activation

Anton O. Chugunov, John Simms, David R. Poyner, Yves Dehouck, Marianne Rooman, Dimitri Gilis and Ingrid Langer
Molecular Pharmacology September 1, 2010, 78 (3) 394-401; DOI: https://doi.org/10.1124/mol.110.063578
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