A Putative α-helical Gβγ-coupling Domain in the Second Intracellular Loop of the 5-HT1A Receptora

Authors

  • P. R. ALBERT,

    Corresponding author
    1. Neuroscience Research Institute, Departments of Medicine and Cellular and Molecular Medicine, University of Ottawa, 451 Smyth Road, Ottawa, Canada K1H-8M5
      Corresponding author: Tel: 613.562.5800 x8307; Fax: 613.562.5403; http://palbert@uottawa.ca
    Search for more papers by this author
  • S. J. MORRIS,

    1. Neuroscience Research Institute, Departments of Medicine and Cellular and Molecular Medicine, University of Ottawa, 451 Smyth Road, Ottawa, Canada K1H-8M5
    Search for more papers by this author
  • M. H. GHAHREMANI,

    1. Department of Pharmacology and Therapeutics, McGill University, Montreal, Canada H3G-1Y6
    Search for more papers by this author
  • J. M. STORRING,

    1. Department of Pharmacology and Therapeutics, McGill University, Montreal, Canada H3G-1Y6
    Search for more papers by this author
  • P. M. C. LEMBO

    1. Department of Pharmacology and Therapeutics, McGill University, Montreal, Canada H3G-1Y6
    Search for more papers by this author

  • a

    P.R.A. is the Novartis/MRC Michael Smith Chair of Neuroscience, J.M.S. is supported by an M.D./Ph.D. Studentship from the MRC, Canada.

Corresponding author: Tel: 613.562.5800 x8307; Fax: 613.562.5403; http://palbert@uottawa.ca

Abstract

ABSTRACT: We have identified a conserved threonine residue in the second intracellular (i2) loop of the 5-HT1A receptor that when mutated to alanine prevents coupling to Gβγ-mediated signaling, while preserving Gαi-induced actions. 48 In this review, we investigate the characteristics and potential role of the i2 domain in the coupling of the 5-HT1A receptor and other receptors to G proteins. The i2 domain, as well as portions of the i3 domain, is predicted to form an amphipathic α-helix with a positively charged face and a hydrophobic face. Mutagenesis experiments support a model in which the hydrophobic faces of these α-helical domains form an intracellular binding “pocket” for interaction with G proteins. Embedded in the hydrophobic face, Thr149 is crucial for signaling through Gβγ subunits, perhaps via interaction with its hydroxyl side-chain. Mutation of other residues of the i2 domain of Gi-coupled receptors is required to substantiate the importance of the α-helical i2 domain in receptor-Gβγ signaling. If confirmed in other receptors, these results support a general model in which activated receptor and Gβγ subunits remain associated to interact with effectors in a receptor-specific manner.

Ancillary