Get access

Modulation of Intracellular Cyclic AMP Levels by Different Human Dopamine D4 Receptor Variants

Authors

  • Vida Asghari,

    1. Departments of Psychiatry and Pharmacology, University of Toronto; and Laboratory for Molecular Neurobiology, Clarke Institute of Psychiatry, Toronto, Ontario, Canada
    Search for more papers by this author
  • Suparna Sanyal,

    1. Departments of Psychiatry and Pharmacology, University of Toronto; and Laboratory for Molecular Neurobiology, Clarke Institute of Psychiatry, Toronto, Ontario, Canada
    Search for more papers by this author
  • Saskia Buchwaldt,

    1. Departments of Psychiatry and Pharmacology, University of Toronto; and Laboratory for Molecular Neurobiology, Clarke Institute of Psychiatry, Toronto, Ontario, Canada
    Search for more papers by this author
  • Andrew Paterson,

    1. Departments of Psychiatry and Pharmacology, University of Toronto; and Laboratory for Molecular Neurobiology, Clarke Institute of Psychiatry, Toronto, Ontario, Canada
    Search for more papers by this author
  • Vera Jovanovic,

    1. Departments of Psychiatry and Pharmacology, University of Toronto; and Laboratory for Molecular Neurobiology, Clarke Institute of Psychiatry, Toronto, Ontario, Canada
    Search for more papers by this author
  • Hubert H. M. Van Tol

    Corresponding author
    1. Departments of Psychiatry and Pharmacology, University of Toronto; and Laboratory for Molecular Neurobiology, Clarke Institute of Psychiatry, Toronto, Ontario, Canada
      Address correspondence and reprint requests to Dr. H. H. M. Van Tol at Laboratory for Molecular Neurobiology, Clarke Institute of Psychiatry, 250 College Street, Toronto, Ontario M5T 1R8, Canada.
    Search for more papers by this author

Address correspondence and reprint requests to Dr. H. H. M. Van Tol at Laboratory for Molecular Neurobiology, Clarke Institute of Psychiatry, 250 College Street, Toronto, Ontario M5T 1R8, Canada.

Abstract

Abstract: To investigate whether polymorphic forms of the human dopamine D4 receptor have different functional characteristics, we have stably expressed cDNAs of the D4.2, D4.4, and D4.7 isoforms in several cell lines. Chinese hamster ovary CHO-K1 cell lines expressing D4 receptor variants displayed pharmacological profiles that were in close agreement with previous data from transiently expressed D4 receptors in COS-7 cells. Dopamine stimulation of the D4 receptors resulted in a concentration-dependent inhibition of the forskolin-stimulated cyclic AMP (cAMP) levels. The potency of dopamine to inhibit cAMP formation was about twofold reduced for D4.7 (EC50 of ∼37 nM) compared with the D4.2 and D4.4 variants (EC50 of ∼16 nM). Antagonists block the dopamine-mediated inhibition of cAMP formation with a rank order of potency of emonapride > haloperidol = clozapine ≫ raclopride. There was no obvious correlation between the efficacy of inhibition of forskolin-stimulated cAMP levels and the D4 subtypes. Dopamine could completely reverse prostaglandin E2-stimulated cAMP levels for all three D4 receptor variants. Deletion of the repeat sequence does not affect functional activity of the receptor. The data presented indicate that the polymorphic repeat sequence causes only small changes in the ability of the D4 receptor to block cAMP production in CHO cells.

Get access to the full text of this article

Ancillary