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Research ArticleArticle

Functional Characterization of the Recombinant Human 5-Hydroxytryptamine7(a) Receptor Isoform Coupled to Adenylate Cyclase Stimulation

Nika Adham, John M. Zgombick, Jonathan Bard and Theresa A. Branchek
Journal of Pharmacology and Experimental Therapeutics November 1998, 287 (2) 508-514;
Nika Adham
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John M. Zgombick
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Jonathan Bard
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Theresa A. Branchek
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Abstract

Functional characterization of the recombinant human 5-hydroxytryptamine7(a) (h5-HT7(a)) receptor isoform was performed using stably transfected LM(tk−) cells. Expression levels of the h5-HT7(a) receptor determined from saturation studies using either a labeled agonist ([3H]5-HT) or antagonist ([3H]LSD) were very similar (Bmax = 160–190 fmol/mg protein), suggesting that all receptors may exist in the high affinity (G protein-coupled) state. In intact cells, 5-HT produced a concentration-dependent elevation of intracellular cAMP levels ([cAMP]i) with an EC50 value of 80 nM and a maximal response of 5-fold increase above basal levels. The rank order of agonist potencies in the second messenger assay paralleled their rank order of binding affinities: 5-carboxamidotryptamine > 5-hydroxytryptamine ≥ 5-methoxytryptamine > 8-hydroxy N,N-dipropyl aminotetralin > sumatriptan. Agonist potencies (EC50 values) to stimulate [cAMP]i were more than 25-fold lower relative to their respective binding affinities (Ki values) obtained in [3H]5-HT competition assays. In contrast, antagonist potencies (Kb values) to block 5-HT-stimulated [cAMP]i were in close agreement with their correspondingKi values. These data may indicate low efficiency of receptor-effector coupling to adenylate cyclase stimulation. Pretreatment of stably transfected cells with cholera toxin abolished the 5-HT-mediated elevation of [cAMP]i, indicating that the 5-HT7(a) subtype directly interacts with Gαs protein(s) to activate adenylate cyclase(s). Clonal cell lines stably expressing h5-HT7 receptor isoforms will serve as valuable cellular models to study their function and regulation, as well as assist in the development of selective 5-HT7 receptor agents to uncover the biological roles and potential therapeutic applications of this novel receptor subtype.

Footnotes

  • Send reprint requests to: Dr. Nika Adham, Synaptic Pharmaceutical Corporation, 215 College Road, Paramus, NJ 07652.

  • 1 Current address: Wyeth Ayerst Research, CNS Department, Monmouth Junction, NJ 08852.

  • Abbreviations:
    [cAMP]i
    intracellular cAMP concentrations
    CRC
    concentration-response curve
    EC50
    concentration of agonist required to produce 50% maximal response
    Emax
    maximal response
    h5-HT7(a)
    human 5-hydroxytryptamine7(a)
    Kb
    apparent antagonist dissociation constant
    Ki
    affinity constant
    RT-PCR
    reverse transcriptase polymerase chain reaction
    5-CT
    5-carboxamidotryptamine
    5-HT
    5-hydroxytryptamine
    5-MeOT
    5-methoxytryptamine
    DP-5-CT
    N,N-dipropyl-5-carboxamidotryptamine
    5-MeO-DMT
    N,N-dimethyl-5-methoxytryptamine
    2-Me-5-HT
    2-methyl-5-hydroxytryptamine
    α-Me-5-HT
    α-methyl-5-hydroxytryptamine
    8-OH-DPAT
    8-hydroxy N,N-dipropyl aminotetralin
    1-NP
    1-naphthylpiperazine
    • Received March 6, 1998.
    • Accepted June 23, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics
Vol. 287, Issue 2
1 Nov 1998
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Research ArticleArticle

Functional Characterization of the Recombinant Human 5-Hydroxytryptamine7(a) Receptor Isoform Coupled to Adenylate Cyclase Stimulation

Nika Adham, John M. Zgombick, Jonathan Bard and Theresa A. Branchek
Journal of Pharmacology and Experimental Therapeutics November 1, 1998, 287 (2) 508-514;

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Research ArticleArticle

Functional Characterization of the Recombinant Human 5-Hydroxytryptamine7(a) Receptor Isoform Coupled to Adenylate Cyclase Stimulation

Nika Adham, John M. Zgombick, Jonathan Bard and Theresa A. Branchek
Journal of Pharmacology and Experimental Therapeutics November 1, 1998, 287 (2) 508-514;
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