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Molecular Pharmacology

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Research ArticleArticle

Novel Brain-Specific 5-HT4 Receptor Splice Variants Show Marked Constitutive Activity: Role of the C-Terminal Intracellular Domain

Sylvie Claeysen, Michèle Sebben, Carine Becamel, Joël Bockaert and Aline Dumuis
Molecular Pharmacology May 1999, 55 (5) 910-920;
Sylvie Claeysen
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Michèle Sebben
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Carine Becamel
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Joël Bockaert
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Aline Dumuis
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Abstract

We have cloned new 5-Hydroxytryptamine 4 (5-HT4) receptor splice variants from mouse (m5-HT4(e)R and m5-HT4(f)R), rat (r5-HT4(e)R), and human brain tissue (h5-HT4(e)R) which differ, as do the previously described 5-HT4 receptor variants, in the length and composition of their intracellular C termini after the common splicing site (L358). These new variants have a unique C-terminal sequence made of two PV repeats and are only expressed in brain tissue. All of the 5-HT4 receptor splice variants have a high constitutive activity when expressed at low and physiological densities (<500 fmol/mg protein). At similar density, they showed a much higher constitutive activity than the native and the mutated β2-adrenergic receptors. The constitutive activity of the new splice variants with short C-terminal sequences (m5-HT4(e)R and m5-HT4(f)R) was higher than that of the long C-terminal sequence variants (m5-HT4(a)R and m5-HT4(b)R). This may indicate that the short variants have a higher capacity for isomerization from the inactive to the active conformation. Moreover, we further identified a sequence within the C-terminal tail upstream of L358, rich in serine and threonine residues, that played a crucial role in maintaining 5-HT4R under its inactive conformation.

Footnotes

  • Send reprint requests to: Dr. Joël Bockaert, Centre National de la Recherche Scientifique, Unité Propre de Recherche 9023; 141 rue de la Cardonille, 34094 Montpellier cedex, 5 France. E-mail: bockaert{at}ccipe.montp.inserm.fr

  • This work was supported by grants from the Fondation pour la Recherche Médicale and Roche Laboratories.

  • 1 This work was supported by grants from the Fondation pour la Recherche Médicale and Roche Laboratories.

  • Abbreviations:
    GPCRs
    G protein coupled receptors
    5-HT
    5-hydroxytryptamine
    TSHR
    thyrotropin receptor
    RT-PCR
    reverse transcription polymerase chain reaction
    β2-AR
    β2-adrenergic receptor
    DMEM
    Dulbecco’s modified Eagle’s medium
    dFBS
    dialyzed fetal bovine serum
    R
    inactive receptor conformation
    R*
    active receptor conformation
    ON
    oligonucleotide
    CAM
    constitutively active mutant
    TM
    transmembrane domain
    i3
    third intracellular loop
    Gs
    G protein that stimulates adenylate cyclase
    • Received November 11, 1998.
    • Accepted January 27, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 55 (5)
Molecular Pharmacology
Vol. 55, Issue 5
1 May 1999
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Research ArticleArticle

Novel Brain-Specific 5-HT4 Receptor Splice Variants Show Marked Constitutive Activity: Role of the C-Terminal Intracellular Domain

Sylvie Claeysen, Michèle Sebben, Carine Becamel, Joël Bockaert and Aline Dumuis
Molecular Pharmacology May 1, 1999, 55 (5) 910-920;

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Research ArticleArticle

Novel Brain-Specific 5-HT4 Receptor Splice Variants Show Marked Constitutive Activity: Role of the C-Terminal Intracellular Domain

Sylvie Claeysen, Michèle Sebben, Carine Becamel, Joël Bockaert and Aline Dumuis
Molecular Pharmacology May 1, 1999, 55 (5) 910-920;
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