Molecular and functional characterization of a 5‐HT4 receptor cloned from human atrium

FEBS Letters

Langlois, Michel¹  Blondel, Olivier¹  Fischmeister, Rodolphe¹  Gastineau, Monique¹  Leclerc, Stéphanie¹  Vandecasteele, Grégoire¹  Dahmoune, Yamina¹ 

[1] Laboratoire de Cardiologie Cellulaire et Moléculaire, INSERM U-446, Université de Paris-Sud, Faculté de Pharmacie, F-92296 Châtenay-Malabry, France

关键词: Human heart;    Serotonin receptor;    5-HT4 receptor;    Calcium channel current;    Human cardiac myocyte;    5-HT4 receptor agonist;    5-HT4 receptor antagonist;    5-HT;    5-hydroxytryptamine (serotonin);    5-MeOT;    5-methoxytryptamine;    BIMU1;    endo-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-2;    3-dihydro-3-ethyl-2-oxo-1H-benzimidazole-1-carboxamide;    GI;    gastrointestinal tract;    GR113808;    [1-[2-(methylsulphonyl)amino]ethyl]-4-piperidinyl]methyl 1-methyl-1H-indole-3-carboxylate;    I Ca;    L-type calcium current;    ML10302;    2-piperidinoethyl 4-amino-5-chloro-2-methoxybenzoate hydrochloride;    ML10375;    2-(cis-3;    5-dimethylpiperidino)ethyl 4-amino-5-chloro-2-methoxybenzoate;    PEI;    polyethylenimine;    renzapride;    (±)-endo-4-amino-5-chloro-2-methoxy-N-(1-azabicyclo[3.3.1]non-4-yl)benzamide monhydrochloride (BRL 24924);    zacopride;    4-amino-5-chloro-2-methoxy -N-(1-azabicyclo[2.2.2]oct-3-yl)benzamide monhydrochloride;   

DOI  :  10.1016/S0014-5793(97)00820-X

学科分类：生物化学/生物物理

来源: John Wiley & Sons Ltd.

【 摘 要 】

5-Hydroxytryptamine (5-HT) has been shown to exert positive inotropic, chronotropic, and lusitropic effects and to stimulate the L-type calcium channel current (I _Ca) in human atrial tissue through activation of the pharmacologically defined 5-HT₄ receptor subtype. However, the molecular nature of the receptor(s) involved in these effects is still unknown. In the present study, we report the molecular nature of a 5-HT₄ receptor cloned from human atrium, h5-HT_4A. Sequence analysis reveals that h5-HT_4A displays a 93% protein identity with the short form of the 5-HT₄ receptor recently isolated from rat brain. h5-HT_4A mRNA is expressed in human atrium but not ventricle, and is also found in brain and GI tract. h5-HT_4A transiently expressed in COS-7 cells displays a classical 5-HT₄ pharmacological profile. However, affinities of the h5-HT_4A receptor for agonists such as ML10302, BIMU1, renzapride or zacopride were 4–10-fold lower than the ones found in brain. Moreover, the stimulatory patterns of cAMP formation by h5-HT_4A in response to the 5-HT₄ agonists ML10302 and renzapride were very similar to the patterns of stimulation of I _Ca obtained in response to these compounds in human atrial myocytes. We conclude that h5-HT_4A likely mediates the effects of 5-HT in human atrium and may differ from 5-HT₄ receptor isoforms present in the brain and GI tract.

【 授权许可】

Unknown