Molecular and functional characterization of a 5-HT4 receptor cloned from human atrium.
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-HT4A. Sequence analysis reveals that h5-HT4A displays a 93% protein identity with the short form of the 5-HT4 receptor recently isolated from rat brain. h5-HT4A mRNA is expressed in human atrium but not ventricle, and is also found in brain and GI tract. h5-HT4A transiently expressed in COS-7 cells displays a classical 5-HT4 pharmacological profile. However, affinities of the h5-HT4A 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-HT4A 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-HT4A 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.
Blondel
O
O
Laboratoire de Cardiologie Cellulaire et Moléculaire, INSERM U-446, Université de Paris-Sud, Châtenay-Malabry, France. U446@vjf.inserm.fr
Vandecasteele
G
G
Gastineau
M
M
Leclerc
S
S
Dahmoune
Y
Y
Langlois
M
M
Fischmeister
R
R
D000293:Adolescent; D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D000818:Animals; D015220:Calcium Channels / Q000187:drug effects; D002648:Child; D003001:Cloning, Molecular; D000242:Cyclic AMP / Q000096:biosynthesis; D006325:Heart Atria / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007211:Indoles; D007700:Kinetics; D008875:Middle Aged; D008969:Molecular Sequence Data; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D009928:Organ Specificity; D051381:Rats; D011985:Receptors, Serotonin / Q000737:chemistry* / Q000235:genetics / Q000502:physiology*; D044422:Receptors, Serotonin, 5-HT4; D012701:Serotonin / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D013449:Sulfonamides
D015220:Calcium Channels; D007211:Indoles; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D013449:Sulfonamides; D044422:Receptors, Serotonin, 5-HT4; D012701:Serotonin; D000242:Cyclic AMP; C082871:GR 113808