Molecular and functional characterization of a 5-HT 4 receptor cloned from human atrium
Abstract
5-Hydroxytryptamine (5-HT) has been shown to exert positive inotropic, chronotropic, and lusitropic effects and to stimulate the L-type calcium channel current (7c a) in human atrial tissue through activation of the pharmacologically defined 5-HT 4 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-HT 4 receptor cloned from human atrium, h5-HT 4 A. Sequence analysis reveals that h5-HT 4 A displays a 93% protein identity with the short form of the 5-HT 4 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 4 A transiently expressed in COS-7 cells displays a classical 5-HT 4 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 4 A in response to the 5-HT 4 agonists ML10302 and renzapride were very similar to the patterns of stimulation of 7ca obtained in response to these compounds in human atrial myocytes. We conclude that h5-HT 4 A likely mediates the effects of 5-HT in human atrium and may differ from 5-HT 4 receptor isoforms present in the brain and GI tract.
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