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

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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 (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.

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