MOLECULAR AND FUNCTIONAL-CHARACTERIZATION OF A 5-HT4 RECEPTOR CLONED FROM HUMAN ATRIUM

5-Hydroxytryptamine (9-HT) has been shown to exert positive inotropic, chronotropic, and lusitropic effects and to stimulate the L-type calc ium channel current (ICa) in human atrial tissue through activation of the pharmacologically defined 5-HT4 receptor subtype. However, the mo lecular nature of the receptor(s) involved in these effects is still u nknown, In the present study, we report the molecular nature of a 5-HT 4 receptor cloned from human atrium, h5-HT4A. Sequence analysis reveal s 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 e xpressed 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 h 5-HT4A receptor for agonists such as ML10302, BIMU1, renzapride or zac opride were 4-10-fold lower than the ones found in brain, Moreover, th e stimulatory patterns of cAMP formation by h5-HT4A in response to the 5-HT4 agonists ML10302 and renzapride mere very similar to the patter ns of stimulation of ICa obtained in response to these compounds in hu man atrial myocytes, We conclude that h5-HT4A likely mediates the effe cts of 5-HT in human atrium and may differ from 5-HT4 receptor isoform s present in the brain and GI tract. (C) 1997 Federation of European B iochemical Societies.