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Pharmacological characterization of the human 5-HT 4(d) receptor splice variant stably expressed in Chinese hamster ovary cells

Abstract : The recently identified C-terminal splice variant of the human 5-HT4 receptor, the h5-HT4(d) receptor, was stably expressed in a CHO cell line at 493±25 fmol mg−1 protein. We analysed its pharmacological properties by measuring binding affinities and 5-HT4 ligand-induced cyclic AMP production. The pharmacological binding profile determined in competition studies with the specific antagonist [3H]-GR113808 revealed a rank order of affinity of 5-HT4 ligands for the h5-HT4(d) receptor that was consistent with those previously reported for other 5-HT4 receptor isoforms. In adenylyl cyclase functional assays, the h5-HT4(d) receptor displayed equipotent coupling for all 5-HT4 agonists tested (EC50 in the range of 1–6 nM). EC50 values were lower than those previously obtained with the 5-HT4(e) receptor stably expressed in CHO cells indicating that the 5-HT4(d) receptor was more efficiently coupled to its effector than the 5-HT4(e) receptor isoform. Moreover, in terms of agonist efficacy (Emax), the benzamide derivative, renzapride displayed full agonist properties at the h5-HT4(d) receptor (same Emax as 5-HT) whereas it was previously shown to be a partial agonist at the h5-HT4(e) receptor. A constitutive activity of the h5-HT4(d) receptor was observed in CHO cells in the absence of any 5-HT4 ligand. Surprisingly, two 5-HT4 ligands, SB204070 and RS39604 which are described as highly potent antagonists in various biological models, revealed partial agonist properties at the h5-HT4(d) receptor. We conclude that C-terminal tails of 5-HT4 receptor isoforms may directly influence their functional properties.
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https://hal-universite-paris-saclay.archives-ouvertes.fr/hal-03611636
Contributor : RODOLPHE FISCHMEISTER Connect in order to contact the contributor
Submitted on : Thursday, March 17, 2022 - 11:45:53 AM
Last modification on : Monday, July 4, 2022 - 8:42:30 AM
Long-term archiving on: : Saturday, June 18, 2022 - 6:48:42 PM

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Jeanne Mialet, Isabelle Berque-Bestel, Sames Sicsic, Michel Langlois, Rodolphe Fischmeister, et al.. Pharmacological characterization of the human 5-HT 4(d) receptor splice variant stably expressed in Chinese hamster ovary cells. British Journal of Pharmacology, Wiley, 2000, 131 (4), pp.827-835. ⟨10.1038/sj.bjp.0703641⟩. ⟨hal-03611636⟩

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