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Eur J Pharmacol. 1999 Mar 12;369(1):125-32.

Identification of a domain affecting agonist potency of meta-chlorophenylbiguanide in 5-HT3 receptors.

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  • 1Molecular Medicine Laboratories, Institute for Drug Discovery Research, Yamanouchi Pharmaceutical, Tsukuba, Ibaraki, Japan. mochizuk@yamanouchi.co.jp


The pharmacological properties of rat and human 5-HT3 receptors expressed in Xenopus oocytes were assessed using a two-electrode voltage clamp technique. Meta-chlorophenylbiguanide (mCPBG), a 5-HT3 receptor-selective agonist, elicited typical current responses in both rat and human 5-HT3 receptor-expressing oocytes. However, the EC50 value for rat 5-HT3 receptors was 13-fold lower than for human 5-HT3 receptors. Using several chimeric human-rat 5-HT3 receptors, we identified a potential domain responsible for this difference in mCPBG-response. The domain is in the N-terminal extracellular region adjacent to the first transmembrane domain of rat 5-HT3 receptors and includes a rat-specific seven amino acid sequence (Phe197, Thr198, Lys199, Gln201, Ile205, Thr207 and Ser210). Replacement of corresponding amino acids in human 5-HT3 receptors by rat receptor residues increased the potency of mCPBG on human receptors indicating these amino acids play an important role in the pharmacological response to mCPBG.

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