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

The pharmacological properties of rat and human 5-HT3 receptors expressed i n Xenopus oocytes were assessed using a two-electrode voltage clamp techniq ue. Meta-chlorophenylbiguanide (mCPBG), a 5-HT3 receptor-selective agonist, elicited typical current responses in both rat and human 5-HT3 receptor-ex pressing oocytes. However, the EC50 value for rat 5-HT3 receptors was 13-fo ld lower than for human 5-HT3 receptors. Using several chimeric human-rat 5 -HT3 receptors, we identified a potential domain responsible for this diffe rence in mCPBG-response. The domain is in the N-terminal extracellular regi on adjacent to the first transmembrane domain of rat 5-HT3 receptors and in cludes a rat-specific seven amino acid sequence (Phe(197), Thr(198), Lys(19 9), Gln(201), Ile(205), Thr(207) and Ser(210)). Replacement of correspondin g amino acids in human 5-HT3 receptors by rat receptor residues increased t he potency of mCPBG on human receptors indicating these amino acids play an important role in the pharmacological response to mCPBG. (C) 1999 Elsevier Science B.V. All rights reserved.