Pharmacological characterization of the apparent splice variants of the murine 5-HT3 R-A subunit expressed in Xenopus laevis oocytes.

The actions of 5-hydroxytryptamine3 (5-HT3) receptor agonists and antagonists have been determined on the recombinant murine 5-HT3 R-A and an apparent splice variant of this subunit, termed 5-HT3 R-AS. When expressed in Xenopus laevis oocytes, both forms of the subunit functioned as a homo-oligomeric complex and exhibited inward current responses to bath applied 5-HT. Analysis of the 5-HT concentration-response curve obtained with either homo-oligomer gave Hill coefficients greater than two, suggesting positive co-operativity within the receptor complex. The rank order of potency of a range of 5-HT3 receptor agonists [m-chlorophenylbiguanide > 5-HT > 2-methyl-5-HT (2-Me-5-HT) > or = phenylbiguanide] was identical for both subunits. Indeed, with the exception of 2-Me-5-HT, for the agonists tested there was little difference across the subunits in either their potency, or the maximal current response that they elicited relative to 5-HT. Although 2-Me-5-HT exhibited a similar potency for both subunits, the maximal response evoked by this agonist at the 5-HT3 R-AS subunit was much reduced when compared to the 5-HT3 R-A subunit. The 5-HT-induced current mediated by either form of the subunit was inhibited by the 5-HT3 receptor selective antagonists BRL 46470, granisetron and ondansetron and the non-selective antagonists (+)-tubocurarine, metoclopramide and cocaine in a reversible and concentration-dependent manner. These antagonists did not discriminate between the subunits and their potencies were similar to those reported previously for 5-HT3 receptors native to murine neuronal cells.(ABSTRACT TRUNCATED AT 250 WORDS)