PHARMACOLOGICAL CHARACTERIZATION OF THE APPARENT SPLICE VARIANTS OF THE MURINE 5-HT3, R-A SUBUNIT EXPRESSED IN XENOPUS-LAEVIS OOCYTES

The actions of 5-hydroxytryptamine(3) (5-HT3) receptor agonists and an tagonists have been determined on the recombinant murine 5-HT, R-A and an apparent splice variant of this subunit, termed 5-HT3 R-A(S). When expressed in Xenopus laevis oocytes, both forms of the subunit functi oned as a homo-oligomeric complex and exhibited inward current respons es to bath applied 5-HT. Analysis of the 5-HT concentration-response c urve obtained with either homo-oligomer gave Hill coefficients greater than two, suggesting positive co-operativity within the receptor comp lex. 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) greater tha n or equal to phenylbiguanide] was identical for both subunits. Indeed , with the exception of 2-Me-5-HT, for the agonists tested there was l ittle difference across the subunits in either their potency, or the m aximal current response that they elicited relative to 5-HT. Although 2-Me-5-HT exhibited a similar potency for both subunits, the maximal r esponse evoked by this agonist at the 5-HT3 R-A(S) subunit was much re duced 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 rec eptor selective antagonists BRL 46470, granisetron and ondansetron and the non-selective antagonists (+)-tubocurarine, metoclopramide and co caine in a reversible and concentration-dependent manner. These antago nists did not discriminate between the subunits and their potencies we re similar to those reported previously for 5-HT3 receptors native to murine neuronal cells. These results are discussed in terms of a possi ble diversity of 5-HT3 receptors within a species.