PHARMACOLOGICAL CHARACTERIZATION OF A RAT 5-HYDROXYTRYPTAMINE TYPE(3)RECEPTOR SUBUNIT (R5-HT3A(B)) EXPRESSED IN XENOPUS-LAEVIS OOCYTES

1 The present study has utilized the two electrode voltage-clamp techn ique to examine the pharmacological profile of a splice variant of the rat orthologue of the 5-hydroxytryptamine type 3A subunit (5-HT3A(b)) heterologously expressed in Xenopus laevis oocytes. 2 At negative hol ding potentials, bath applied 5-HT (300 nM -10 mu M) evoked a transien t, concentration-dependent (EC50=1.1+/-0.1 mu M), inward current. The response reversed in sign at a holding potential of -2.1+/-1.6 mV. 3 T he response to 5-HT was mimicked by the 5-HT3 receptor selective agoni sts 2-methyl-5-HT (EC50=4.1+/-0.2 mu M), 1-phenylbiguanide (EC50=3.0+/ -0.1 mu M), 3-chlorophenylbiguanide (EC50=140+/- 10 nM), 3,5-dichlorop henylbiguanide (EC50=14.5+/-0.4 nM) and 2,5-dichlorophenylbiguanide (E C50= 10.2+/-0.6 nM). With the exception of 2-methyl-5-HT, all of the a gonists tested elicited maximal current responses comparable to those produced by a saturating concentration (10 mu M) of 5-HT. 4 Responses evoked by 5-HT at EC50 were blocked by the 5-HT3 receptor selective an tagonist ondansetron (IC50=231+/-22 pM) and by the less selective agen ts (+)-tubocurarine (IC50=31.9+/- 0.01 nM) and cocaine (IC50=2.1+/-0.2 mu M). 5 The data are discussed in the context of results previously obtained with the human and mouse orthologues of the 5-HT3A subunit. O verall, the study reinforces the conclusion that species differences d etected for native 5-HT3 receptors extend to, and appear largely expla ined by, differences in the properties of homo-oligomeric receptors fo rmed from 5-HT3A subunit orthologues.