Pharmacological characterization of a rat 5-hydroxytryptamine type3 receptor subunit (r5-HT3A(b)) expressed in Xenopus laevis oocytes

1 The present study has utilized the two electrode voltage-clamp technique 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 holding potentials, bath applied 5-HT (300 nM -10 mu M) evoked a transient, 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 The response to 5-HT was mimicked by the 5-HT3 receptor selective agonists 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-dichlorophenylbiguanide (EC50=14.5+/-0.4 nM) and 2,5-dichlorophenylbiguanide (EC50= 10.2+/-0.6 nM). With the exception of 2-methyl-5-HT, all of the agonists 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 antagonist ondansetron (IC50=231+/-22 pM) and by the less selective agents (+)-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. Overall, the study reinforces the conclusion that species differences detected for native 5-HT3 receptors extend to, and appear largely explained by, differences in the properties of homo-oligomeric receptors formed from 5-HT3A subunit orthologues.