ENHANCEMENT BY 5-HYDROXYTRYPTAMINE AND ANALOGS OF DESENSITIZATION OF NEURONAL AND MUSCLE NICOTINIC RECEPTORS EXPRESSED IN XENOPUS OOCYTES

1 The action of 5-hydroxytryptamine (5-HT) on neuronal and muscle nicotinic acetylcholine receptors (nicotinic AChR) expressed in Xenopus oocytes was studied. 2 5-HT enhanced the rate of desensitization of the acetylcholine (ACh) current response in all receptor subtypes investigated (muscle, alpha beta(2) gamma delta and alpha(4) beta(2)), acting in a dose-dependent manner. 3 5-HT also reduced the peak current elicited by ACh in a dose-dependent manner. The IC50 value for the muscle type receptor was 227 +/- 0.44 mu M, and 166 +/- 0.47 mu M and 283 +/- 0.28 mu M for the combinations alpha beta(2) gamma delta and alpha(4) beta(2) respectively. 4 The effect of 5-HT on the responses to ACh (10 mu M) was found to be independent of membrane voltage over the range tested (-80 to -10 mV), and to be readily reversed by washout. 5 The action of 5-HT could be mimicked by structurally similar molecules. The homologue tryptamine was less potent than 5-HT in blocking the ACh current, with an IC50 of 1.0 +/- 0.02 mM. Ketanserin, a 5-HT2 receptor antagonist, was more potent than 5-HT, the IC50 being 49.0 +/- 1.4 mu M. 6 We postulate that a highly conserved portion of the tertiary structure of nicotinic AChRs, which includes some part of the ACh binding site, has affinity for 5-HT and structural analogues.