HOMOLOGOUS DESENSITIZATION OF 5-HYDROXYTRYPTAMINE(4) RECEPTORS IN RATESOPHAGUS - FUNCTIONAL AND 2ND MESSENGER STUDIES

We have studied agonist-induced desensitization of 5-hydroxytryptamine (5-HT4) receptor-mediated relaxation and 5-HT4 receptor-mediated incr eases in cAMP in rat esophageal tunica muscularis mucosae. In both cas es, the desensitization time course was biphasic. The first phase was very rapid because more than 50% of desensitization was obtained after a 5-min incubation period with 10 mu M of 5-HT. The second phase was slower and led to a complete suppression of the response after 2 h. De sensitization progressively reduced the maximal relaxation of esophagu s induced by 5-HT without significantly affecting the EC,,. Desensitiz ation was a receptor-mediated event because cross-desensitization was observed between two chemically unrelated 5-HT4 receptor agonists, 5-H T itself and (S)-zacopride. Inasmuch as the kinetics of desensitizatio n were the same when second messenger production or final responses we re measured, this suggests that the limiting step in the desensitizati on process is at the level of the receptor itself or in its coupling t o adenylyl cyclase. The desensitization was of the homologous type bec ause exogenously applied cAMP, 8-Bromo-cAMP, or compounds increasing c AMP in the esophageal tunica muscularis mucosae such as isoproterenol and forskolin, were unable to induce any desensitization of the 5-HT4 receptor-induced relaxation response. Homologous desensitization was n ot followed by a rapid down-regulation of 5-HT4 receptors because no d ecrease in the B-max of [H-3]-GR113808 binding was observed after 30-m in incubation with 10 mu M 5-HT.