Homologous desensitization of 5-hydroxytryptamine4 receptors in rat esophagus: functional and second messenger studies.

We have studied agonist-induced desensitization of 5-hydroxytryptamine (5-HT4) receptor-mediated relaxation and 5-HT4 receptor-mediated increases in cAMP in rat esophageal tunica muscularis mucosae. In both cases, 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 microM of 5-HT. The second phase was slower and led to a complete suppression of the response after 2 h. Desensitization progressively reduced the maximal relaxation of esophagus induced by 5-HT without significantly affecting the EC50. Desensitization was a receptor-mediated event because cross-desensitization was observed between two chemically unrelated 5-HT4 receptor agonists, 5-HT itself and (S)-zacopride. Inasmuch as the kinetics of desensitization were the same when second messenger production or final responses were measured, this suggests that the limiting step in the desensitization process is at the level of the receptor itself or in its coupling to adenylyl cyclase. The desensitization was of the homologous type because exogenously applied cAMP, 8-Bromo-cAMP, or compounds increasing cAMP 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 not followed by a rapid down-regulation of 5-HT4 receptors because no decrease in the Bmax of [3H]-GR113808 binding was observed after 30-min incubation with 10 microM 5-HT.