Characterization of homologous 5-hydroxytryptamine4 receptor desensitization in colliculi neurons

• Published in: Molecular pharmacology Vol. 42; no. 5; pp. 808 - 816
• Main Authors: ANSANAY, H, SEBBEN, M, BOCKAERT, J, DUMUIS, A
• Format: Journal Article
• Language: English
• Published: Bethesda, MD American Society for Pharmacology and Experimental Therapeutics 01.11.1992
• Subjects: Animals; Biological and medical sciences; Cations, Divalent; Cells, Cultured; Central nervous system; Central neurotransmission. Neuromudulation. Pathways and receptors; Cyclic AMP - biosynthesis; Fundamental and applied biological sciences. Psychology; Heparin - pharmacology; Mice; Neurons - drug effects; Neurons - enzymology; Neurons - metabolism; Protein Kinase Inhibitors; Protein Kinases - metabolism; Receptors, Serotonin - drug effects; Receptors, Serotonin - metabolism; Signal Transduction; Tectum Mesencephali - cytology; Tectum Mesencephali - drug effects; Tectum Mesencephali - metabolism; Vertebrates: nervous system and sense organs; Zinc - pharmacology; Desensitization; Serotonin; Rodentia; Central nervous system; Cyclic AMP; In vitro; Colliculus superior; Characterization; Vertebrata; Mammalia; Neuron; Colliculus inferior; Mouse; Animal; S4 receptor; Brain (vertebrata)
• ISSN: 0026-895X; 1521-0111

Exposure of mouse colliculi neurons to selective 5-hydroxytryptamine (5-HT)4 agonists was accompanied by a rapid desensitization of the receptor-stimulated adenylyl cyclase response. Half-maximal desensitization occurred after 2 min. Only exposure of neurons to selective 5-HT4 agonists led to a potent desensitization of the 5-HT4-mediated response. Neurons exposed to other agents, like isoproterenol, vasoactive intestinal peptide, or forskolin, that increase cAMP levels did not undergo any desensitization of 5-HT4 receptors. Activation of protein kinase A with either 8-bromo-cAMP or dibutyryl-cAMP or application of inhibitors of protein kinase A-dependent phosphorylation did not change the rate of 5-HT4-induced desensitization. No shift to lower potency of 5-HT4 agonists in the concentration-response curve was observed. These results suggest that 5-HT4 receptor agonists induced homologous but not cAMP-mediated heterologous desensitization. A good correlation was found between the affinities of nine 5-HT4 agonists and their abilities to desensitize the adenylyl cyclase response. This may indicate that homologous desensitization is a function of the mean occupancy time of the receptors by agonists. When permeabilized neurons were loaded with heparin, an inhibitor of the beta-adrenergic receptor kinase (beta ARK), 5-HT4 receptor desensitization was reduced by 30-40%. Interestingly, Zn2+, an other inhibitor of beta ARK, totally prevented 5-HT4-induced desensitization. Pretreatment of neurons with concanavalin A, reported to inhibit sequestration of beta-adrenergic receptors from the cell surface, reduced the desensitization process by 70%. These data suggest that both sequestration and phosphorylation by beta ARK, or another specific agonist-dependent receptor kinase, are involved in homologous desensitization of 5-HT4 receptors coupled to adenylyl cyclase.