Characterization of homologous 5-hydroxytryptamine4 receptor desensitization in colliculi neurons
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 pote...
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Published in | Molecular pharmacology Vol. 42; no. 5; pp. 808 - 816 |
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Main Authors | , , , |
Format | Journal Article |
Language | English |
Published |
Bethesda, MD
American Society for Pharmacology and Experimental Therapeutics
01.11.1992
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Subjects | |
Online Access | Get full text |
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Summary: | 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. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0026-895X 1521-0111 |