Agonist-induced desensitization of adenylyl cyclase activity mediated by 5-hydroxytryptamine7 receptors in rat frontocortical astrocytes.
Our previous study has demonstrated that astrocytes derived from the rat frontal cortex contain 5-hydroxytryptamine (5-HT)7 receptors positively coupled to adenylyl cyclase. In this study, we observed a desensitization of 5-HT7 receptors induced by a treatment with agonists (0.1, 1, and 10 muM, 0.5 to 3.5 h). Maximum responses, but not the EC50 values, in the concentration-response curve of 5-HT-induced cyclic AMP formation were decreased after pretreatment with 5-HT. Pretreatment with 5-carboxamidotryptamine (5-CT) elicited a potent desensitization of 5-HT-induced cyclic AMP formation. Neither 2-methyl-5-HT nor alpha-methyl-5-HT caused the desensitization. When the astrocytes were treated with isoproterenol, N-ethylcarboxamidoadenosine, and dibutyryl cyclic AMP (all of which increase intracellular cyclic AMP levels), 5-HT-induced cyclic AMP responses were not affected. Conversely, adenylyl cyclase activity mediated by either isoproterenol or N-ethylcarboxamidoadenosine was attenuated by pretreatment with each of these agonists, but not 5-HT. In addition, our study showed that the administration of 5-HT, 5-CT, and 8-hydroxy-2-(di-n-propylamino)tetralin to the astrocytes stimulated cyclic AMP formation both in the presence and absence of forskolin, whereas in neuron-rich cultures of the frontal cortex, these agonists did not change basal cyclic AMP levels and decreased forskolin-stimulated cyclic AMP formation. Neurons may predominantly contain 5-HT1A receptors that are negatively coupled to adenylyl cyclase. These results suggest that 5-HT7 receptors are highly expressed in astrocytes but not in neuronal cells, and that pretreatment with their agonists results in a homologous desensitization of the receptors.
Shimizu
M
M
Department of Psychiatry and Neuroscience, Institute of Clinical Research, Kure National Hospital, 3-1 Aoyama, Kure 737, Japan.
Nishida
A
A
Zensho
H
H
Miyata
M
M
Yamawaki
S
S
D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D017397:Prefrontal Cortex / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D047428:Protein Kinase Inhibitors; D051381:Rats; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000187:drug effects*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D013997:Time Factors
D047428:Protein Kinase Inhibitors; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; D000242:Cyclic AMP; D000262:Adenylyl Cyclases