Mechanisms of ligand-induced desensitization of the 5-hydroxytryptamine (2A) receptor

ABSTRACT We have examined the cellular processes underlying the desensitization of the 5-hydroxytryptamine (5-HT) 2A receptor induced by agonist or antagonist exposure. Treatment of C6 glioma cells with either 5-HT or the 5-HT 2A receptor antagonist ketanserin resulted in an attenuation in 5-HT 2A receptor function, specifically the accumulation of inositol phosphates stimulated by the partial agonist quipazine. 5-HT-induced desensitization of the 5-HT 2A receptor involved receptor internalization through a clathrin-and dynamin-dependent process because it was prevented by concanavalin A, monodansylcadaverine, and by expression of the dominant negative mutants ␤-arrestin (319 -418) and dynamin K44A. Although short-term (i.e., 10 min) 5-HT and ketanserin exposure resulted in the same degree of desensitization, ketanserin-induced desensitization was not prevented by these agents and did not involve receptor internalization. In contrast, prolonged ketanserin exposure (i.e., 2 h) resulted in 5-HT 2A receptor internalization through a clathrinand dynamin-dependent process, as was observed after agonist treatment. Inhibitors of protein kinase C or calcium-calmodulin kinase II did not attenuate or prevent 5-HT-induced desensitization of the receptor. 5-HT 2A receptor desensitization induced by 5-HT and prolonged ketanserin treatment, but not by short-term ketanserin treatment, was prevented by the expression of the dominant negative mutant of G protein-coupled receptor kinase (GRK)2, GRK2-K220R, and by an anti-GRK2/3 antibody. Our data indicate a dual mechanism of early and late desensitization by the antagonist ketanserin. Short-term ketanserin treatment reduced the specific binding of the agonist radioligand Desensitization of G protein-coupled receptors occurs during agonist exposure, often in a matter of minutes. Mechanisms underlying the desensitization of many G proteincoupled receptors have been elucidated in part by using the ␤-adrenergic receptor as a prototype The 5-hydroxytryptamine (5-HT) 2A receptor has been implicated in the mechanism of action of many psychoactive drugs such as hallucinogens, atypical neuroleptics, and antidepressants. The regulation of the 5-HT 2A receptor, however, does not appear to follow the pattern established for many other G protein-coupled receptors. Repeated administration of agonists Given the interest in the role of the 5-HT 2A receptor in the action of many psychoactive drugs and the apparent anomalous regulation of 5-HT 2A receptors by antagonists, including atypical neuroleptics and many antidepressant drug

Neurotrophic Factor Signaling in Alcoholism

This article presents the proceedings of a symposium presented at the meeting of the International Society for the Biomedical Research on Alcoholism (ISBRA), held in Manheim, Germany, in September 2004. The organizers and chairpersons were Subhash C. Pandey and Toshikazu Saito. The presentations were (1) Ethanol and NMDA receptor coupling to ERK signaling, by L.J. Chandler;(2) Ethanol modulation of CREB: Role in neurogenesis, by Fulton Crews;(3) Serotonin dysfunction and alcohol preference in mice deficient in brain-derived neurotrophic factor (BDNF), by Julie G. Hensler; (4) BDNF gene and related signaling: role in anxiety and alcohol dependence and preference, by Subhash C. Pandey; (5) BDNF and CREB: role in ethanol induced neuronal damage, Wataru Ukai

On the reporting and review requirements of ISO 14044

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5-Hydroxytryptamine receptors (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

oai:ojs.pkp.sfu.ca:article/31555-HT receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on 5-HT receptors [194] and subsequently revised [176]) are, with the exception of the ionotropic 5-HT3 class, GPCRs where the endogenous agonist is 5-hydroxytryptamine. The diversity of metabotropic 5-HT receptors is increased by alternative splicing that produces isoforms of the 5-HT2A (non-functional), 5-HT2C (non-functional), 5-HT4, 5-HT6 (non-functional) and 5-HT7 receptors. Unique amongst the GPCRs, RNA editing produces 5-HT2C receptor isoforms that differ in function, such as efficiency and specificity of coupling to Gq/11 and also pharmacology [40, 482]. Most 5-HT receptors (except 5-ht1e and 5-ht5b) play specific roles mediating functional responses in different tissues (reviewed by [463, 382])

5-Hydroxytryptamine receptors in GtoPdb v.2023.1

5-HT receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on 5-HT receptors [198] and subsequently revised [180]) are, with the exception of the ionotropic 5-HT3 class, GPCRs where the endogenous agonist is 5-hydroxytryptamine. The diversity of metabotropic 5-HT receptors is increased by alternative splicing that produces isoforms of the 5-HT2A (non-functional), 5-HT2C (non-functional), 5-HT4, 5-HT6 (non-functional) and 5-HT7 receptors. Unique amongst the GPCRs, RNA editing produces 5-HT2C receptor isoforms that differ in function, such as efficiency and specificity of coupling to Gq/11 and also pharmacology [40, 491]. Most 5-HT receptors (except 5-ht1e and 5-ht5b) play specific roles mediating functional responses in different tissues (reviewed by [471, 387])

Inhibition of fatty-acid amide hydrolase and CB1 receptor antagonism differentially affect behavioural responses in normal and PCP-treated rats

The cannabinoid hypothesis of schizophrenia tulates that over-activity of the endocannabinoid system might contribute to the aetiology of schizophrenia. In keeping with this hypothesis, increased expression of CB1 receptors, elevation of the endocannabinoid anandamide (AEA) and cannabinoid-induced cognitive changes have been reported in animal models of schizophrenia and psychotic patients. In this study we measured brain endocannabinoid levels and [35S]GTPS binding stimulated by the CB receptor agonist CP55,940 in rats undergoing withdrawal from subchronic administration of phencyclidine (PCP), a well-established pharmacological model of schizophrenia. We also investigated whether systemic application of the fatty-acid amide hydrolase (FAAH) inhibitor URB597 or CB1 receptor blockade by AM251 affected the following PCP-induced behavioural deficits reminiscent of schizophrenia-like symptoms: (1) working-memory impairment (cognitive deficit), (2) social withdrawal (negative symptom), and (3) hyperactivity in response to d-amphetamine challenge (positive symptoms). PCP-treated rats showed increased endocannabinoid levels in the nucleus accumbens and ventral tegmental area, whereas CB1 receptor expression and CP55,940-stimulated [35S]GTPS binding were unaltered. URB597 reversed the PCP-induced social withdrawal but caused social withdrawal and working-memory deficits in saline-treated rats that were comparable to those observed after PCP treatment. Administration of AM251 ameliorated the working-memory deficit in PCP-treated rats, but impaired working memory in saline-injected controls. Taken together, these results suggest that FAAH inhibition may improve negative symptoms in PCP-treated rats but produce deleterious effects in untreated animals, possibly by disturbing endocannabinoid tone. A similar pattern (beneficial for schizophrenia-related cognitive deficits, but detrimental under normal conditions) accompanies CB1 receptor blockade. © 2009 CINP