Elsevier

Brain Research Bulletin

Volume 56, Issue 5, 15 November 2001, Pages 441-451
Brain Research Bulletin

Article
Paradoxical trafficking and regulation of 5-HT2A receptors by agonists and antagonists

https://doi.org/10.1016/S0361-9230(01)00623-2Get rights and content

Abstract

5-Hydroxytryptamine2A (serotonin2A, 5-HT2A) receptors are important for many physiologic processes including platelet aggregation, smooth muscle contraction, and the modulation of mood and perception. A large number of pharmaceutical agents mediate their actions, at least in part, by modulating the number and/or activity of 5-HT2A receptors. Drugs with action at 5-HT2A receptors are used in the treatment of many disorders, including schizophrenia, depression, and anxiety disorders. This review summarizes over two decades of research on the regulation of 5-HT2A receptors and provides a comprehensive review of numerous in vivo studies describing the paradoxical phenomenon of 5-HT2A receptor down-regulation by chronic treatment with antidepressants and antipsychotics. In addition, studies reporting antagonist-induced internalization of 5-HT2A receptors and other G protein-coupled receptors will be highlighted as a possible mechanism to explain this paradoxical down-regulation. Finally, a review of the cellular and molecular mechanisms that may be responsible for agonist-mediated desensitization and internalization of 5-HT2A receptors will be presented.

Introduction

Serotonin 5-HT2A receptors are important for mediating a large number of physiologic processes both in the periphery and in the central nervous system. These processes include platelet aggregation, smooth muscle contraction, and the modulation of mood and perception. 5-HT2A receptors belong to a family of serotonin receptors currently made up of more than 15 different receptors encoded by distinct genes which are divided into seven major classes: 5-HT1, 5-HT2, 5-HT3, 5-HT4, 5-HT5, 5-HT6, and 5-HT7 [87]. Most of these classes have multiple subtypes, including the 5-HT2 class that is divided into 5-HT2A, 5-HT2B, and 5-HT2C 56, 84, 90, 91. With the exception of 5-HT3 receptors, which are ligand-gated ion channels 22, 68, 5-HT receptors are members of the G protein-coupled receptor (GPCR) superfamily. A large number of drugs mediate their actions, at least in part, by interactions with 5-HT2A receptors. These include hallucinogens, atypical antipsychotic drugs and antidepressants.

GPCRs comprise at least two percent of the estimated 30,000 genes in the human genome and are targets for a wide array of molecules ranging from hormones and neurotransmitters to odorants and even light. GPCRs are characterized by seven membrane-spanning helices with an extracellular amino-terminus, an intracellular carboxy-terminus, and three intracellular and three extracellular loops connecting each of the transmembrane segments. Binding of an agonist to its GPCR leads to conformational changes in the receptor that induce the dissociation and activation of a receptor-specific heterotrimeric G protein into its α- and βγ- subunits. These dissociated subunits can then activate or inhibit a number of downstream effectors, such as nucleotide cyclases, phospholipases, and kinases, resulting in a variety of downstream cellular effects.

In addition to initiating intracellular signal transduction cascades, agonist activation of GPCRs also triggers cellular and molecular mechanisms that lead to the attenuation of receptor signaling. Thus, GPCR responsiveness to agonist-induced stimulation wanes over time, a process termed desensitization. Other regulatory phenomena include resensitization, a recovery of receptor responsiveness following desensitization, and down-regulation, a reduction in receptor number. The past decade has seen much progress in elucidating the cellular events mediating GPCR regulation and these processes will be briefly reviewed. Specifically, receptor trafficking via the endocytic pathway will be discussed in relation to its role in mediating and modulating the pharmacologically defined patterns of GPCR regulation. This review will briefly describe the classical mechanistic models of receptor regulation as a prelude to a summary of the paradoxical behavior of 5-HT2A receptors.

Section snippets

5-HT2A desensitization and the role of kinases

Desensitization is an adaptive mechanism by which cells regulate receptor responsiveness to repetitive environmental stimuli. Two major patterns of rapid GPCR desensitization have been characterized, homologous or agonist-specific, and heterologous or agonist-nonspecific 18, 33. Homologous desensitization refers to the attenuation of a cell’s response to only that agonist. For example, a cell exposed to a 5-HT2A receptor agonist would, over time, become desensitized to repeated exposure to the

Mechanisms of long-term GPCR regulation

In addition to short-term regulation of GPCRs by the processes of desensitization, resensitization, and internalization, receptors can be regulated on a longer time scale. Thus, following prolonged or repetitive activation of receptors by agonists, there is a measurable reduction in the number of receptors within cells or tissues. This results in a long-term attenuation of the receptor’s ability to signal in the presence of new stimuli. This phenomenon, known as down-regulation, is

Conclusions

As is clear from the studies reviewed here, 5-HT2A receptors are paradoxically regulated by endogenous and exogenous factors. Though two decades have passed since the first report of 5-HT2A receptor down-regulation by antidepressants, we still have only an elementary understanding of the molecular and cellular processes involved in mediating this phenomenon. As is becoming clear, studies of the regulation of prototypical GPCRs, such as the β2-adrenergic receptor, only provide the barest of

Acknowledgements

In Table 1, Table 2, Table 3 we have attempted to provide a comprehensive review of 5-HT2A receptor down-regulation by antidepressants and antipsychotics. We sincerely apologize for any studies we may have unintentionally omitted. This work was supported in part by RO1MH61887, KO2MH01366, and a NARSAD Independent Investigator Award to B.L.R.

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