5-Hydroxytryptamine Receptor 2C
The 5-hydroxytryptamine-type 2C receptor (5-HT2C, previously 5-HT1C) is one of the 14 G protein-coupled receptor subtypes activated by serotonin. 5-HT2C receptors are involved in a large variety of physiological functions such as nociception, motor behavior, endocrine secretion, thermoregulation, modulation of appetite, and the control of exchanges between the central nervous system and the cerebrospinal fluid. They have also been implicated in numerous pathologies such as schizophrenia, anxiety, depression, Parkinson’s disease, drug addiction, and obesity (Berg et al. 2008; Chagraoui et al. 2016). In line with their implication in various pathological situations, 5-HT2C receptors are considered as a major pharmacological target for the development of new treatments (see “Ligand-Dependent Nuclear Receptor Corepressor (LCoR)”) (Di Giovanni and De Deurwaerdere 2016).
With regard to signaling, 5-HT2C receptors are positively coupled to phospholipase Cß protein via Gαq in several brain regions (Berg et al. 2008). Native 5-HT2C receptors also activate phospholipase D through a mechanism involving Gα13 and Gβγ subunits in choroid plexus. Transactivation of the small GTPase RhoA seems to be required for 5-HT2C receptor-mediated phospholipase D activation. Activation of phospholipase A2 and ERK1,2 by 5-HT2C receptors has also been reported in heterologous cells and/or native tissues (Berg et al. 2008; Cassier et al. 2017; Labasque et al. 2008).
5-HT2C receptors expressed along ascending dopaminergic pathways play a prominent role in the control of mesocorticolimbic and nigrostriatal dopaminergic systems. Constitutive and/or agonist-induced 5-HT2C receptor activation inhibits dopamine release (Berg et al. 2008; Bubar and Cunningham 2008). Atypical antipsychotics and antidepressants, in particular those exhibiting inverse agonist activity at 5-HT2C receptors, relieve this inhibition, leading to activation of the mesocorticolimbic dopaminergic system (Berg et al. 2008). Systemic administration of RO600175 (agonist) and SB242084 (antagonist) inhibits and potentiates cocaine-induced behaviors, respectively. Microdialysis of RO600175 or SB242084 in the ventral tegmental area (VTA) or nucleus accumbens also revealed that dopamine efflux induced by systemic cocaine injection is controlled by 5HT2C receptors expressed in the VTA and the Nac (Berg et al. 2008; Bubar and Cunningham 2008).
5-HT2C receptor activation, likewise, exerts a tonic inhibitory influence on the activity of locus coeruleus-derived noradrenergic pathways innervating cortico-limbic structures.
5-HT2C receptors are expressed in pro-opiomelanocortin (POMC)/cocaine amphetamine-regulated transcript neurons of the arcuate nucleus of hypothalamus (Heisler et al. 2003). A series of elegant studies has shown that 5-HT2C receptor activation by administration of fenfluramine, a 5-HT reuptake inhibitor/5-HT releasing compound or by selective agonists like BVT.X, regulates melanocortin signaling and inhibits food intake (Heisler et al. 2003; Miller 2005). Studies showed that mice lacking 5-HT2C receptors displayed hepatic insulin resistance. Moreover, 5-HT2C receptor-deficient mice are resistant to the antidiabetic effects of the 5-HT2C agonist mCPP. Specific re-expression of 5-HT2C receptors in POMC neurons restored the wild-type phenotype (Xu et al. 2010), underlying the potential of 5-HT2C agonists for the treatment of obesity.
5-HT2C receptors are also expressed in basolateral nucleus of amygdala where they contribute to neuropathic pain mechanism. A recent study performed in a rat model of neuropathic pain has shown that local 5-HT2C receptors’ knockdown in the amygdala input region (basolateral nucleus) inhibits neuronal activity in the amygdala output region (central nucleus) by normalizing the imbalance between excitatory drive and synaptic inhibition. This imbalance between excitatory and inhibitory drive of amygdala output neurons might result from an increase 5-HT2C receptor expression in non-GABAergic cells in the basolateral nucleus (Ji et al. 2017).
Indeed, 5HT2C receptor-deficient mice are obese due to an abnormal control of feeding behavior (Berg et al. 2008). Developmental studies of food intake have revealed a chronic hyperphagia in young mutants (from the first 2 months of life through the first year of age) without changes in their body weights, adiposity levels, and in total energy expenditure, compared to wild-type animals (Nonogaki et al. 2003; Nonogaki et al. 1998). In contrast, by 9/10 months of age, mutants exhibit elevations of body weight and adiposity, accompanied by an increase in leptin and insulin levels and a reduction in the total energy expense in older mutant animals (Nonogaki et al. 1998, 2003).
Mice lacking 5HT2C receptors exhibit lower thresholds for the expression of generalized seizures (Applegate and Tecott 1998), an effect modulated by other genetic factors and aging (Brennan et al. 1997).
Mutant mice also exhibit an anxiolytic phenotype (Heisler et al. 2007) and an increased responsiveness to novelty. They are also more sensitive to the effects of acute cocaine treatment on both locomotor activity and on nucleus accumbens dopamine levels (Bubar and Cunningham 2008). Mutant mice display an approximately 50% reduction in DOI-induced head-twitch response compare to their wild-type littermates, suggesting the involvement of 5-HT2C receptors in the psychoactive response to hallucinogenic drugs (Canal et al. 2010).
Regulation of Concentration and Activity
Exposure of 5-HT2C receptors to agonists leads to receptor desensitization (i.e., a decrease in receptor responsiveness) and downregulation (i.e., a reduction in the total number of specific receptor binding sites without a change in apparent affinity for 5-HT) in vivo and in vitro (Bockaert et al. 2006). Several studies indicated that chronic treatment with antagonists and monoamine oxidase inhibitors induces an atypical downregulation of 5-HT2C receptor in the choroid plexus as well as in several heterologous models (Berg et al. 2008). Chronic administration of SSRIs increases 5HT2C receptors density in the choroid plexus (Berg et al. 2008; Bockaert et al. 2006). Paradoxically, the density and functional status of 5-HT2C receptors is also elevated in experimental models of depression as well as in depressed patients (Berg et al. 2008).
Desensitization is initiated by receptor phosphorylation by G protein receptor kinase (GRK)2 (Berg et al. 2008). Receptor phosphorylation is followed by the recruitment of β-arrestins, which uncouple receptor from G protein and promote its internalization into endosomes. This phenomenon not only contributes to receptor desensitization but also allows receptor dephosphorylation and recycling to the plasma membrane in a fully resensitized state.
In addition to agonist-dependent activation, 5-HT2C receptors undergo constitutive activity. Constitutive activity toward phospholipase C effector pathway is accompanied by constitutive receptor desensitization and internalization (Berg et al. 2008). Constitutive activity at 5-HT2C receptors expressed on VTA GABAergic interneurons is responsible for tonic inhibition of mesocorticolimbic dopaminergic neurons (De Deurwaerdere et al. 2004).
The non-edited form exhibits a constitutive activity at β-arrestin- and calmodulin-dependent ERK signaling (Labasque et al. 2010).
Editing alters 5-HT2C receptor trafficking in and out of the plasma membrane, a process reflecting their ability to associate with β-arrestins (Marion et al. 2004).
Editing is modulated by 5-HT itself. Depletion of 5-HT increases the expression of receptor forms exhibiting the highest agonist affinity, whereas opposite changes of editing profile are detected following 5-HT2C receptor activation (Sanders-Bush et al. 2003; Werry et al. 2008). A study performed on mutant mice solely expressing the fully edited form of the receptor has suggested that editing may regulate the density of 5-HT2C receptor binding sites in the brain (Olaghere da Silva et al. 2010).
Altered patterns of 5-HT2C receptor editing are observed in postmortem brains from suicide victims with a history of major depression. Chronic treatments with antidepressants generate opposite changes of editing profiles (Sanders-Bush et al. 2003; Werry et al. 2008). Moreover, early life stress alters adult 5-HT2C receptor mRNA editing and expression of Gαq protein. Kishore and Stamm reported that Prader-Willi syndrome patients (characterized by neonatal muscular hypotonia, early childhood obesity, hypogonadism, and mental retardation) do not express the small nucleolar RNA Snord115 (previously called HBII-52), a regulator of 5-HT2C receptor mRNA splicing. These patients exhibit abnormally low levels of non-edited 5-HT2C-INI receptor. Moreover, mutant mice solely expressing the fully edited form of the receptor display phenotypic characteristics of Prader-Willy syndrome, suggesting a role of serotonergic systems in Prader-Willi syndrome (Garfield et al. 2016; Morabito et al. 2010).
Polymorphism is another mechanism contributing to receptor diversity. Three single nucleotide polymorphisms (SNPs) have been found in the promoter region of the receptor that may regulate the expression level of the 5-HT2C receptor and confer resistance to obesity and type II diabetes (Buckland et al. 2005; Deckert et al. 2000; Meyer et al. 2002; Nocjar et al. 2015; Risselada et al. 2012; Yuan et al. 2000). One non-synonymous SNP (C23S), identified in the coding region of the receptor (Lappalainen et al. 1995; Nocjar et al. 2015), does not seem to have functional consequences (Fentress et al. 2005; Nocjar et al. 2015). Another SNP was also found in the 3′ untranslated region (Nocjar et al. 2015; Song et al. 1999).
Several studies have also demonstrated a critical role of 5HT2C receptors in the onset time of therapeutic response to antidepressants (Berg et al. 2008). Long-term treatment with selective 5-HT reuptake inhibitors (SSRIs) and other antidepressant classes progressively downregulates 5HT2C receptor in rats and human, a process paralleling their gradual onset of actions.
PSD95 is essential for maintaining normal 5-HT2C receptor expression level and downstream signaling in vivo. PSD95null mice exhibit a significant reduction in 5-HT2C expression level particularly in the striatal and hippocampal regions and display a decrease in c-fos induction upon 5-HT2C receptor activation (Abbas et al. 2009). As previously reported for the association of 5-HT2C receptors with MUPP1, the interactions between the receptor and both PSD-95 and MPP3 are negatively regulated by the phosphorylation of 5-HT2C receptors on the PDZ ligand (Ser457, Ser458) (Gavarini et al. 2006).
5-HT2C receptors also interact with non-PDZ proteins. These include calmodulin, which binds to the receptor C-terminus (Becamel et al. 2002; Labasque et al. 2008). Additional calmodulin binding motifs have been identified in intracellular loops of the 5-HT2C receptor (Labasque et al. 2008). A combination of genetic and molecular approaches indicated that activation of Erk1,2 by 5-HT2C receptor, which is entirely independent of receptor’ cognate G proteins, requires a physical association of CaM with the juxta-membrane region of the receptor C-terminus. CaM requirement was established in both heterologous system and authentic cellular contexts such as cortical neurons and choroid plexus epithelial cells. Differing from the classic mechanism of Erk1,2 activation by numerous GPCRs, phosphorylation of Erk1,2 induced by 5-HT2C receptor activation was entirely dependent on β-arrestins, which thereby acts in concert with CaM to activate Erk (Fig. 3c). More recently, it was demonstrated in HEK cells that β-arrestin2, Raf, and MEK are recruited to agonist-stimulated 5-HT2C receptor, resulting in MEK activation. Then, active MEK phosphorylates β-arrestin2 at Thr383 allowing the recruitment of Erk to the receptor/β-arrestin complex and its activation (Cassier et al. 2017).
It was also shown that 5HT2C receptors, Src, and GluN2A subunits are in a same multiprotein complex in synaptosomes from rat spinal cord and that GluN2A subunits and 5HT2C receptors co-localize on the processes of spinal neurons. Moreover, both receptors are functionally coupled as 5HT2C receptors positively modulate NMDA-mediated motoneuronal depolarization, through non-G protein-mediated mechanisms, by increasing the phosphorylation of the tyrosine kinase Src on its residue 416 (Bigford et al. 2012; Nocjar et al. 2015).
5-HT2C receptors interact with β-arrestins (mainly β-arrestin2) via their second intracellular loop (Berg et al. 2008). RNA editing of 5-HT2C receptors directly influences receptor interaction with β-arrestin2 (Marion et al. 2004). The unedited 5-HT2C-INI receptor is capable of interacting with β-arrestin2 in the absence of agonist, leading to constitutive receptor internalization and its accumulation within endocytic vesicles. Application of inverse agonists induces a marked redistribution of 5-HT2C-INI receptors to the plasma membrane of HEK-293 cells (Chanrion et al. 2008; Marion et al. 2004). Fully edited 5-HT2C-VGV receptors, which display the lowest level of constitutive activity, do not associate with β-arrestin2 in the absence of agonist and are mainly detected at the cell surface. Nevertheless, upon agonist treatment, the fully edited receptor associates with β-arrestin2 and undergoes rapid internalization.
5-HT2C receptors physically interact via their third intracellular loop with the tumor suppressor PTEN, an enzyme exhibiting both lipid and protein phosphatase activities (Ji et al. 2006). PTEN (for phosphatase and tensin homolog) association with 5-HT2C receptors prevents agonist-induced receptor phosphorylation at serine residues located in the receptor PDZ motif (Fig. 3d). Interaction between PTEN and 5-HT2C receptors occurs in dopaminergic neurons of the ventral tegmental area innervating the NAC, which are tonically inhibited by activated 5-HT2C receptors. This interaction plays an important role in mediating the reinforcing role of drugs (Ji et al. 2006).
Major Sites of Expression and Subcellular Localization
5-HT2C receptors are exclusively expressed in the CNS. 5-HT2C receptors were first identified by radioligand binding using [3H]-5-HT and [3H]-mesulergine in pig choroid plexus. Further studies using autoradiography with [3H]-mesulergine confirmed highest receptor density in choroid plexus in all mammalian species. 5-HT2C receptors expressed in choroid plexus control the secretion of the cerebrospinal fluid (Sanders-Bush et al. 2003). High receptor densities were detected in the substantia nigra, globus pallidus and ventromedial thalamus. A large amount of 5-HT2C receptors was also detected in the suprachiasmatic nucleus where they may be involved in the circadian rhythm. Several studies have shown that 5HT2C receptors are expressed on GABAergic and dopaminergic neurons within the rat ventral tegmental area and on GABAergic neurons within the prelimbic prefrontal cortex, a subregion of the medial prefrontal cortex (Berg et al. 2008; Bubar and Cunningham 2008; Bubar et al. 2011). Immunohistochemistry experiments with confocal microscopy have suggested that 5-HT2C and 5-HT2A receptors may be commonly co-expressed on GABAergic cells within the deep layers of the prelimbic mPFC and perhaps co-localized on a small population of local pyramidal projection cells (Nocjar et al. 2015). 5HT2C receptors are also expressed on glutamatergic neurons of the subthalamic nucleus and the pyramidal cells of the amygdala (Bonn et al. 2013).
[3H]-mesulergine binding in monkey and human brains followed by receptor autoradiography has revealed both pre- and postsynaptic localizations of 5-HT2C receptor (Berg et al. 2008) which were further confirmed by electron-microscopy studies (Becamel et al. 2002). 5-HT2C receptors exist as constitutive homodimers at the plasma membrane of living cells (Berg et al. 2008; Mancia et al. 2008). Two distinct dimerization interfaces have been characterized: the first one, located at TMI, is insensitive to receptor activation state, whereas the second one, located between TMs IV and V, depends on the nature of the ligand bound to receptors ((Herrick-Davis et al. 2007, 2015). It was recently shown that 5-HT2C receptors are also able to form functional heterodimers with 5-HT2A or 5-HT2B receptors when co-express in transfected cells or in neurons. This heterodimerization with 5-HT2C receptors does not alter 5-HT2C Gαq-dependent inositol-phosphate signaling; however 5-HT2A- or 5-HT2B-receptor-mediated signaling is totally blunted (Moutkine et al. 2017).
As previously mentioned, cell surface expression of 5-HT2C receptor isoforms decreases in parallel with the degree of their constitutive activity (Marion et al. 2004). Inverse agonist treatments induce redistribution to the cell surface of constitutively active 5-HT2C receptors (Marion et al. 2004).
Ligands Interacting with the 5-HT2C Receptor
In line with its broad localization and physiological functions, the 5-HT2C receptor is considered as a therapeutic target for treating obesity, obsessive-compulsive disorder, drug abuse, sleep disorders, and anxiodepressive states (Jensen et al. 2010). During the last decade, the characterization of selective 5HT2C receptor ligands has been complicated by its close structural homology with the two other 5-HT2 receptor subtypes, namely, the 5-HT2A and 5-HT2B receptors. Accordingly, many compounds bind with high affinity to all three receptor subtypes.
Anorexic Properties of Agonists
5-HT2C receptors are activated by a variety of synthetic agonists such as RO60–0175, WAY163909, WAY 161503, YM348, VER2692, and BTV.X, which reduce food intake in rodents and enhance satiety (Jensen et al. 2010). More recently, lorcaserin (ADP356) was characterized as a novel selective, high-affinity 5HT2C receptor agonist, which reduces food intake in rats (Thomsen et al. 2008).
Antidepressant Effects of 5-HT2C Ligands
Several studies have suggested that some of the therapeutic effects of serotonin reuptake inhibitors (SSRIs) are mediated in part by the 5HT2C receptor. Chronic treatment with SSRI is associated with the downregulation of 5HT2C receptors. This may lead to a disinhibition of the mesolimbic dopamine system that might contribute to their antidepressant action (Berg et al. 2008; Bubar and Cunningham 2008; Jensen et al. 2010). Numerous clinically effective antidepressants act as antagonists at 5-HT2C receptors. These include amitriptyline and clomipramine (tricyclics), trazodone and nefazodone (both behave as weak SSRI), citalopram and fluoxetine (SSRIs) (Berg et al. 2008), and agomelatine (a mixed 5-HT2C antagonist/melatonin agonist) (de Bodinat et al. 2010). Tetracyclic antidepressants such as mianserin and mirtazapine, which behave as antagonists of α2-adrenergic receptors and 5-HT3 receptors, were recently identified as inverse agonists at 5-HT2C receptors based on their ability to suppress basal inositol-phosphate production and to increase plasma membrane localization of unedited 5-HT2C-INI receptors in HEK-293 cells as well as in cortical cultured neurons (Chanrion et al. 2008). Paradoxically, 5-HT2C receptor agonists such as WAY161503, RO 60–0175, and RO 60–0332 also exhibited antidepressant-like activity in selected models of depression, an effect that might reflect their ability to promote neurogenesis (Millan 2005).
Anxiolytic Effects of Antagonists
Several 5-HT2C receptor antagonists (e.g., SB206553) exert a robust anxiolytic activity. These compounds also behave as inverse agonists at 5-HT2C receptors (Chanrion et al. 2008). Moreover, it was recently shown that mianserin is able to suppress the evoked anxiety-like behavior in crayfish (Fossat et al. 2015). Corroborating the anxiolytic action of antagonists, agonists like RO60–0175, WAY163909, and mCPP (m-chlorophenylpiperazine) display anxiogenic properties in the social interaction test (Millan 2005).
Antipsychotic Properties of Antagonists
Numerous antipsychotics act as antagonists (or inverse agonists) at 5-HT2C receptors (Berg et al. 2008; Jensen et al. 2010; Sullivan et al. 2015). Moreover, the 5HT2C inverse agonist SB 206553 potentiates the effect of haloperidol on dopamine release (Berg et al. 2008; Bubar and Cunningham 2008). It has been reported that selective 5-HT2C antagonists and agonists reduce DOI-induced head twitches. The effect of the agonists is likely due to the competition with DOI (Canal et al. 2013).
Efficacy of 5-HT2C Ligands in the Treatment of Drug Addiction
It appears that the 5-HT2C agonists or antagonists alter the behaviors induced by drugs of abuse (Canal et al. 2013; Higgins and Fletcher 2015; Howell and Cunningham 2015). Indeed, the enhancement of locomotor activity induced by cocaine is reduced by intra-VTA injection of 5-HT2C agonists and unaffected by 5-HT2C antagonists (Canal et al. 2013; McMahon et al. 2001); the expression of the behavioral sensitization associated with chronic cocaine administration is reduced by the intra-NAc application of a selective 5-HT2C antagonist (Canal et al. 2013; Zayara et al. 2011). It was also shown that SB 206553 attenuated methamphetamine seeking in rats (Canal et al. 2013; Graves and Napier 2012).
Other Properties of 5HT2C Ligands
SB242084 behaves as a neutral antagonist at 5HT2C receptor signaling via phospholipase C, whereas it acts as partial inverse agonist at phospholipase A2, suggesting that it might be a protean ligand (Chanrion et al. 2008).
PNU-69176E, a positive allosteric modulator, highly selective for 5-HT2C receptors has been characterized in different mammalian expression systems. PNU-69176E enhances [3H]-5-HT binding to the human 5-HT2C receptor by selectively increasing 5-HT affinity for its low-affinity sites without affecting antagonist binding (Berg et al. 2008).
The selective 5-HT2C R agonist lorcaserin, used for the treatment of obesity, inhibits oxycodone intake and decreases cue reactivity associated with relapse, highlighting the therapeutic potential for lorcaserin in the treatment of opioid use disorder (Canal et al. 2013; Neelakantan et al. 2017). Another 5-HT2C receptor agonist, the CP809.101, improves cognitive flexibility and reversal learning abilities (Canal et al. 2013; Del’Guidice et al. 2014).
5-HT2C receptors still raise particular attention in view of their implication in many physiological functions and behaviors and in a large spectrum of psychiatric disorders such as anxiodepressivestates, schizophrenia, obsessive-compulsive behaviors, and obesity. Accordingly, 5-HT2C receptors are considered as a major therapeutic target for the development of improved treatments of these diseases. Moreover, 5-HT2C is unique within G protein-coupled receptor superfamily to exhibit mRNA editing. Editing generates numerous 5-HT2C isoforms exhibiting different coupling properties, subcellular localization, and constitutive activity levels. Getting further insight into mechanisms controlling 5-HT2C receptor mRNA editing, signal transduction properties of receptor variants, and their interaction with accessory proteins in neurons as well as their role in synaptic transmission and synaptic plasticity is therefore essential to discover innovative approaches in psychiatric disorders related to receptor dysfunction.
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