5-HT2C receptor

The 5-HT2C receptor, also known as 5-hydroxytryptamine receptor 2C and encoded by the HTR2C gene located on the X chromosome at Xq23, is a seven-transmembrane G protein-coupled receptor (GPCR) that binds the neurotransmitter serotonin (5-hydroxytryptamine) to mediate diverse physiological responses primarily in the central nervous system.^[1] Its pre-mRNA undergoes extensive adenosine-to-inosine RNA editing at five sites within the second intracellular loop, generating up to 32 distinct mRNA isoforms encoding 24 protein variants that variably attenuate G protein coupling and receptor desensitization, thereby fine-tuning signaling efficiency.^[1]^[2] The 5-HT2C receptor is predominantly expressed in the brain, with high levels in regions such as the choroid plexus, cerebral cortex, hippocampus, striatum, hypothalamus, and substantia nigra, where it influences neuronal excitability and network activity.^[2] ^[3] Upon ligand binding, it primarily couples to Gq/11 proteins, activating phospholipase C (PLC) to hydrolyze phosphatidylinositol 4,5-bisphosphate into inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG), which mobilizes intracellular calcium and activates protein kinase C; it also engages phospholipase A2 (PLA2) and additional pathways like extracellular signal-regulated kinases (ERK1/2).^[4] ^[5] Physiologically, the receptor regulates key processes including satiety and feeding behavior via actions in pro-opiomelanocortin (POMC) neurons of the arcuate nucleus, anxiety and fear responses in the amygdala, mood stabilization, motoneuron activity, and reward modulation through interactions with dopamine systems in the ventral tegmental area.^[6] ^[2] ^[7] Dysregulation of 5-HT2C receptor function, often linked to RNA editing deficits or genetic polymorphisms, contributes to psychiatric and metabolic disorders such as depression, anxiety, schizophrenia, obsessive-compulsive disorder, drug addiction, and obesity.^[1] ^[7] Therapeutically, selective 5-HT2C agonists like lorcaserin (withdrawn in 2020 due to increased cancer risk) have been developed to promote weight loss by enhancing satiety without cardiovascular risks associated with non-selective serotonergics, while antagonists are investigated for alleviating negative symptoms in schizophrenia and enhancing antipsychotic efficacy; however, challenges include the receptor's homology with 5-HT2A, which can lead to off-target hallucinogenic effects. Recent studies as of 2025 explore its roles in binge eating disorders and psychedelic-assisted therapies for depression.^[7] ^[8] ^[9] ^[10]

Molecular Structure

Gene Organization

The HTR2C gene, encoding the 5-HT2C receptor, is located on the long arm of the human X chromosome at cytogenetic band Xq23, spanning genomic coordinates X:114,584,086-114,910,061 (GRCh38 assembly).^[1]^[11] The gene encompasses approximately 326 kb of DNA and consists of seven exons separated by six introns, with the mature mRNA derived from alternative splicing of these elements.^[1]^[12] The coding region for the functional receptor protein is primarily distributed across exons 4 through 7, indicating introns interrupt the open reading frame.^[12] The promoter region upstream of the first exon lacks a canonical TATA box, a feature common to many G-protein-coupled receptor genes that rely on alternative basal transcription mechanisms.^[13] This TATA-less architecture contributes to the complex regulation of HTR2C expression in neural tissues. The gene undergoes post-transcriptional A-to-I RNA editing primarily within exon 5, generating protein isoform diversity without altering the overall genomic organization.^[14] The genomic structure of HTR2C, including its exon-intron arrangement and overall size, exhibits strong evolutionary conservation across mammalian species, with orthologs identified in over 200 vertebrates, reflecting its essential role in serotonin signaling.^[15] This conservation underscores the gene's fundamental importance in central nervous system function from rodents to primates.^[1]

Protein Topology

The 5-HT2C receptor is a class A G-protein-coupled receptor (GPCR) characterized by a canonical seven-transmembrane topology, consisting of seven α-helical transmembrane domains (TM1–TM7) that span the plasma membrane, three extracellular loops (ECL1–ECL3) connecting the extracellular sides of the helices, three intracellular loops (ICL1–ICL3) on the cytoplasmic side, an extracellular N-terminal domain, and an intracellular C-terminal tail. High-resolution crystal structures of the 5-HT2C receptor, solved in 2018, confirm the canonical class A GPCR topology and reveal details of the orthosteric binding pocket.^[16] This architecture facilitates ligand binding in the orthosteric pocket formed primarily by residues from TM3, TM5, TM6, and TM7, as well as ECL2, while the intracellular loops and C-terminus mediate interactions with G-proteins and other effectors.^[1] The mature human 5-HT2C receptor protein comprises 458 amino acids, with an unglycosylated molecular weight of approximately 52 kDa.^[17]^[18] Key structural features include an aspartic acid residue at position 120 (Asp3.32 in Ballesteros-Weinstein numbering) in TM3, which forms a salt bridge with the positively charged amine group of serotonin and other ligands, stabilizing receptor-ligand interactions.^[1] Additionally, the conserved DRY motif (Asp-Arg-Tyr) at the junction of TM3 and ICL2 plays a critical role in G-protein activation by undergoing conformational changes upon agonist binding to facilitate coupling with Gq/11 proteins.^[3] Post-translational modifications contribute to the receptor's structural maturation and membrane localization. N-linked glycosylation occurs at asparagine residues in ECL2 (notably Asn4.60), resulting in a mature glycoprotein of ~60 kDa that influences trafficking and stability.^[19] The 5-HT2C receptor exhibits higher sequence homology to the 5-HT2A receptor (~50% identity overall, with greater conservation in transmembrane domains) than to the 5-HT2B receptor (~46% identity), reflecting shared evolutionary origins within the 5-HT2 subfamily while allowing subtype-specific ligand selectivity.^[20] RNA-edited isoforms can alter the amino acid sequence in ICL2, potentially affecting G-protein coupling efficiency without disrupting the core topology.^[3]

Genetics and RNA Editing

Genetic Variants

The HTR2C gene, located on the X chromosome at Xq23, exhibits X-linked inheritance, resulting in hemizygosity in males and potential dosage compensation via X-inactivation in females, which may contribute to sex-specific effects on receptor expression and function.^[1] This chromosomal location can lead to differences in variant penetrance between sexes, as observed in association studies where male carriers show more pronounced phenotypic impacts compared to females.^[21] Among common polymorphisms, the -759T/C (rs3813929) variant in the promoter region influences transcriptional activity, with the T allele associated with reduced HTR2C mRNA expression compared to the C allele, acting as a cis-eQTL.^[22] This polymorphism has been linked to antipsychotic drug response in schizophrenia patients, particularly improved efficacy of clozapine in carriers of the C allele among males, though evidence for schizophrenia risk itself remains mixed.^[22] Another key variant is the Cys23Ser (rs6318) substitution in the coding region, which alters receptor trafficking by causing endoplasmic reticulum retention and reduced cell surface expression, thereby diminishing signaling efficiency such as calcium mobilization.^[23] Population frequencies of the -759T/C variant vary by ethnicity, with the minor T allele reaching approximately 24% in European cohorts, higher than in some Asian groups where it is around 12%.^[24] These differences underscore the need for ancestry-specific genetic analyses in clinical contexts. Rare mutations in HTR2C, including frameshift and missense variants, have been reported in neurodevelopmental disorders such as attention-deficit/hyperactivity disorder (ADHD) and Tourette syndrome, potentially disrupting receptor function and contributing to symptom severity.^[25]^[26] For instance, certain missense changes alter ligand binding or signaling, with minor allele frequencies below 1% in affected individuals.^[27] Genetic variants in HTR2C may interact with RNA editing to further modulate receptor isoform diversity and functional outcomes, though this requires additional study.^[1]

RNA Editing Sites and Isoforms

The HTR2C gene, located on the X chromosome at Xq23, undergoes A-to-I RNA editing primarily at five sites (A through E) within exon 5, which encodes a 70-nucleotide region of the second intracellular loop (ICL2); this editing is catalyzed by ADAR1 and ADAR2 enzymes.^[28] These sites are clustered in a predicted double-stranded RNA stem-loop structure that facilitates substrate recognition by the ADAR enzymes.^[29] Editing at these sites generates multiple mRNA isoforms through combinatorial deamination of adenosines to inosines, which are recognized as guanosines during translation and reverse transcription. Theoretically, the five sites allow for up to 32 mRNA variants, but due to interdependent editing efficiencies and structural constraints, approximately 14 isoforms are commonly observed in human brain tissue, with fewer in peripheral tissues.^[28]^[30] Notable examples include the fully unedited isoform INI (isoleucine-asparagine-isoleucine at positions 156, 158, and 160) and fully edited variants such as VSV (valine-serine-valine) or VGV (valine-glycine-valine), reflecting changes primarily at sites A, B, C, D, and E. Sites A, B, and C directly alter the amino acid sequence: site A changes Ile156 to Val156 (codon ATA to GTA), site B changes Asn158 to Asp158 (codon AAC to GAC), and site C changes Ile160 to Val160 (codon ATA to GTA), while sites D and E (the latter also termed C') are positioned within or adjacent to codon 158 and enable further variations at that residue, such as Ser158 (AGC from editing D) or Gly158 (GGC from editing both B and D).^[31] These amino acid substitutions in ICL2 reduce the receptor's constitutive activity by altering G-protein coupling efficiency.^[32] Editing patterns exhibit tissue specificity, with higher overall editing efficiency in the central nervous system compared to peripheral tissues; for instance, human brain regions like the thalamus show predominant VSV isoforms (up to 50% edited), whereas peripheral samples display more unedited or partially edited forms.^[30]^[33] This differential editing contributes to region-specific receptor function, with brain tissues averaging 40-60% editing across sites versus less than 20% in non-neuronal tissues.^[34] Site-directed mutagenesis studies mimicking these editing-induced changes have confirmed site-specific impacts on receptor desensitization; for example, mutating residues at positions 156, 158, and 160 to edited forms (e.g., VSV) results in isoforms with prolonged desensitization upon agonist stimulation, reduced agonist potency, and altered internalization rates compared to the INI isoform.85266-6/fulltext) These experiments demonstrate that editing at individual sites, particularly B and C, distinctly modulates β-arrestin recruitment and receptor trafficking, thereby fine-tuning signaling duration.^[35]

Functional Consequences of Editing

RNA editing of the 5-HT2C receptor mRNA is primarily catalyzed by adenosine deaminases acting on RNA (ADAR) enzymes, specifically ADAR1 and ADAR2, which convert adenosine to inosine in double-stranded RNA (dsRNA) structures.^[36] ADAR2 serves as the predominant enzyme for editing at sites A through D within the receptor's second intracellular loop (ICL2), while both enzymes contribute to site E editing; these enzymes localize to the nucleus, where the dsRNA substrate forms via base-pairing between exon 5 and adjacent intron sequences of the HTR2C pre-mRNA.^[37]^[38] The editing process is dynamically regulated, with ADAR expression upregulated by environmental stressors or antidepressant treatments such as fluoxetine, leading to altered editing patterns in brain regions like the prefrontal cortex.^[39] Additionally, feedback loops exist wherein 5-HT2C receptor activation via phospholipase C signaling elevates inositol hexakisphosphate (IP6) levels, which in turn enhances ADAR2 activity and promotes further editing.^[40] Isoform-specific functional outcomes arise from these edits at five sites (A-E) in ICL2, generating up to 32 possible receptor variants. Unedited isoforms, such as INI, exhibit heightened Gq protein coupling, elevated constitutive activity, and increased agonist-independent desensitization through GRK/β-arrestin pathways.^[41] In contrast, fully edited isoforms like VGV display reduced Gq coupling efficiency, lower constitutive activity, diminished agonist potency, and attenuated desensitization, thereby fine-tuning serotonin signaling and receptor responsiveness.^[41]^[42] Pathological dysregulation of editing has been observed, with hyper-editing (increased editing at key sites) associated with depression and linked to enhanced receptor isoform diversity that dampens signaling, while hyper-editing correlates with heightened aggression through low-activity edited forms.^[30]^[43] Furthermore, editing influences splice site selection in the HTR2C gene, where A-to-I changes near exon-intron boundaries alter splicing efficiency and contribute to isoform production.^[14] Editing efficiency varies across sites and tissues, with site C showing 50-90% editing in the human brain, higher than in rodents (e.g., ~60% in humans versus ~35% in rats), reflecting adaptive modulation of receptor function.87278-2/pdf)^[30]

Distribution and Expression

Central Nervous System

The 5-HT2C receptor displays the highest density of expression within the central nervous system in the choroid plexus, where it is abundantly localized to epithelial cells and contributes to the regulation of the blood-cerebrospinal fluid (CSF) barrier.^[44] Autoradiographic and mRNA studies have confirmed this enrichment, with receptor binding sites and transcripts far exceeding those in other brain regions, underscoring its prominent role in CSF production and composition.^[17] In contrast, moderate levels of expression are observed in several key limbic and cortical areas, including the prefrontal cortex, hippocampus, basal ganglia (particularly the caudate and nigrostriatal pathway), and amygdala, as identified through radioligand binding and in situ hybridization techniques in both rodent and primate models.^[17]^[45] Expression is notably lower in the cerebellum and most brainstem nuclei, with minimal detection in granular layers of the cerebellum and sparse distribution outside specific midbrain structures like the substantia nigra. At the cellular level, 5-HT2C receptors are primarily localized postsynaptically on GABAergic interneurons, such as parvalbumin-positive cells in the prefrontal cortex, and on glutamatergic pyramidal neurons across cortical and limbic regions, enabling modulation of inhibitory and excitatory transmission.^[46]^[47] Additionally, lower levels of expression occur on astrocytes, where receptor activation can influence signaling pathways like ERK1/2 phosphorylation in response to serotonin.^[48] Developmentally, 5-HT2C receptor expression undergoes upregulation in the postnatal period in rodents, with mRNA and protein levels increasing progressively in regions like the choroid plexus and cortex, reaching peak abundance in adulthood to support maturing neural circuits. RNA editing of the receptor transcript varies across brain regions, contributing to isoform diversity that may fine-tune regional functions.^[31]

Peripheral Tissues

The 5-HT2C receptor exhibits low overall expression in peripheral tissues compared to the central nervous system, with detectable mRNA and protein levels in select organs based on transcriptomic and immunohistochemical analyses. In the human gastrointestinal tract, expression is observed in the enteric nervous system, including the myenteric plexus, where 5-HT2C receptors contribute to serotonergic modulation of intestinal motility through excitatory signaling on cholinergic neurons and interstitial cells.^[49]^[50] The 5-HT2C receptor shows low expression in the cardiovascular system. The receptor is also expressed in adipose tissue, where it participates in local serotonin-mediated regulation of adipocyte function and lipid metabolism.^[51] Moderate expression occurs in the pancreas, liver, and kidney, supporting roles in endocrine and metabolic processes, while levels remain low in skeletal muscle.^[52] Notable species differences exist in peripheral 5-HT2C expression, with rodents displaying higher levels across multiple tissues relative to humans, which may influence translational studies on metabolic and gastrointestinal functions.^[53] Functionally, peripheral 5-HT2C receptors modulate insulin secretion in pancreatic β-cells, potentially linking to glycemic control.^[54] This peripheral distribution shows limited overlap with central appetite circuits, primarily serving local tissue-specific roles.^[55]

Physiological Functions

Signal Transduction Pathways

The 5-HT2C receptor primarily couples to Gq/11 proteins upon activation by serotonin or agonists, leading to the stimulation of phospholipase C (PLC). This activation results in the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) into inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). IP3 subsequently binds to receptors on the endoplasmic reticulum, triggering the release of intracellular calcium (Ca²⁺), while DAG activates protein kinase C (PKC), which phosphorylates downstream targets to modulate cellular responses.^[6]^[56]^[57] In addition to the canonical Gq/11 pathway, the 5-HT2C receptor engages secondary signaling cascades depending on cellular context and ligand. It can couple to Gi/o proteins, inhibiting adenylyl cyclase and thereby reducing cyclic AMP (cAMP) levels. The receptor also interacts with G12/13 proteins, which activate Rho guanine nucleotide exchange factors (RhoGEFs) to stimulate RhoA, influencing cytoskeletal dynamics. Furthermore, β-arrestin recruitment following receptor activation scaffolds and activates the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway, independent of G protein signaling.^[10]^[58]^[59] The 5-HT2C receptor exhibits constitutive activity, particularly in its non-edited isoform (INI), where it spontaneously activates Gq/11-mediated PLC signaling in the absence of ligand. RNA editing at multiple sites in the second intracellular loop reduces this basal activity by altering receptor conformation and impairing G protein coupling efficiency, with fully edited isoforms (VGV) showing minimal constitutive signaling.^[28]^[60] Recent studies have identified biased agonism at the 5-HT2C receptor, where certain ligands preferentially activate specific pathways. For instance, psychedelics like psilocin demonstrate stronger Gq/11 coupling compared to β-arrestin recruitment, potentially contributing to distinct physiological effects while minimizing off-target signaling.^[10] Receptor desensitization occurs through phosphorylation by G protein-coupled receptor kinases (GRKs), particularly GRK2, which creates binding sites for β-arrestins. β-Arrestin binding uncouples the receptor from G proteins, promotes internalization via clathrin-mediated endocytosis, and can lead to either resensitization or downregulation depending on the ligand and editing state.^[61]^[62]^[63]

Roles in Behavior and Homeostasis

The 5-HT2C receptor plays a significant role in modulating anxiety and mood through its expression in limbic and cortical regions. Antagonism of 5-HT2C receptors reduces anxiety-like behaviors in rodent models, such as decreased time spent in open arms of the elevated plus-maze and reduced defensive burying.^[64]^[65] Similarly, 5-HT2C antagonists exhibit antidepressant-like effects in chronic unpredictable stress paradigms, enhancing resilience to depressive symptoms without altering baseline locomotor activity.^[66] These effects are mediated primarily through the Gq/PLC signaling pathway, which influences neuronal excitability in anxiety-regulating circuits.^[67] In cognition and reward processing, 5-HT2C receptors contribute to executive functions via prefrontal cortical circuits. Activation of 5-HT2C receptors in the medial prefrontal cortex impairs cognitive flexibility, as evidenced by increased perseveration in reversal learning tasks in rats, while antagonism enhances performance in touchscreen-based assays.^[68]^[69] Regarding reward, 5-HT2C agonists like Ro60-0175 and lorcaserin dose-dependently reduce cocaine self-administration and cue-induced reinstatement in rodents, attenuating motivational drive for psychostimulants under fixed-ratio and progressive-ratio schedules.^[70]^[71] The 5-HT2C receptor influences sleep-wake regulation, particularly through its expression in hypothalamic and brainstem nuclei. In mice lacking 5-HT2C receptors, there is increased wakefulness and reduced non-REM sleep, with altered REM sleep homeostasis during recovery from sleep deprivation, indicating a role in stabilizing REM transitions.^[72] Pharmacological blockade of 5-HT2C receptors decreases REM sleep duration and non-REM to REM transitions, underscoring its contribution to REM promotion in hypothalamic circuits.^[73] In homeostatic processes, 5-HT2C receptors participate in temperature control and nociception. Activation of central 5-HT2C receptors by agonists like m-chlorophenylpiperazine induces hyperthermia in rats, reflecting enhanced thermogenic responses in hypothalamic thermoregulatory centers.^[74] In the spinal cord, 5-HT2C receptor expression on nociceptive neurons modulates pain transmission; agonists produce antiallodynic effects in neuropathic models via intrathecal administration, reducing mechanical hypersensitivity.^[75] Conversely, some evidence suggests a pronociceptive role under certain conditions, highlighting context-dependent spinal modulation.^[76] The 5-HT2C receptor also regulates seizure susceptibility by promoting inhibitory interneuron activity and tonically suppressing neuronal hyperexcitability. Genetic knockout of the receptor in mice leads to spontaneous seizures and increased seizure susceptibility, while agonists, such as bexicaserin, reduce seizure frequency in models of developmental epileptic encephalopathies.^[77]^[78] Circuit-specific actions of the 5-HT2C receptor include inhibition of dopamine release in the nigrostriatal pathway. Striatal 5-HT2C receptors tonically suppress nigrostriatal dopamine transmission by enhancing GABAergic inhibition on dopaminergic neurons in the substantia nigra, as demonstrated by increased dopamine efflux following selective antagonism.^[79] This inhibitory control contributes to balanced motor output and prevents excessive dopaminergic activity in basal ganglia circuits.^[80] Additionally, 5-HT2C receptors modulate spinal motor function, regulating both volitional and involuntary behaviors; loss-of-function variants alter motor patterns in male and female rodents. As of 2025, agonism has been shown to enhance motor coordination and strength in aged mice, suggesting a role in counteracting age-related motor decline such as sarcopenia.^[81]^[82]

Endocrinology

Appetite and Metabolic Regulation

The 5-HT2C receptor plays a pivotal role in appetite suppression through its expression in the arcuate nucleus of the hypothalamus, where activation inhibits orexigenic neuropeptide Y (NPY)/agouti-related peptide (AgRP) neurons and excites anorexigenic pro-opiomelanocortin (POMC)/cocaine- and amphetamine-regulated transcript (CART) neurons.^[83]^[84] This reciprocal regulation enhances melanocortin signaling, promoting satiety and reducing food-seeking behavior via downstream projections to second-order neurons in the paraventricular nucleus.^[84] Selective 5-HT2C receptor agonists, such as lorcaserin, exert anorectic effects in animal models by reducing the size and duration of meals, leading to decreased overall caloric intake without significantly altering the frequency of eating episodes.^[85] In rodents, lorcaserin administration dose-dependently suppresses operant responding for food and ad libitum chow consumption, mimicking the receptor's endogenous role in meal termination.^[86] These effects are mediated centrally, as they persist in models with intact hypothalamic circuitry but are abolished in 5-HT2C receptor knockout animals.^[6] In humans, the therapeutic potential of 5-HT2C receptor agonism is exemplified by lorcaserin, which received FDA approval in 2012 for chronic weight management in obesity but was withdrawn in 2020 following post-marketing studies indicating an increased risk of cancer.^[87] Dysregulation of 5-HT2C receptor function, including altered RNA editing and splicing, has been linked to hyperphagia in Prader-Willi syndrome, a genetic disorder characterized by insatiable appetite and obesity.^[88] Knockout studies in mice confirm this, demonstrating that 5-HT2C receptor deletion results in hyperphagia, late-onset obesity, and heightened susceptibility to diet-induced weight gain.^[6]^[89] Beyond appetite control, 5-HT2C receptor activation influences metabolic processes by enhancing lipolysis in adipose tissue through central sympathetic outflow and improving insulin sensitivity in models of diet-induced obesity.^[90]^[91] Agonist treatment reduces hyperinsulinemia and enhances glucose tolerance independently of weight loss in some contexts, underscoring the receptor's broader role in energy homeostasis.^[91]^[92] Peripheral expression in gut tissues may contribute modestly to these effects by modulating nutrient sensing.^[93]

Hormonal Interactions

The 5-HT2C receptor contributes to prolactin regulation through serotonergic pathways in the hypothalamus, particularly in the paraventricular nucleus, where it mediates serotonin-induced stimulation of prolactin release. Activation of 5-HT2C receptors inhibits tuberoinfundibular dopaminergic neurons, thereby reducing dopamine-mediated suppression of prolactin secretion from the anterior pituitary.^[94]^[95] This interaction highlights the receptor's role in modulating prolactin under conditions like stress or hyperestrogenic states, where 5-HT2A/2C agonism significantly elevates circulating prolactin levels.^[96] Antagonism of 5-HT2C receptors, as seen with certain pharmacological agents, attenuates these prolactin responses, though complex interactions with dopamine systems can influence net effects in clinical contexts.^[97] In thyroid function, 5-HT2C receptors participate in the modulation of thyrotropin-stimulating hormone (TSH) secretion, with serotonergic signaling generally exerting inhibitory effects at the hypothalamic level. Administration of 5-HT2 antagonists like ketanserin has been associated with increased TSH release in euthyroid subjects, suggesting tonic 5-HT2C-mediated suppression of TSH under normal conditions.^[98] This mechanism may link 5-HT2C dysregulation to symptoms of hyperthyroidism, such as anxiety and agitation, which overlap with serotonergic hyperactivity and altered thyroid hormone feedback.^[99] The 5-HT2C receptor is expressed in gonadal tissues, influencing steroidogenesis and exhibiting sex differences in density and function. In species like zebrafish, 5-HT2C mRNA is present in ovarian cells.^[100] These patterns underscore the receptor's role in reproductive physiology beyond central neural circuits. 5-HT2C receptors interact with the hypothalamic-pituitary-adrenal (HPA) axis to alter cortisol responses, primarily through activation in the paraventricular nucleus that stimulates corticotropin-releasing hormone (CRH) release and subsequent glucocorticoid elevation. Genetic variations in the HTR2C gene, encoding the 5-HT2C receptor, predict heightened cortisol reactivity to psychosocial stress, indicating its modulatory influence on HPA dynamics.^[101]^[102] This interaction is particularly relevant in stress-related endocrine disruptions, where 5-HT2C stimulation amplifies cortisol output. Pharmacological blockade of 5-HT2C receptors by antipsychotics, such as olanzapine, elevates growth hormone levels by disrupting inhibitory interactions between 5-HT2C and ghrelin receptors (GHSR1a), thereby enhancing ghrelin signaling that promotes anterior pituitary growth hormone secretion.^[103] This effect contrasts with the receptor's typical suppressive role in hormonal homeostasis and contributes to metabolic side effects observed in long-term antipsychotic treatment.^[104]

Pharmacology

Agonists

The endogenous agonist for the 5-HT2C receptor is serotonin (5-HT), which binds with high affinity (pKi ≈ 8.0) and activates Gq-mediated signaling pathways.^[105] Synthetic full agonists such as m-chlorophenylpiperazine (mCPP) and 1-(m-trifluoromethylphenyl)piperazine (TFMPP) potently activate the 5-HT2C receptor but exhibit limited selectivity, also engaging 5-HT2A and 5-HT2B subtypes with comparable affinities.^[106]^[107] Partial agonists include lorcaserin, a selective compound with an EC50 of approximately 9 nM at 5-HT2C receptors, demonstrating full efficacy at this subtype while showing partial activity at 5-HT2A.^[108] Aripiprazole functions as a partial agonist at 5-HT2C receptors as part of its broader multi-receptor profile, contributing to its antipsychotic effects with minimal weight gain liability.^[109] Biased agonists, particularly serotonergic psychedelics like psilocin and DOI, preferentially activate Gq/11 signaling over β-arrestin recruitment at 5-HT2C receptors, as revealed in 2025 signaling profiling studies.^[10] Structure-activity relationship studies of tryptamine derivatives indicate that substitutions at the 4- or 5-position of the indole ring enhance 5-HT2C agonist potency and selectivity, with N-benzyl modifications further optimizing efficacy.^[110] Clinical trials have evaluated 5-HT2C agonists such as lorcaserin (FDA-approved in 2012 but withdrawn in 2020 due to potential cancer risk)^[111] for obesity, demonstrating significant weight loss in phase III studies, and vabicaserin (development discontinued circa 2012)^[112] for schizophrenia, showing antipsychotic efficacy without substantial weight gain in phase II trials.^[113]^[114]

Antagonists and Inverse Agonists

Antagonists of the 5-HT2C receptor block the binding of serotonin and inhibit receptor activation, while inverse agonists suppress both ligand-induced and constitutive receptor activity. These compounds are distinguished by their selectivity profiles, with non-selective agents often interacting with other serotonin receptor subtypes, particularly 5-HT2A. Selective antagonists and inverse agonists have been instrumental in dissecting 5-HT2C-mediated functions in preclinical models.^[115] Non-selective antagonists such as ketanserin and mianserin exhibit affinity for both 5-HT2C and 5-HT2A receptors. Ketanserin displays a Ki of approximately 200 nM at 5-HT2C receptors, effectively blocking serotonin-stimulated cyclic GMP formation in choroid plexus cells. Mianserin, with a higher potency (Ki ≈ 1.3 nM), similarly antagonizes 5-HT2C signaling but also down-regulates both receptor subtypes upon chronic exposure in human neuroblastoma cells. These agents have been used in early pharmacological studies to probe 5-HT2 family involvement in behaviors like anxiety and locomotion.^[116]^[116]^[117] Selective 5-HT2C antagonists, including SB-242084 and RS-102221, offer greater specificity, with SB-242084 showing a pKi of approximately 9 and over 100-fold selectivity versus 5-HT2A. These compounds penetrate the brain and have demonstrated anxiolytic effects in rodent models without significant off-target activity at other serotonin receptors. Peripherally restricted antagonists like SB-206553, which exhibit limited central nervous system penetration, are particularly useful for targeting peripheral 5-HT2C functions.^[118]^[115]^[119] Inverse agonists at the 5-HT2C receptor, such as SB-228357, reduce constitutive receptor activity independent of agonist presence, as evidenced by decreased basal inositol phosphate accumulation in cells expressing the receptor. SB-228357 displays high selectivity and potency, making it a tool for studying unliganded receptor signaling. Agomelatine, a melatonin receptor agonist, acts as a neutral antagonist at edited human 5-HT2C receptors (VSV isoform), though it exhibits inverse agonist properties in certain contexts, contributing to its antidepressant effects by enhancing frontal cortex neurotransmitter release.^[120]^[120]^[121] In clinical contexts, 5-HT2C antagonism by atypical antipsychotics like olanzapine and risperidone helps mitigate extrapyramidal side effects associated with dopamine D2 blockade. These drugs exhibit inverse agonist activity at constitutively active 5-HT2C receptors, which correlates with their reduced motor side effect profile compared to typical antipsychotics. Peripherally selective 5-HT2C antagonists, such as derivatives of SB-206553, have been explored for gastrointestinal motility disorders by avoiding central effects while modulating enteric serotonin signaling to improve gut transit.^[122]^[122]^[119]

Allosteric Modulators

Allosteric modulators of the 5-HT2C receptor bind to sites distinct from the orthosteric serotonin-binding pocket, thereby influencing receptor conformation and modulating the efficacy or potency of orthosteric agonists without directly activating the receptor.^[123] Positive allosteric modulators (PAMs) enhance agonist-induced signaling, while negative allosteric modulators (NAMs) diminish it, offering a strategy to fine-tune receptor activity with potentially improved subtype selectivity over 5-HT2A and 5-HT2B receptors.^[124] This approach is particularly appealing for avoiding off-target effects associated with orthosteric ligands. A seminal example of a 5-HT2C PAM is PNU-69176E, which selectively potentiates serotonin-induced calcium mobilization and inositol phosphate accumulation by increasing agonist potency up to 10-fold without intrinsic agonist activity.^[125] Structurally featuring a long alkyl chain and an α-D-galactopyranoside polar moiety, PNU-69176E likely anchors in the membrane and interacts with an allosteric site involving transmembrane domains to stabilize the active receptor conformation. More recent PAMs, such as CYD-1-79 and VA012, demonstrate similar enhancement of serotonin efficacy (e.g., increasing Emax by approximately 20-127% in functional assays) and exhibit high selectivity for 5-HT2C over 5-HT2A and 5-HT2B. As of 2025, investigations into PAMs like CYD-1-79 have shown attenuation of cocaine cue reactivity in preclinical models by promoting biased Gi/o-coupled signaling over Gq.^[123]^[123] These compounds bind to extracellular vestibule regions or transmembrane helices, promoting biased signaling profiles that favor Gq-mediated pathways.^[123] Negative allosteric modulators of the 5-HT2C receptor are less extensively characterized but include compounds like Compound 1, which reduces serotonin-evoked calcium release in cellular assays by stabilizing inactive conformations and decreasing agonist efficacy.^[123] Certain dual-acting ligands, such as Compound 5, function as PAMs at 5-HT2C while serving as NAMs at 5-HT2B, potentially mitigating valvulopathy risks associated with 5-HT2B activation.^[126] These NAMs typically interact with allosteric sites in the transmembrane bundle, reducing orthosteric ligand binding affinity or signal transduction efficiency.^[123] Therapeutically, 5-HT2C PAMs hold promise for enhancing endogenous serotonin signaling with greater specificity, supporting applications in obesity (e.g., VA012 reduces food intake in rodent models) and neuropsychiatric disorders like depression through improved mood regulation.^[127] In addiction, recent investigations highlight PAMs such as CYD-1-79, which attenuate cocaine cue reactivity in preclinical models by promoting biased Gi/o-coupled signaling over Gq, suggesting potential for substance use disorder interventions.^[123] Overall, allosteric modulation enables subtype-selective tuning, though clinical translation remains in early stages pending further optimization of pharmacokinetics and safety profiles.^[124]

Protein Interactions

Intracellular Signaling Partners

The 5-HT2C receptor primarily couples to heterotrimeric Gq/11 proteins, consisting of Gαq/11 subunits along with Gβ and Gγ subunits, to initiate intracellular signaling upon agonist binding.^[128] This coupling occurs through the receptor's third intracellular loop and C-terminal tail, facilitating GDP-GTP exchange on the Gα subunit and subsequent dissociation of the heterotrimer.^[129] The interaction with Gq/11 is a core feature of 5-HT2C receptor activation, enabling downstream effector engagement in various neuronal and non-neuronal tissues.^[130] Among effectors, the 5-HT2C receptor activates phospholipase C-β (PLC-β) isoforms, particularly PLC-β1 and PLC-β3, which hydrolyze phosphatidylinositol 4,5-bisphosphate (PIP2) into inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG).^[130] The generated IP3 then binds to IP3 receptors (IP3R) on the endoplasmic reticulum, triggering calcium release into the cytosol and amplifying signaling cascades.^[129] This PLC-β-mediated pathway represents the primary Gq/11-dependent mechanism for 5-HT2C receptor function.^[17] Beta-arrestins, specifically β-arrestin-1 and β-arrestin-2, interact with the phosphorylated C-terminus of the 5-HT2C receptor to promote desensitization by uncoupling it from G proteins and facilitating clathrin-mediated endocytosis.^[59] Beyond desensitization, β-arrestins serve as scaffolds for extracellular signal-regulated kinase (ERK1/2) activation, enabling G protein-independent signaling that modulates gene expression and cellular responses.^[59] This dual role underscores β-arrestins' importance in regulating 5-HT2C receptor trafficking and biased agonism.^[10] Additional partners include postsynaptic density protein 95 (PSD-95), which binds to the C-terminal PDZ-binding motif of the 5-HT2C receptor to anchor it at synaptic sites, enhancing receptor stability and localization in postsynaptic densities.^[131] Calmodulin (CaM) physically interacts with a Ca2+-dependent motif in the proximal C-tail of the receptor, influencing agonist-dependent phosphorylation and β-arrestin recruitment independent of G protein activation.^[132] RNA editing of the 5-HT2C receptor pre-mRNA generates multiple isoforms that alter β-arrestin recruitment efficiency, with fully edited variants (e.g., 5-HT2C-VGV) exhibiting reduced constitutive association with β-arrestin-2 compared to non-edited forms.^[133] This editing-induced variation modulates desensitization rates and receptor trafficking, contributing to isoform-specific signaling profiles in the brain.^[133]

Receptor Heterodimerization

The 5-HT2C receptor, a G protein-coupled receptor (GPCR), engages in heterodimerization with other receptors, forming complexes that modulate its signaling properties and physiological roles. These interactions occur primarily through transmembrane (TM) domains, with biophysical evidence from bioluminescence resonance energy transfer (BRET) and fluorescence resonance energy transfer (FRET) assays demonstrating specific dimer interfaces at TM4 and TM5. Such oligomerization influences receptor conformation, ligand affinity, and intracellular trafficking, often resulting in allosteric effects that alter functional outcomes. For instance, heterodimer formation can reduce agonist binding affinity or promote receptor internalization, thereby fine-tuning serotonin-mediated responses in key brain regions like the cortex and striatum.^[134] Heterodimerization of the 5-HT2C receptor with the 5-HT2A receptor has been observed in cortical regions, where the 5-HT2C protomer exerts a dominant influence, masking 5-HT2A signaling efficacy through complex formation. BRET, luminescence complementation assay (LCA), and proximity ligation assay (PLA) studies in transfected cells confirm this interaction, showing that 5-HT2C-containing heterodimers exhibit preserved Gq coupling via 5-HT2C and decreased 5-HT2A responsiveness to serotonin agonists. This cortical heterodimerization has implications for hallucinogen tolerance, as chronic exposure to psychedelics like LSD, which primarily target 5-HT2A, may indirectly desensitize 5-HT2C activity via these complexes, contributing to diminished behavioral effects over time.^[135] In the striatum, 5-HT2C receptors form heterodimers with dopamine D2 receptors, modulating locomotor activity through integrated dopaminergic-serotonergic signaling. These complexes lead to synergistic enhancement of 5-HT2C-mediated phospholipase C activation and attenuation of D2-mediated adenylyl cyclase inhibition, providing fine-tuned control of striatal dopamine release. Functional studies indicate that D2-5-HT2C heterodimers in this region contribute to suppression of excessive locomotion, providing a molecular basis for 5-HT2C's role in motor regulation. The striatum's dense expression of these interacting receptors supports their relevance in such behavioral contexts.^[136]^[137]^[138]

Clinical Significance

Associations with Disorders

The 5-HT2C receptor has been implicated in the pathophysiology of several psychiatric disorders through dysregulation of its expression and function. In schizophrenia, reduced RNA editing of the 5-HT2C receptor mRNA has been observed in postmortem brain tissue, leading to hyposensitivity of the receptor and altered serotonergic signaling that may contribute to dopaminergic imbalances in the prefrontal cortex.^[139] A meta-analysis of genetic studies on the Ser23Cys polymorphism in the HTR2C gene indicated an association with better antipsychotic response in schizophrenia, with an odds ratio of approximately 2.0 for the Ser23 allele in males, highlighting its role in treatment outcomes.^[140] In obsessive-compulsive disorder (OCD), evidence suggests hyperfunction of the 5-HT2C receptor, as knockout models exhibit increased compulsive behaviors such as excessive grooming, and pharmacological blockade of the receptor attenuates compulsive-like responses in animal paradigms relevant to OCD.^[141] Neurological disorders also show links to 5-HT2C receptor dysregulation. Promoter variants and loss-of-function mutations in the HTR2C gene have been associated with increased risk of epilepsy, particularly sudden unexpected death in epilepsy (SUDEP), where enrichment of non-synonymous variants disrupts serotonergic modulation of seizure thresholds and respiratory control.^[27] In Parkinson's disease, altered 5-HT2C receptor activity influences dopamine modulation in the basal ganglia, with increased receptor binding in the substantia nigra pars reticulata contributing to motor symptoms and dyskinesia through interactions with dopaminergic pathways.^[142] Metabolic disorders are strongly tied to 5-HT2C receptor polymorphisms that affect appetite regulation. The promoter polymorphism HTR2C -759C/T (rs3813929) is associated with obesity susceptibility, particularly in women, with the C allele linked to higher risk (OR 1.72) and greater body mass index by increasing receptor expression and satiety signaling; the T allele reduces expression and protects against weight gain in population studies.^[143] In Prader-Willi syndrome, imprinting defects at the 15q11-q13 locus lead to loss of non-coding RNAs that regulate 5-HT2C receptor RNA editing and splicing, resulting in disrupted receptor-mediated appetite control and hyperphagia characteristic of the disorder.^[144] Beyond these categories, the 5-HT2C receptor is associated with addiction and trauma-related conditions. Knockout mouse models demonstrate increased preference for cocaine and enhanced reinforcing effects, indicating that receptor absence heightens vulnerability to psychostimulant addiction through unchecked dopaminergic responses in the nucleus accumbens.^[145] In post-traumatic stress disorder (PTSD), elevated RNA editing of the 5-HT2C receptor in the central nucleus of the amygdala (CeA) correlates with resilience deficits, as observed in rodent models where editing changes exacerbate fear responses and PTSD-like behaviors.^[146]

Therapeutic Targeting

The 5-HT2C receptor has been targeted therapeutically primarily through agonists for obesity and antagonists incorporated into antipsychotics, though challenges such as off-target effects have limited progress. Lorcaserin, a selective 5-HT2C agonist, was approved by the FDA in 2012 for chronic weight management in obese or overweight adults but was voluntarily withdrawn from the market in 2020 after a post-marketing study indicated an increased risk of cancer, with incidence rates of 7.8% in lorcaserin-treated patients versus 7.2% in placebo, outweighing its modest weight loss benefits of approximately 3-5% body weight reduction.^[111] Iloperidone, an atypical antipsychotic approved in 2009 for schizophrenia, exerts partial antagonism at 5-HT2C receptors alongside stronger blockade of 5-HT2A and D2 receptors, contributing to its efficacy in reducing positive symptoms with a lower risk of extrapyramidal side effects compared to typical antipsychotics.^[147] In the drug development pipeline, selective 5-HT2C agonists like vabicaserin showed promise in phase II trials for schizophrenia, demonstrating improvements in positive and negative symptoms without significant weight gain, but development was halted around 2014 due to failure to meet primary efficacy endpoints in later studies. For insomnia, 5-HT2C antagonists such as agomelatine, which combines 5-HT2C antagonism with melatonin receptor agonism, have been utilized in treating major depressive disorder with comorbid sleep disturbances, enhancing slow-wave sleep and reducing wakefulness after sleep onset in clinical evaluations.^[148] Key challenges in 5-HT2C-targeted therapies include cross-reactivity with the 5-HT2B receptor, where agonism can induce cardiac valvulopathy through mitogenic signaling in heart valve cells, as observed with earlier serotonergic agents like fenfluramine; this risk necessitates rigorous selectivity screening in preclinical models. Additionally, the X-linked genomic location of the HTR2C gene leads to sex-specific expression differences, with males being hemizygous and potentially more sensitive to variants like the Cys23Ser polymorphism, influencing therapeutic responses in disorders such as schizophrenia and depression.^[149]^[150] Recent studies on serotonergic psychedelics highlight biased agonists that preferentially activate Gq/11 signaling over β-arrestin pathways at 5-HT2C receptors, potentially contributing to rapid antidepressant effects in treatment-resistant depression without full hallucinogenic profiles; for instance, analyses of compounds like psilocin reveal such bias, supporting their exploration in mood disorders.^[10] Positive allosteric modulators (PAMs) of 5-HT2C receptors are emerging for substance use disorders (SUD), enhancing endogenous serotonin signaling to reduce reward-seeking behaviors in preclinical models of alcohol and psychostimulant dependence.^[151] As of 2025, further research includes 5-HT2C modulation for binge eating disorders via full agonism or PAMs, and preclinical development of selective agonists for alcohol use disorder and Prader-Willi syndrome hyperphagia.^[9]^[152]^[153] Ongoing clinical efforts include phase II trials evaluating 5-HT2C modulation as augmentation therapy in schizophrenia, building on historical data from vabicaserin to improve negative symptoms when added to standard antipsychotics. Biomarkers such as RNA editing levels of HTR2C mRNA, which generate up to 14 isoforms altering receptor constitutive activity, are being investigated to predict therapeutic outcomes and personalize treatments in psychiatric conditions like bipolar disorder and depression.^[154]^[155]