5-hydroxytryptamine receptor 2C, 5HT2C/5HT2CR, also known as serotonin receptor 2C, is a transmembrane (TM) receptor subtype in the 5-HT₂R family of class A G-protein coupled receptors (GPCRs). 5HT2CR is encoded by the HTR2C gene and mediates various physiological functions, including disease-related pathways and behaviors due to its effects on the central nervous system (CNS).^1,2

The 5HT2C receptor is composed of seven TM helices (TM I – VII), three extracellular (ECL 1–3) and three intracellular loops (ICL 1–3), an intracellular carboxy-terminus, and an extracellular amino-terminus. Activation of 5HT2CR through 5-HT binding to Gα_q/11 triggers G protein-dependent signaling that activates phospholipase C_β (PLC_β) and leads to phosphatidylinositol 4,5-bisphosphate (PIP2) hydrolysis to produce inositol-1,4,5-trisphosphate (IP₃), accumulation of the downstream IP₃ metabolite inositol monophosphate (IP₁), and diacylglycerol (DAG), resulting in increased levels of intracellular mobilization of Ca²⁺ and IP₁.¹

Activation of 5HT2CR can regulate ion channels and transport processes, as well as activate other downstream effectors including phospholipase A₂ (PLA₂), phospholipase D (PLD), cyclic nucleotides, and extracellular signal-regulated kinases (ERK_1/2). Stimulation of 5HT2CR can activate cytosolic PLA₂ to produce free arachidonic acid and its metabolites. Depending on the ligand, agonist signaling bias can activate either PLC_β or PLA₂. Activation of 5HT2CR leads to protein kinase C (PKC) activation and downstream stimulation of the mitogen-activated protein kinase cascade, resulting in ERK_1/2 phosphorylation. 5HT2CR has been shown to couple ERK_1/2 through a PLD- and PKC-dependent pathway, potentially with Gα_12/13 proteins.¹

5HT2CR has been shown to interact with proteins including PSD-95/disk large/zonula occludens domain-containing proteins, calmodulin, β-arrestins, and phosphatase and tensin homolog, which all modulate receptor kinetics. β-arrestins play a significant role in regulating the functional activity of 5HT2CR by controlling desensitization and resensitization processes. Agonist-dependent desensitization of 5HT2CR involves phosphorylation by G-protein receptor kinase 2 (GRK₂), binding of β-arrestin, and uncoupling of the receptor from G protein resulting in subsequent internalization into endosomes. Resensitization and recycling back to the plasma membrane occur upon dephosphorylation.¹

The expression and function of 5HT2CR play a primary role in the CNS. Serotonergic cell bodies in the midbrain dorsal raphe nuclei project to various brain regions, including the ventral tegmental area (VTA), nucleus accumbens (NAc), and prefrontal cortex (PFC), which are associated with reward and executive function. 5HT2CR is expressed postsynaptically in various neuronal cell types that use neurotransmitters such as acetylcholine, dopamine, and γ-aminobutyric acid (GABA), with a significant outcome of 5HT2CR stimulation being the modulation of dopamine neuronal function.¹

5HT2CR plays a crucial role in regulating several physiological brain functions such as food intake, anxiety, stress response, motoneuron activity, and sleep. Dysregulation of 5HT2CR is observed in conditions such as depression, schizophrenia, suicidal behavior, spinal cord injury, and obesity.²