What is the 5-hydroxytryptamine 2C (5HT2C) receptor responsible for?

5-HT2C Receptor Function and Clinical Significance

Primary Functions

The 5-HT2C receptor is primarily responsible for appetite suppression, satiety enhancement, and modulation of mood, motor behavior, and endocrine secretion through its actions on anorexigenic pro-opiomelanocortin (POMC) neurons in the hypothalamus. 1

Weight Regulation and Appetite Control

• The 5-HT2C receptor selectively activates POMC neurons in the hypothalamus, which reduces food intake and increases satiety 1
• This mechanism is exploited therapeutically by lorcaserin, an FDA-approved weight loss medication that selectively binds 5-HT2C receptors at recommended doses 1
• The receptor's role in appetite control is so significant that selective 5-HT2C agonists produce clinically meaningful weight loss (5-6% body weight reduction) in obesity treatment 1

Neuropsychiatric Functions

• 5-HT2C receptors modulate monoaminergic transmission and play important roles in mood regulation, anxiety, and depression 2, 3
• The receptor exhibits constitutive activity (signals without ligand binding), which is decreased by RNA editing and alternative splicing 4
• Alterations in 5-HT2C functional status have been detected in anxiodepressive states 2
• The receptor is involved in the mechanism of action of multiple antidepressants and antipsychotics 2, 3, 5

Motor and Neurological Functions

• 5-HT2C receptors control motoneuron activity and are implicated in Parkinson's disease, levodopa-induced dyskinesia, and epilepsy 3, 4
• The receptor regulates spasticity and is a potential target for anti-spasm agents 4

G-Protein Coupling and Signaling

• The 5-HT2C receptor primarily couples to Gq/11 proteins and signals through phospholipase C, but also engages Gi/o/z and G12/13 pathways 6
• The receptor preferentially recruits β-arrestin2 over β-arrestin1 6
• Increased RNA editing attenuates signaling across all G protein pathways, particularly G12/13, while preserving β-arrestin recruitment 6

Gut-Brain Axis Communication

• 5-HT (serotonin) serves as a major neurotransmitter in the gut-brain axis, though peripheral and central serotonin systems are separated by the blood-brain barrier 1, 7
• Altered serotonin metabolism involving 5-HT2C receptors has been observed in irritable bowel syndrome (IBS) 1, 7

Clinical Distinction from Other 5-HT2 Receptors

• At therapeutic doses, selective 5-HT2C agonists avoid activation of 5-HT2A receptors (associated with hallucinations) and 5-HT2B receptors (associated with cardiac valve insufficiency) 1
• This selectivity is critical for safety, as non-selective serotonin agonists like fenfluramine caused valvular heart disease through 5-HT2B activation 1

Therapeutic Implications

• 5-HT2C receptor blockade by antidepressants (nefazodone, mirtazapine) contributes to their therapeutic effects by stimulating dopaminergic and adrenergic pathways 2
• Progressive down-regulation of 5-HT2C receptors parallels the gradual onset of clinical efficacy of SSRIs 2
• At treatment onset, indirect 5-HT2C activation by SSRIs contributes to initial anxiogenic effects and inhibition of sleep, sexual behavior, and appetite 2