Gene Number: 3356

Location: 13q14.2

Key Functions: Serotonin signaling, mood regulation, cognitive function, sleep regulation, sensory perception

HTR2A encodes the 5-hydroxytryptamine receptor 2A (5-HT₂A), a G protein–coupled receptor (GPCR) primarily coupled to the Gq/11 signaling pathway. It plays a pivotal role in mediating the effects of serotonin (5-HT) on neuronal excitability, synaptic plasticity, and cortical integration. The receptor is widely distributed in the central nervous system (CNS)—particularly in the prefrontal cortex, anterior cingulate cortex, hippocampus, amygdala, and thalamus—where it influences mood, cognition, perception, and consciousness.

Upon serotonin binding, 5-HT₂A receptors activate phospholipase C (PLC), resulting in the generation of inositol triphosphate (IP₃) and diacylglycerol (DAG), leading to intracellular Ca²⁺ release and protein kinase C (PKC) activation. This signaling cascade modulates neuronal firing, synaptic strength, and neurotransmitter release, thus impacting affective, cognitive, and perceptual processes.

Key physiological and neurobiological functions of HTR2A include:

1. Mood regulation:The 5-HT₂A receptor is integral to the serotonergic control of emotional processing and affective stability. It modulates the activity of glutamatergic pyramidal neurons in the prefrontal cortex, facilitating top-down regulation of emotion and stress reactivity. Dysregulation or downregulation of HTR2A signaling has been observed in major depressive disorder (MDD) and anxiety disorders, whereas excessive receptor activation can contribute to psychotic or hallucinatory states.

   
   

2. Cognitive and executive function:Through its influence on cortical pyramidal neurons, HTR2A modulates working memory, attentional control, and cognitive flexibility. It also interacts with dopaminergic and glutamatergic systems, particularly in the prefrontal cortex, to shape goal-directed behavior and decision-making.

   
   

3. Sleep and circadian regulation:HTR2A receptors influence slow-wave sleep (SWS) and rapid eye movement (REM) cycles by modulating serotonergic and cholinergic neurotransmission in sleep-regulating brain regions. Antagonism of 5-HT₂A receptors—such as that induced by atypical antipsychotics and certain antidepressants (e.g., trazodone, mirtazapine)—enhances slow-wave sleep continuity and reduces sleep fragmentation, improving overall sleep quality.

   
   

4. Perception and consciousness:HTR2A serves as the principal molecular target for classic serotonergic psychedelics such as LSD, psilocybin, and DMT. Activation of cortical 5-HT₂A receptors by these compounds disrupts normal sensory and cognitive integration, producing altered states of consciousness characterized by enhanced connectivity, sensory distortion, and ego dissolution. The same receptor-mediated mechanism has been implicated in the therapeutic effects of psychedelics on mood and trauma-related disorders through neuroplasticity and emotional recalibration.

   
   

5. Pharmacogenomic and clinical relevance:Genetic variations in HTR2A influence individual susceptibility to psychiatric conditions and differential response to pharmacological treatments. The rs6311 (−1438G>A) and rs6313 (102T>C) polymorphisms are among the most studied:

   
   

   • The A allele of rs6311 is associated with reduced promoter activity and lower receptor expression, which may correspond to blunted antidepressant response and higher depression vulnerability.

     
     

   • The C allele of rs6313 has been linked to altered receptor density and variable response to SSRIs, SNRIs, and atypical antipsychotics.

     
     

   Moreover, atypical antipsychotics such as clozapine, risperidone, and olanzapine act as potent HTR2A antagonists or inverse agonists, reducing psychotic symptoms by restoring cortical glutamatergic and dopaminergic balance

   
   

6. Interaction with other neurotransmitter systems:HTR2A signaling modulates and is modulated by dopaminergic and glutamatergic transmission. In cortical networks, its activation enhances NMDA receptor–mediated excitatory postsynaptic potentials, while in subcortical circuits, HTR2A antagonism indirectly increases dopamine release in the prefrontal cortex, a mechanism believed to underlie the pro-cognitive and antipsychotic effects of certain serotonergic drugs.

   
   

In summary, HTR2A functions as a critical molecular integrator of serotonergic activity across the brain, shaping emotional tone, cognitive processes, sleep regulation, and perceptual experiences. Genetic and functional variations in this receptor contribute to interindividual differences in mood stability, stress sensitivity, drug responsiveness, and susceptibility to psychiatric and perceptual disorders, making HTR2A a central target in both neuropsychiatric research and therapeutic drug development.