HTR2A

Official Full Name

5-hydroxytryptamine receptor 2A

Organism

Homo sapiens

GeneID

3356

Background

This gene encodes one of the receptors for serotonin, a neurotransmitter with many roles. Mutations in this gene are associated with susceptibility to schizophrenia and obsessive-compulsive disorder, and are also associated with response to the antidepressant citalopram in patients with major depressive disorder (MDD). MDD patients who also have a mutation in intron 2 of this gene show a significantly reduced response to citalopram as this antidepressant downregulates expression of this gene. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2009]

Synonyms

HTR2; 5-HT2A;

Bio Chemical Class

GPCR rhodopsin

Protein Sequence

MDILCEENTSLSSTTNSLMQLNDDTRLYSNDFNSGEANTSDAFNWTVDSENRTNLSCEGCLSPSCLSLLHLQEKNWSALLTAVVIILTIAGNILVIMAVSLEKKLQNATNYFLMSLAIADMLLGFLVMPVSMLTILYGYRWPLPSKLCAVWIYLDVLFSTASIMHLCAISLDRYVAIQNPIHHSRFNSRTKAFLKIIAVWTISVGISMPIPVFGLQDDSKVFKEGSCLLADDNFVLIGSFVSFFIPLTIMVITYFLTIKSLQKEATLCVSDLGTRAKLASFSFLPQSSLSSEKLFQRSIHREPGSYTGRRTMQSISNEQKACKVLGIVFFLFVVMWCPFFITNIMAVICKESCNEDVIGALLNVFVWIGYLSSAVNPLVYTLFNKTYRSAFSRYIQCQYKENKKPLQLILVNTIPALAYKSSQLQMGQKKNSKQDAKTTDNDCSMVALGKQHSEEASKDNSDGVNEKVSCV

Open

Disease

Acute diabete complication, Addictive disorder, Alzheimer disease, Anxiety disorder, Attention deficit hyperactivity disorder, Bipolar disorder, Cardiovascular disease, Central nervous system disease, Cerebral ischaemia, Chronic insomnia, Chronic kidney disease, Chronic pain, Dementia, Depression, Glaucoma, Haemorrhoids, Hypertension, Idiopathic interstitial pneumonitis, Insomnia, Mental/behavioural/neurodevelopmental disorder, Migraine, Mood disorder, Pancreatic cancer, Pancreatitis, Parkinsonism, Pituitary gland disorder, Post-traumatic stress disorder, Prostate hyperplasia, Psychotic disorder, Schizoaffective disorder, Schizophrenia, Sexual dysfunction, Sleep-wake disorder, Social anxiety disorder, Substance abuse, Type 2 diabetes mellitus

Approved Drug

9 +

Clinical Trial Drug

24 +

Discontinued Drug

28 +

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Detailed Information

The HTR2A gene encodes the 5-hydroxytryptamine receptor 2A (5-HT2A), which is a G protein-coupled receptor (GPCR). This receptor is located in various important regions of the brain, including the cerebral cortex, caudate nucleus, hippocampus, and nucleus accumbens, and is also widely distributed in both smooth muscle and non-smooth muscle cells. As one of the major receptors for 5-HT (serotonin), the 5-HT2A receptor plays a crucial role in the nervous system. Its primary function is to regulate neuronal activity by binding to 5-HT and other drugs or chemicals, thereby activating downstream G protein signaling pathways.

Ligand binding and activation of the 5-HT2A receptor trigger a series of intracellular reactions, primarily through the phosphatidylinositol pathway (PLC), activating diacylglycerol (DAG) and inositol trisphosphate (IP3), which in turn regulate the release of intracellular calcium ions, producing various biological effects in neurons and other cells. It is also involved in regulating neuronal excitability, synaptic plasticity, and higher brain functions such as emotion and cognition.

In addition to natural serotonin binding, the 5-HT2A receptor is closely related to the effects of a range of psychoactive substances, including classic psychedelics like LSD (lysergic acid diethylamide) and psilocybin. These substances alter brain neural network activity by activating the 5-HT2A receptor, leading to significant changes in perception, emotion, and cognition. Therefore, studying this receptor not only helps to understand the hallucinogenic mechanisms of these drugs but also offers new insights for treating related mental disorders.

Role of HTR2A in Mental Disorders and Its Clinical Significance

The HTR2A gene is closely associated with various neuropsychiatric disorders, playing an important role in the onset and development of conditions such as schizophrenia, obsessive-compulsive disorder (OCD), depression, and anxiety disorders.

Schizophrenia, one of the most common severe mental illnesses, has its positive symptoms (e.g., hallucinations, delusions) closely related to dysfunction of the 5-HT2A receptor. Research has found that the function of the 5-HT2A receptor in schizophrenia patients is often inhibited or abnormally activated. This has led to the development of certain antipsychotic drugs (such as iloperidone and lurasidone) as antagonists of the 5-HT2A receptor to alleviate symptoms. By blocking the 5-HT2A receptor, these medications effectively reduce positive symptoms like hallucinations and delusions. Additionally, because the 5-HT2A receptor is closely related to neural network activity in the cerebral cortex, its abnormality may lead to cognitive impairment, a significant clinical manifestation in patients with schizophrenia.

Obsessive-compulsive disorder (OCD) is characterized by repetitive compulsive behaviors and thoughts, and the 5-HT2A receptor plays a role in this condition. Research indicates that the function and expression levels of the 5-HT2A receptor may be abnormal in OCD patients, leading to neurotransmitter imbalances. Some OCD treatments (such as selective serotonin reuptake inhibitors, and SSRIs) are believed to alleviate symptoms by regulating the activity of the 5-HT2A receptor. Understanding how the HTR2A gene affects neurotransmitter system regulation will help develop new, more targeted treatments.

The pathologic mechanisms of depression are complex, involving various neurotransmitters and receptors. Studies suggest that mutations or abnormal expression of the HTR2A gene may affect patients' responses to antidepressant drugs. In particular, depression patients carrying specific mutations (such as those located in the second intron region) respond significantly less well to antidepressants like citalopram. This indicates that the 5-HT2A receptor plays a critical role in the treatment response for depression, with future research potentially aiding in the development of more personalized treatment plans.

Anxiety disorders, characterized by prolonged anxiety, also involve the 5-HT2A receptor. Research has shown that anxiety patients may have certain disorders in the activity and expression of the 5-HT2A receptor, potentially leading to an overreaction to environmental threats, which exacerbates anxiety symptoms. Modulation of the 5-HT2A receptor is considered an important target in anxiety disorder treatment, with research into related medications possibly offering new options for therapy.

Research Progress on HTR2A-Related Drugs and Treatment Strategies

The development of drugs targeting the HTR2A receptor is ongoing, with these medications showing great potential in the treatment of mental disorders. Different types of drugs act on the 5-HT2A receptor through various mechanisms, including receptor antagonists, agonists, and inverse agonists.

Some atypical antipsychotics alleviate symptoms of mental disorders, like schizophrenia, through the antagonism of the 5-HT2A receptor. For example, iloperidone and lurasidone work by binding to the 5-HT2A receptor, reducing its abnormal activation, and thereby improving hallucinations and cognitive impairments. These medications are considered to have fewer side effects compared to traditional antipsychotics, particularly in terms of motor disorders and weight gain.

Psychedelic drugs, such as LSD and psilocybin, initially garnered attention for their hallucinogenic effects. However, recent research has found that by activating the 5-HT2A receptor, they can promote neural plasticity and cortical reconstruction, improving mood and cognitive functions. Some clinical trials have shown that these drugs have lasting effects in alleviating anxiety and depression, even demonstrating potential in the treatment of treatment-resistant depression.

Despite concerns over abuse and safety in the clinical use of psychedelic drugs, current research is progressing toward the development of non-hallucinogenic 5-HT2A agonists. These new drugs retain the beneficial effects of 5-HT2A agonists without causing hallucinations or other side effects, possibly representing a new direction in psychotherapy.

With the development of genomics and precision medicine, personalized treatment based on HTR2A gene mutations and individual gene expression is becoming a significant area for future research. Studies have indicated that variations in the HTR2A gene may influence patients' drug responses. For instance, certain patients with specific gene mutations may have poorer effects with antidepressants; thus, the application of genetic testing in the clinical setting will assist in personalized drug selection, enhancing treatment outcomes.

References:

Norton N, Owen MJ. HTR2A: association and expression studies in neuropsychiatric genetics. Ann Med. 2005;37(2):121-129.
Mattina GF, Samaan Z, Hall GB, et al. The association of HTR2A polymorphisms with obsessive-compulsive disorder and its subtypes: A meta-analysis. J Affect Disord. 2020;275:278-289.

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