Theserotonin receptors were split into two classes byJohn Gaddum and Picarelli in 1957 when it was discovered that some of the serotonin-induced changes in thegut could be blocked bymorphine, while the remainder of the response was inhibited bydibenzyline (phenoxybenzamine), leading to the naming of M and D receptors, respectively.[7][8] The 5-HT2A receptor is thought to correspond to what was originally described as D subtype of serotonin receptors by Gaddum and Picarelli.[7][8]
In the era beforemolecular cloning, whenradioligand binding and displacement was the only major tool,spiperone andLSD were shown to label two different 5-HT receptors, and neither of them displaced morphine, leading to naming of the5-HT1,5-HT2 and5-HT3 receptors, corresponding to high affinity sites from LSD, spiperone and morphine, respectively.[9] Later, it was shown that the 5-HT2 receptor was very close to the 5-HT1C receptor and they were thus were grouped together, renaming the 5-HT2 receptor into 5-HT2A receptor and the 5-HT1C reeptor into the 5-HT2C receptor. Thus, the 5-HT2 receptor family is composed of three separate molecular entities: the 5-HT2A (formerly known as 5-HT2 or D), the5-HT2B (formerly known as 5-HT2F) and the5-HT2C (formerly known as 5-HT1C) receptors.[10]
The serotonin 5-HT2A receptor was identified via radioligand binding in 1978 by Leysen and colleagues.[11][12] Peroutka and Snyder identified two distinct serotonin receptors and named them the 5-HT1 receptor and 5-HT2 receptor in 1979.[13][14] Later, both of these receptors were found to have several subtypes, including the serotonin 5-HT2A receptor.[13] The serotonin 5-HT2A receptor was characterized as a membrane protein by Wouters and colleagues in 1985.[11][15] The gene encoding the rat serotonin 5-HT2A receptor,HTR2A, was cloned in 1988 by Pritchett and colleagues.[11][16] The human gene was cloned by Branchek and colleagues in 1990.[13][17]
The 5-HT2A receptors is coded by theHTR2A gene. In humans the gene is located onchromosome 13. The gene has previously been called just HTR2 until the description of two related genesHTR2B andHTR2C. Several interestingpolymorphisms have been identified for HTR2A:A-1438G (rs6311),C102T (rs6313), andHis452Tyr (rs6314). Many more polymorphisms exist for the gene. A 2006 paper listed 255.[18][19]
Probable role in fibromyalgia as the T102C polymorphisms of the gene 5HT2A were common in fibromyalgia patients.[20]
Human HTR2A gene is thought to consist of 3introns and 4exons and to overlap with human gene HTR2A-AS1 which consists of 18 exons.[21] There are over 200 organisms that haveorthologs with the human HTR2A. Currently, the best documented orthologs forHTR2A gene are the mouse,[22] and zebrafish.[23] There are 8paralogs for the HTR2A gene. TheHTR2A gene is known to interact and activateG-protein genes such asGNA14,GNAI1,GNAI3,GNAQ, andGNAZ.[24] These interactions are critical for cell signaling[25][26] and homeostasis[27] in many organisms.[28]
There are a few mechanisms of regulation forHTR2A gene such regulated by DNA methylation at particular transcript binding sites.[29][30] Another mechanism for the correct regulation of gene expression is achieved throughalternative splicing. This is aco-transcriptional process, which allows the generation of multiple forms of mRNA transcript from a single coding unit and is emerging as an important control point for gene expression. In this process, exons or introns can be either included or excluded from precursor-mRNA resulting in multiple mature mRNA variants.[31] These mRNA variants result in differentisoforms which may have antagonistic functions or differential expression patterns, yielding plasticity and adaptability to the cells.[32] One study found that the common genetic variantrs6311 regulates expression ofHTR2A transcripts containing the extended 5' UTR.[21]
In the periphery, it is highly expressed inplatelets and many cell types of thecardiovascular system, infibroblasts, and in neurons of the peripheral nervous system. Additionally, 5-HT2A mRNA expression has been observed in humanmonocytes.[48] Whole-body distribution of the 5-HT2A/2C receptor agonist, [11C]Cimbi-36 show uptake in several internal organs and brown adipose tissue (BAT), but it is not clear if this represents specific 5-HT2A receptor binding.[49]
The 5-HT2A receptor is a member of the class A (rhodopsin-like) G protein-coupled receptor (GPCR) family, characterized by seven transmembrane α-helices connected by extracellular and intracellular loops.[50][51] Its ligand-binding pocket is composed of two adjacent subpockets: the orthosteric binding pocket (OBP) and an extended binding pocket (EBP), with a unique side-extended cavity near the orthosteric site that distinguishes it from related receptors.[52][53] Ligands are anchored primarily through a conserved aspartate residue (D155^3.32) that interacts with their charged amine groups, while additional interactions involve hydrophobic contacts and hydrogen bonds with residues in both the OBP and EBP.[53][54] Structural studies reveal that the receptor undergoes significant conformational changes upon activation, particularly in transmembrane helices 3 and 6, which facilitate G protein coupling and signal transduction.[50][53] The extracellular ligand-binding pocket is closed by a flexible "lid," and the intracellular region includes a short helix (H8) stabilized by π-stacking interactions, both of which contribute to the receptor's dynamic conformational landscape.[53] These structural features underlie the receptor's ability to recognize diverse ligands and mediate complex signaling behaviors.
The 5-HT2A receptor is a subtype of serotonin receptor that plays a critical role in the central nervous system, particularly in regions involved in cognition, learning, and memory.[57] It is highly expressed in thecerebral cortex, especially in layer Vpyramidal neurons and certaininterneurons, where it modulatesthalamocortical information processing and may influencegamma oscillations, which are important for sensory integration and perception.[58] Functionally, the 5-HT2A receptor is a G protein-coupled receptor (GPCR) that primarily signals through the phospholipase C (PLC) pathway, leading to the production ofinositol triphosphate (IP3) anddiacylglycerol, but it can also activate other signaling cascades such asarachidonic acid and2-arachidonylglycerol pathways.[58] Notably, the receptor exhibits "functional selectivity," meaning different ligands can differentially activate these signaling pathways, which is relevant for the distinct effects of hallucinogens, antipsychotics, and antidepressants that target the receptor.[58][54] Activation of the 5-HT2A receptor by agonists is associated with enhanced cognition and hallucinogenic effects, while antagonists have antipsychotic and antidepressant properties.[57] Dysregulation of 5-HT2A receptor function has been implicated in psychiatric disorders such as depression, schizophrenia, and drug addiction.[57] Additionally, the receptor undergoes unique regulatory processes, including desensitization and internalization that are partly independent ofβ-arrestin, further distinguishing it from other GPCRs and influencing its response to long-term pharmacological modulation.[58]
The 5-HT2A receptor is known primarily to couple to theGαq signal transduction pathway. Upon receptor stimulation with agonist, Gαq andβ-γ subunits dissociate to initiate downstream effector pathways. Gαq stimulatesphospholipase C (PLC) activity, which subsequently promotes the release ofdiacylglycerol (DAG) andinositol triphosphate (IP3), which in turn stimulateprotein kinase C (PKC) activity andCa2+ release.[59]
Physiological processes mediated by the receptor include:
CNS: neuronal excitation, hallucinations,out-of-body experiences, and fear. Primarily responsible for the psychedelic effects associated with 5-HT2A receptor agonists such asLSD,DMT, etc.[60][61]
Activation of the 5-HT2Areceptor is necessary for the effects of the "classic"psychedelics likeLSD,psilocin andmescaline, which act asfull orpartialagonists at this receptor, and represent the three main classes of 5-HT2A agonists, theergolines,tryptamines andphenethylamines, respectively. A very large family of derivatives from these three classes has been developed, and theirstructure-activity relationships have been extensively researched.[73][74] Agonists acting at 5-HT2A receptors located on theapical dendrites ofpyramidal cells within regions of theprefrontal cortex are believed to mediate hallucinogenic activity. Some findings reveal that psychoactive effects of classic psychedelics are mediated by thereceptor heterodimer 5-HT2A–mGlu2 and not bymonomeric 5-HT2A receptors.[75][76][60] However, newer research suggests that 5HT2A and mGlu2 receptors do not physically associate with each other, so the former findings have questionable relevance.[77] Agonists enhance dopamine in PFC,[36] enhance memory and play an active role in attention and learning.[78][79]
The potencies of psychedelics and other serotonin 5-HT2A receptor agonists as anti-inflammatory drugs vary, with2C-I,DOIB,2C-B,4-HO-DiPT,DOI,2,5-DMA,DOET,DOM, psilocin, and2C-H being highly potent and fully efficacious anti-inflammatories;TMA-2,2C-B-Fly,TCB-2,ETH-LAD,LSD, and2C-T-33 being partially efficacious anti-inflammatories; andlisuride,1-methylpsilocin,5-MeO-DMT, andDMT having negligible efficacy.[93][98] Both non-hallucinogenic agents with full anti-inflammatory effects, such as 2,5-DMA, and non-anti-inflammatory agents with full psychedelic effects, such asDOTFM, are known.[98][99][100] Hence, the psychedelic and anti-inflammatory effects of serotonin 5-HT2A receptor agonists appear to be fully dissociable.[98][99][100] These effects appear to be mediated by differentintracellular signaling pathways, although the exact pathways are unclear.[100]
Serotonin 5-HT2A receptor agonists with anti-inflammatory effects but reduced psychedelic effects, such as2C-iBu (ELE-02), are under development for the potential treatment ofinflammatory conditions.[101][102][103] They may also have applications in the treatment ofneuroinflammation.[92][95] The anti-inflammatory effects of psychedelics might be involved in the claimed effects of psychedelicmicrodosing.[104][105] Relatedly, LSD microdosing is being studied in the treatment ofAlzheimer's disease specifically for its anti-inflammatory effects.[106][107]
DMBMPP – a structurally constrained derivative of25B-NBOMe, which acts as a potent partial agonist with 124× selectivity for 5-HT2A over 5-HT2C, making it the most selective agonist ligand identified to date.[117]
(R)-DOI – traditionally the most common 5-HT2A reference agonist used in research[118]
Efavirenz – an antiretroviral drug, produces psychiatric side effects thought to be mediated by 5-HT2A.[119]
IHCH-7113 – 5-HT2A agonist derived by simplification of the 5-HT2A antagonist antipsychoticlumateperone.[120]
Mefloquine – an antimalarial drug, also produces psychiatric side effects which may be mediated through 5-HT2A and/or 5-HT2C receptors.[123]
Methysergide – a congener ofmethylergonovine, used in treatment ofmigraine blocks 5-HT2A and 5-HT2C receptors, but sometimes acts as partial agonist, in some preparations.
One effect of 5-HT2A receptor activation is a reduction in intraocular pressure, and so 5-HT2A agonists can be useful for the treatment ofglaucoma. This has led to the development of compounds such asAL-34662 that are hoped to reduce pressure inside the eyes but without crossing theblood–brain barrier and producing hallucinogenic side effects.[143] Animal studies with this compound showed it to be free of hallucinogenic effects at doses up to 30 mg/kg, although several of its more lipophilic analogues did produce thehead-twitch response known to be characteristic of hallucinogenic effects in rodents.[144]
Ergot alkaloids are mostly nonspecific 5-HT receptor antagonists, but a few ergot derivatives such asmetergoline andnicergoline bind preferentially to members of the 5-HT2 receptor family.
Ketanserin – The discovery of ketanserin was a landmark in the pharmacology of 5-HT2 receptors. Ketanserin, though capable of blocking 5-HT induced platelet adhesion, however does not mediate its well-known antihypertensive action through 5-HT2 receptor family, but through its high affinity for alpha1 adrenergic receptors. It also has high affinity for H1 histaminergic receptors equal to that at 5-HT2A receptors. Compounds chemically related to ketanserin such asritanserin are more selective 5-HT2A receptor antagonists with low affinity for alpha-adrenergic receptors. However, ritanserin, like most other 5-HT2A receptor antagonists, also potently inhibits 5-HT2C receptors.
Increased 5-HT2A expression is observed in patients with coronary thrombosis, and the receptor has been associated with processes that influenceatherosclerosis.[166] As the receptor is present incoronary arteries[167] and capable of mediating vasoconstriction, 5-HT2A has also been linked to coronary artery spasms.[168] 5-HT antagonism, therefore, has potential in the prevention of cardiovascular disease, however, no studies have been published so far.[166]
Eplivanserin (Sanofi Aventis) – sleeping pill that reached phase II trials (but for which the application for approval was withdrawn), acts as a selective 5-HT2A inverse agonist.
Nelotanserin (APD-125) – selective 5-HT2A inverse agonist developed byArena Pharmaceuticals for the treatment of insomnia. APD-125 was shown to be effective and well tolerated in clinical trials.[171]
Pimavanserin (ACP-103) – more selective than AC-90179, orally active, antipsychoticin vivo, now FDA approved for the treatment of hallucinations and delusions associated with Parkinson's disease.[172][173][174][175][176]
Recent research has suggested potential signaling differences within the somatosensory cortex between 5-HT2A agonists that produceheadshakes in themouse and those that do not, such aslisuride, as these agents are also non-hallucinogenic in humans despite being active 5-HT2A agonists.[183][184] One known example of differences in signal transduction is between the two 5-HT2A agonists serotonin andDOI that involves differential recruitment of intracellular proteins called β-arrestins, more specificallyarrestin beta 2.[185][186] Cyclopropylmethanamine derivatives such as (−)-19 have also been shown to act as 5-HT2A/2C agonists with functional selectivity for Gq-mediated signaling compared with β-arrestin recruitment.[187]
Western blot with an affinity-purified antibody and examination of 5-HT2A receptor protein samples by electrophoresis has been described. Immunohistochemical staining of 5-HT2A receptors is also possible.[5]
The T102C polymorphism has also been studied in relation tosuicide attempts, with a study finding excess of the C/C genotype among the suicide attempters.[208] A number of other studies were devoted to finding an association of the gene with schizophrenia, with diverging results.[209]
These individual studies may, however, not give a full picture: A review from 2007 looking at the effect of different SNPs reported in separate studies stated that "genetic association studies [ofHTR2A gene variants with psychiatric disorders] report conflicting and generally negative results" with no involvement, small or a not replicated role for the genetic variant of the gene.[210]
Polymorphisms in the promoter gene codingEarly growth response 3 (EGR3) are associated withschizophrenia. Studies have demonstrated a relationship between EGR3 andHTR2A, and schizophrenia-like behaviors intransgenic animals.[211][212] Exactly how these results translate over to further biopsychological understanding of schizophrenia is still widely debated.[213][214] There is some evidence that dysfunction ofHTR2A can impact pharmacological interventions.[215]
Several studies have assessed a relationship between 5-hydroxytryptamine (serotonin) 2A receptor (5-HTR2A) gene polymorphisms with an increased risk of suicidal behavior. One study revealed that T102C polymorphism is associated with suicidal behavior[216] but other studies failed to replicate these findings and found no association between polymorphism and suicidal behavior.[217]
Polymorphisms in the 5-HT2A receptor coding geneHTR2A (rs6313 and s6311) have been shown to have conflicting associations with alcohol misuse. For example, A polymorphism in the 5-HT2A receptor coding geneHTR2A (rs6313) was reported to predict lower positivealcohol expectancy, higher refusalself-efficacy, and lower alcohol misuse in a sample of 120 young adults. However, this polymorphism did not moderate the linkages between impulsivity, cognition, and alcohol misuse.[219] There are conflicting results as other studies have found associations between T102C polymorphisms alcohol misuse.[220][221]
There is some evidence that methylation patterns may contribute torelapse behaviors in people who use stimulants.[222] In mice, psychotropic drugs such asDOI,LSD,DOM, andDOB which produced differing transcriptional patterns among several different brain regions.[212]
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