| TAAR6 | |||||||||||||||||||||||||||||||||||||||||||||||||||
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| Aliases | TAAR6 , TA4, TAR4, TAR6, TRAR4, taR-4, taR-6, trace amine associated receptor 6 | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | OMIM: 608923 MGI: 2685074 HomoloGene: 27874 GeneCards: TAAR6 | ||||||||||||||||||||||||||||||||||||||||||||||||||
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Trace amine associated receptor 6, also known as TAAR6, is a protein which in humans is encoded by the TAAR6 gene. [5] [6]
TAAR6 belongs to the trace amine-associated receptor family. Trace amines are endogenous amine compounds that are chemically similar to classic biogenic amines like dopamine, norepinephrine, serotonin, and histamine. Trace amines were thought to be 'false transmitters' that displace classic biogenic amines from their storage and act on transporters in a fashion similar to the amphetamines, but the identification of brain receptors specific to trace amines indicates that they also have effects of their own. [7] [8] RNA expression analysis shows hTAAR6 is expressed in the hippocampus, where murine TAAR receptors have been shown to be involved with neurogenesis. [9]
Computational modeling suggests TAAR6 can bind to the foul smelling compounds produced by rotting flesh, putrescine and cadaverine. [10]
TAAR6 mutant mice have differences in behavior compared with wild-type mice. [11] Also, they have elevated brain serotonin levels in several brain regions and enhanced hypothermic response to 5-HT1A receptor agonist 8-OH-DPAT. [12]
Monoamine neurotransmitters are neurotransmitters and neuromodulators that contain one amino group connected to an aromatic ring by a two-carbon chain (such as -CH2-CH2-). Examples are dopamine, norepinephrine and serotonin.
Tryptamine is an indolamine metabolite of the essential amino acid, tryptophan. The chemical structure is defined by an indole—a fused benzene and pyrrole ring, and a 2-aminoethyl group at the second carbon (third aromatic atom, with the first one being the heterocyclic nitrogen). The structure of tryptamine is a shared feature of certain aminergic neuromodulators including melatonin, serotonin, bufotenin and psychedelic derivatives such as dimethyltryptamine (DMT), psilocybin, psilocin and others. Tryptamine has been shown to activate trace amine-associated receptors expressed in the mammalian brain, and regulates the activity of dopaminergic, serotonergic and glutamatergic systems. In the human gut, symbiotic bacteria convert dietary tryptophan to tryptamine, which activates 5-HT4 receptors and regulates gastrointestinal motility. Multiple tryptamine-derived drugs have been developed to treat migraines, while trace amine-associated receptors are being explored as a potential treatment target for neuropsychiatric disorders.
Monoamine transporters (MATs) are proteins that function as integral plasma-membrane transporters to regulate concentrations of extracellular monoamine neurotransmitters. The three major classes are serotonin transporters (SERTs), dopamine transporters (DATs), and norepinephrine transporters (NETs) and are responsible for the reuptake of their associated amine neurotransmitters (serotonin, dopamine, and norepinephrine. MATs are located just outside the synaptic cleft, transporting monoamine transmitter overflow from the synaptic cleft back to the cytoplasm of the pre-synaptic neuron. MAT regulation generally occurs through protein phosphorylation and post-translational modification. Due to their significance in neuronal signaling, MATs are commonly associated with drugs used to treat mental disorders as well as recreational drugs. Compounds targeting MATs range from medications such as the wide variety of tricyclic antidepressants, selective serotonin reuptake inhibitors such as fluoxetine to stimulant medications such as methylphenidate and amphetamine in its many forms and derivatives methamphetamine and lisdexamfetamine. Furthermore, drugs such as MDMA and natural alkaloids such as cocaine exert their effects in part by their interaction with MATs, by blocking the transporters from mopping up dopamine, serotonin, and other neurotransmitters from the synapse.
A biogenic amine is a biogenic substance with one or more amine groups. They are basic nitrogenous compounds formed mainly by decarboxylation of amino acids or by amination and transamination of aldehydes and ketones. Biogenic amines are organic bases with low molecular weight and are synthesized by microbial, vegetable and animal metabolisms. In food and beverages they are formed by the enzymes of raw material or are generated by microbial decarboxylation of amino acids.
The dopamine transporter (DAT) also is a membrane-spanning protein coded for in the human by the SLC6A3 gene,, that pumps the neurotransmitter dopamine out of the synaptic cleft back into cytosol. In the cytosol, other transporters sequester the dopamine into vesicles for storage and later release. Dopamine reuptake via DAT provides the primary mechanism through which dopamine is cleared from synapses, although there may be an exception in the prefrontal cortex, where evidence points to a possibly larger role of the norepinephrine transporter.
3-Iodothyronamine (T1AM) is an endogenous thyronamine. T1AM is a high-affinity ligand for the trace amine-associated receptor TAAR1 (TAR1, TA1), a recently discovered G protein-coupled receptor. T1AM is the most potent endogenous TAAR1 agonist yet discovered. Activation of TAAR1 by T1AM results in the production of large amounts of cAMP. This effect is coupled with decreased body temperature and cardiac output. Wu et al. have pointed out that this relationship is not typical of the endocrine system, indicating that TAAR1 activity may not be coupled to G-proteins in some tissues, or that T1AM may interact with other receptor subtypes.
Trace amines are an endogenous group of trace amine-associated receptor 1 (TAAR1) agonists – and hence, monoaminergic neuromodulators – that are structurally and metabolically related to classical monoamine neurotransmitters. Compared to the classical monoamines, they are present in trace concentrations. They are distributed heterogeneously throughout the mammalian brain and peripheral nervous tissues and exhibit high rates of metabolism. Although they can be synthesized within parent monoamine neurotransmitter systems, there is evidence that suggests that some of them may comprise their own independent neurotransmitter systems.
Trace amine-associated receptors (TAARs), sometimes referred to as trace amine receptors, are a class of G protein-coupled receptors that were discovered in 2001. TAAR1, the first of six functional human TAARs, has gained considerable interest in academic and proprietary pharmaceutical research due to its role as the endogenous receptor for the trace amines phenylethylamine, tyramine, and tryptamine – metabolic derivatives of the amino acids phenylalanine, tyrosine and tryptophan, respectively – ephedrine, as well as the synthetic psychostimulants, amphetamine, methamphetamine and methylenedioxymethamphetamine. In 2004, it was shown that mammalian TAAR1 is also a receptor for thyronamines, decarboxylated and deiodinated relatives of thyroid hormones. TAAR2–TAAR9 function as olfactory receptors for volatile amine odorants in vertebrates.
Dopamine receptor D2, also known as D2R, is a protein that, in humans, is encoded by the DRD2 gene. After work from Paul Greengard's lab had suggested that dopamine receptors were the site of action of antipsychotic drugs, several groups, including those of Solomon Snyder and Philip Seeman used a radiolabeled antipsychotic drug to identify what is now known as the dopamine D2 receptor. The dopamine D2 receptor is the main receptor for most antipsychotic drugs. The structure of DRD2 in complex with the atypical antipsychotic risperidone has been determined.
5-Hydroxytryptamine (serotonin) receptor 5A, also known as HTR5A, is a protein that in humans is encoded by the HTR5A gene. Agonists and antagonists for 5-HT receptors, as well as serotonin uptake inhibitors, present promnesic (memory-promoting) and/or anti-amnesic effects under different conditions, and 5-HT receptors are also associated with neural changes.
Trace amine-associated receptor 2 (TAAR2), formerly known as G protein-coupled receptor 58 (GPR58), is a protein that in humans is encoded by the TAAR2 gene. TAAR2 is coexpressed with Gα proteins; however, as of February 2017, its signal transduction mechanisms have not been determined.
Putative trace amine-associated receptor 3 (TAAR3) is a human pseudogene with the gene symbol TAAR3P. In other species such as mice, TAAR3 is a functional protein-coding gene that encodes a trace amine-associated receptor protein.
Metabotropic glutamate receptor 7 is a protein that in humans is encoded by the GRM7 gene.
Trace amine-associated receptor 5 is a protein that in humans is encoded by the TAAR5 gene. In vertebrates, TAAR5 is expressed in the olfactory epithelium.
Trace amine-associated receptor 8 is a protein that in humans is encoded by the TAAR8 gene. In humans, TAAR8 is the only trace amine-associated receptor that is known to be Gi/o-coupled.
Trace amine-associated receptor 1 (TAAR1) is a trace amine-associated receptor (TAAR) protein that in humans is encoded by the TAAR1 gene. TAAR1 is an intracellular amine-activated Gs-coupled and Gq-coupled G protein-coupled receptor (GPCR) that is primarily expressed in several peripheral organs and cells, astrocytes, and in the intracellular milieu within the presynaptic plasma membrane of monoamine neurons in the central nervous system (CNS). TAAR1 was discovered in 2001 by two independent groups of investigators, Borowski et al. and Bunzow et al. TAAR1 is one of six functional human trace amine-associated receptors, which are so named for their ability to bind endogenous amines that occur in tissues at trace concentrations. TAAR1 plays a significant role in regulating neurotransmission in dopamine, norepinephrine, and serotonin neurons in the CNS; it also affects immune system and neuroimmune system function through different mechanisms.
Trace amine-associated receptor 9 is a protein that in humans is encoded by the TAAR9 gene.
Glutamate receptor delta-1 subunit also known as GluD1 or GluRδ1 is a transmembrane protein encoded by the GRID1 gene. A C-terminal GluD1 splicing isoform has been described based on mRNA analysis.
o-Phenyl-3-iodotyramine (o-PIT) is a drug which acts as a selective agonist for the trace amine-associated receptor 1. It has reasonable selectivity for TAAR1 but relatively low potency, and is rapidly metabolised in vivo, making it less useful for research than newer ligands such as RO5166017.
Ulotaront is an investigational antipsychotic that is undergoing clinical trials for the treatment of schizophrenia and Parkinson's disease psychosis. The medication was discovered in collaboration between PsychoGenics Inc. and Sunovion Pharmaceuticals using PsychoGenics' behavior and AI-based phenotypic drug discovery platform, SmartCube. Ulotaront is in Phase III of clinical development.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.
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