# Trace amine-associated receptor

Trace amine-associated receptors (TAARs), sometimes referred to as trace amine receptors (TAs or TARs), 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 phenethylamine, 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 (MDMA, ecstasy). 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.

## Animal TAAR complement

The following is a list of the TAARs contained in selected animal genomes:
* Human – 6 genes (TAAR1, TAAR2, TAAR5, TAAR6, TAAR8, TAAR9) and 3 pseudogenes (TAAR3, TAAR4P, TAAR7P)
* Chimpanzee – 3 genes and 6 pseudogenes
* Mouse – 15 genes and 1 pseudogene
* Rat – 17 genes and 2 pseudogenes
* Zebrafish – 112 genes and 4 pseudogenes
* Frog – 3 genes and 0 pseudogenes
* Medaka – 25 genes and 1 pseudogenes
* Stickleback – 25 genes and 1 pseudogenes

## Human trace amine-associated receptors

Six human trace amine-associated receptors (hTAARs) – hTAAR1, hTAAR2, hTAAR5, hTAAR6, hTAAR8, and hTAAR9 – have been identified and partially characterized. The table below contains summary information from literature reviews, pharmacology databases, and supplementary primary research articles on the expression profiles, signal transduction mechanisms, ligands, and physiological functions of these receptors.
The pharmacology and molecular biology of human trace amine-associated receptors :
| TAAR subtype | Prior names | Signal transduction | Expression profile | Known or putative function in humans | Known ligands | Sources |
| hTAAR1 | TA$_1$ TAR1 | G$_s$, G$_q$, GIRKs, β-arrestin 2 | CNS: brain (widespread), spinal cord Periphery: pancreatic β-cells, stomach, duodenum, intestines, leukocytes, elsewhere | • CNS: modulation of monoamine/glutamate neurotransmission • CNS: regulation of cognitive processes & mood states • Periphery: leukocyte chemotaxis • Periphery: regulation of GI hormone release & blood glucose • Regulation of satiety & body weight | • Trace amines (e.g., tyramine, PEA, NMPEA) • Monoamine neurotransmitters (e.g., dopamine) • Amphetamine and some structural analogs | [3][13] [15][16] |
| hTAAR2 | GPR58 | G$_{olf}$, other G protein coupling unknown | CNS: brain (restricted)  Periphery: olfactory epithelium, intestines, heart, testes, leukocytes | • Periphery: leukocyte chemotaxis • Olfaction: chemoreceptor for volatile odorants | | [9][13] [15][16] [17][18] |
| TAAR3 | GPR57 | N/A | N/A | Pseudogene in humans – N/A | N/A | [12][13] [15] |
| TAAR4 | TA$_2$ | N/A | N/A | Pseudogene in humans – N/A | N/A | [12][13] [15] |
| hTAAR5 | PNR | G$_s$, G$_{olf}$, G$_q$, G$_{12/13}$ | CNS: brain (restricted), spinal cord Periphery: olfactory epithelium, intestines, testes, leukocytes | • Olfaction: chemoreceptor for volatile & foul odorants | • Agonists: trimethylamine, N,N-DMEA • Inverse agonists: 3-iodothyronamine | [9][13] [15][20] [21][22] [23] |
| hTAAR6 | TA$_4$ TAR4 | G$_{olf}$, other G protein coupling unknown | CNS: brain Periphery: olfactory epithelium, intestines, testes, leukocytes, kidneys | • Olfaction: chemoreceptor for volatile odorants | • Agonists: putrescine and cadaverine | [9][13] [15][25] |
| TAAR7 | – | N/A | N/A | Pseudogene in humans – N/A | N/A | [9][13] [15] |
| hTAAR8 | TA$_5$ GPR102 | G$_{olf}$, G$_{i/o}$ | CNS: brain Periphery: olfactory epithelium, melanocytes, stomach, intestines, heart, testes, leukocytes, kidneys, lungs, muscle, spleen | • Olfaction: chemoreceptor for volatile odorants | • Agonists: putrescine and cadaverine | [9][13] [15][27] |
| hTAAR9 | TA$_3$ TAR3 | G$_{olf}$, other G protein coupling unknown | CNS: spinal cord Periphery: olfactory epithelium, intestines, leukocytes, pituitary gland, skeletal muscle, spleen | • Olfaction: chemoreceptor for volatile odorants | • Agonist: N-Methyl piperidine (CAS: 626-67-5) | [9][13] [15][29] |
| Notes ↑ As of December 2017, the functions of hTAAR2, hTAAR5, hTAAR6, hTAAR8, and hTAAR9 in the CNS and peripheral tissues outside the olfactory epithelium have not been determined. ↑ hTAAR1 is the only TAAR subtype that is not expressed within the human olfactory epithelium. Hence, unlike all other human trace amine-associated receptors, hTAAR1 does not function as an olfactory receptor in humans. ↑ hTAAR2 is a non-functional receptor in 10–15% of Asians due to the occurrence of a single-nucleotide polymorphism involving a premature stop codon in the human TAAR2 gene. ↑ hTAAR2 has been found to be coexpressed with G$_α$ proteins, however its exact signal transduction mechanisms have not yet been established. ↑ hTAAR2 expression has been observed in the human cerebellum. 1 2 3 4 5 In humans and other animals, TAARs that are expressed in the olfactory epithelium function as olfactory receptors that detect volatile amine odorants, including certain pheromones; these TAARs putatively function as a class of pheromone receptors involved in the olfactive detection of social cues. A review of studies involving non-human animals indicated that TAARs in the olfactory epithelium can mediate attractive or aversive behavioral responses to an agonist. This review also noted that the behavioral response evoked by a TAAR can vary across species. For example, TAAR5 mediates attraction to trimethylamine in mice and aversion to trimethylamine in rats. In humans, hTAAR5 presumably mediates aversion to trimethylamine, which is known to act as an hTAAR5 agonist and to possess a foul, fishy odor that is aversive to humans; however, hTAAR5 is not the only olfactory receptor that is responsible for trimethylamine olfaction in humans. As of December 2015, hTAAR5-mediated trimethylamine aversion has not been examined in published research. ↑ hTAAR9 is a functional receptor in most individuals, but a loss-of-function mutation – specifically, a polymorphic premature stop codon – in the human TAAR9 gene occurs in 10–30% of individuals. |||||||

### Disease links and clinical significance

Ulotaront / SEP 363856 is a TAAR1 agonist in phase 3 clinical trials for schizophrenia and earlier trials for Parkinson's Disease psychosis. The medicine has obtained Breakthrough designation from the US FDA.