TAAR1

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 a primarily intracellular amine-activated and G protein-coupled receptor (GPCR) that is primarily expressed in several peripheral organs and cells (e.g., the stomach, small intestine, duodenum, and white blood cells), astrocytes, and in the intracellular milieu within the presynaptic plasma membrane (i.e., axon terminal) of monoamine neurons in the central nervous system (CNS).

TAAR1 is one of six functional human TAARs, 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.

Endogenous ligands of the TAAR1 include trace amines, monoamine neurotransmitters, and certain thyronamines. The trace amines β-phenethylamine, tyramine, tryptamine, and octopamine, the monoamine neurotransmitters dopamine and serotonin, and the thyronamine 3-iodothyronamine (3-IT) are all agonists of the TAAR1 in different species. Other endogenous agonists are also known. A variety of exogenous compounds and drugs are TAAR1 agonists as well, including various phenethylamines, amphetamines, tryptamines, and ergolines, among others. There are marked species differences in the interactions of ligands with the TAAR1, resulting in greatly differing affinities, potencies, and efficacies of TAAR1 ligands between species. Many compounds that are TAAR1 agonists in rodents are much less potent or inactive at the TAAR1 in humans.

A number of selective TAAR1 ligands have been developed, for instance the TAAR1 full agonist RO5256390, the TAAR1 partial agonist RO5263397, and the TAAR1 antagonists EPPTB and RTI-7470-44. Selective TAAR1 agonists are used in scientific research, and a few TAAR1 agonists, such as ulotaront and ralmitaront, are being developed as novel pharmaceutical drugs, for instance to treat schizophrenia and substance use disorder.

Discovery The TAAR1 was discovered in 2001 by two independent groups, Borowski et al. and Bunzow et al.. To find the genetic variants responsible for TAAR1 synthesis, they used mixtures of oligonucleotides with sequences related to G protein-coupled receptors (GPCRs) of serotonin and dopamine to discover novel DNA sequences in rat genomic DNA and cDNA, which they then amplified and cloned. The resulting sequence was not found in any database and coded for TAAR1. Further characterization of the functional role of TAAR1 and other receptors from this family was performed by other researchers including Raul Gainetdinov and his colleagues.

Structure TAAR1 shares structural similarities with the class A rhodopsin GPCR subfamily. It has 7 transmembrane domains with short N and C terminal extensions. TAAR1 is 62–96% identical with TAARs2-15, which suggests that the TAAR subfamily has recently evolved; while at the same time, the low degree of similarity between TAAR1 orthologues suggests that they are rapidly evolving. TAAR1 shares a predictive peptide motif with all other TAARs. This motif overlaps with transmembrane domain VII, and its identity is NSXXNPXX[Y,H]XXX[Y,F]XWF. TAAR1 and its homologues have ligand pocket vectors that utilize sets of 35 amino acids known to be involved directly in receptor-ligand interaction.

Gene All human TAAR genes are located on a single chromosome spanning 109 kb of human chromosome 6q23.1, 192 kb of mouse chromosome 10A4, and 216 kb of rat chromosome 1p12. Each TAAR is derived from a single exon, except for TAAR2, which is coded by two exons. The human TAAR1 gene is thought to be an intronless gene.

Tissue distribution

To date, TAAR1 has been identified and cloned in five different mammal genomes: human, mouse, rat, monkey, and chimpanzee. In rats, mRNA for TAAR1 is found at low to moderate levels in peripheral tissues like the stomach, kidney, intestines and lungs, and at low levels in the brain. Rhesus monkey Taar1 and human TAAR1 share high sequence similarity, and TAAR1 mRNA is highly expressed in the same important monoaminergic regions of both species. These regions include the dorsal and ventral caudate nucleus, putamen, substantia nigra, nucleus accumbens, ventral tegmental area, locus coeruleus, amygdala, and raphe nucleus. hTAAR1 has also been identified in human astrocytes.

Outside of the human central nervous system, hTAAR1 also occurs as an intracellular receptor and is primarily expressed in the stomach, intestines, duodenum, pancreatic , and white blood cells. In the duodenum, TAAR1 activation increases (GLP-1) and peptide YY (PYY) release; in the stomach, hTAAR1 activation has been observed to increase somatostatin (growth hormone) secretion from delta cells.

hTAAR1 is the only human trace amine-associated receptor subtype that is not expressed within the human olfactory epithelium.

Location within neurons TAAR1 is a primarily intracellular receptor expressed within the presynaptic terminal of monoamine neurons in humans and other animals. In model cell systems, hTAAR1 has extremely poor membrane expression. A method to induce hTAAR1 membrane expression has been used to study its pharmacology via a bioluminescence resonance energy transfer cAMP assay.

Because TAAR1 is an intracellular receptor in monoamine neurons, exogenous TAAR1 ligands must enter the presynaptic neuron through a membrane transport protein or be able to diffuse across the presynaptic membrane in order to reach the receptor and produce reuptake inhibition and neurotransmitter efflux. Consequently, the efficacy of a particular TAAR1 ligand in producing these effects in different monoamine neurons is a function of both its binding affinity at TAAR1 and its capacity to move across the presynaptic membrane at each type of neuron. The variability between a TAAR1 ligand's substrate affinity at the various monoamine transporters accounts for much of the difference in its capacity to produce neurotransmitter release and reuptake inhibition in different types of monoamine neurons. E.g., a TAAR1 ligand which can easily pass through the norepinephrine transporter, but not the serotonin transporter, will produce – all else equal – markedly greater TAAR1-induced effects in norepinephrine neurons as compared to serotonin neurons.

A 2016 study found that most TAAR1 was expressed in intracellular membranes near the nucleus and that 2.3% of TAAR1 was expressed at the cell surface. In addition, TAAR1 signaling via the protein kinase A (PKA) pathway was predominantly associated with cell-surface TAAR1.

TAAR1 ligands have also been found to enter neurons by transporters other than the monoamine transporters.

Receptor oligomers TAAR1 forms GPCR oligomers with monoamine autoreceptors in neurons in vivo. These and other reported TAAR1 hetero-oligomers include:

TAAR1 D2sh TAAR1 α2A TAAR1 TAAR2 [note 2] in the TAAR1- D2sh example shows that TAAR1 can be located at cell membranes, and in the case of enterochromaffin cells in the gut epithelium, TAAR1 can be activated by high doses of dietary 'trace' amines, proximal to vesicles packed with catecholamines, impacting the vagal nerve system and CNS. This raises questions about where T1AM might find TAAR1 and cause similar unexpected nerve firing. TAAR1 gene knockout in mice leads to shifts in microbial community richness and stability.

Ligands

Agonists

Endogenous

The known endogenous agonists of the TAAR1 include trace amines like β-phenethylamine (PEA), monoamine neurotransmitters like dopamine, and thyronamines like 3-iodothyronamine (T1AM).

Trace amines are endogenous amines which act as agonists at TAAR1 and are present in extracellular concentrations of 0.1–10nM in the brain, constituting less than 1% of total biogenic amines in the mammalian nervous system. Some of the human trace amines include tryptamine, phenethylamine (PEA), , , , , , , and synephrine. These share structural similarities with the three common monoamine neurotransmitters: serotonin, dopamine, and norepinephrine. Each ligand has a different potency, measured as increased cyclic AMP (cAMP) concentration after the binding event. The rank order of potency for the primary endogenous ligands at the human TAAR1 is: tyramine> β-phenethylamine> dopamine= octopamine. Tryptamine and histamine also interact with the human TAAR1 with lower potency, whereas serotonin and norepinephrine have been found to be inactive.

Thyronamines are molecular derivatives of thyroid hormone involved in endocrine system function. 3-Iodothyronamine (T1AM) is one of the most potent TAAR1 agonists yet discovered. It also interacts with a number of other targets. Unlike the monoamine neurotransmitters and trace amines, T1A is not a monoamine transporter (MAT) substrate, although it does still weakly interact with the MATs. 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.

Other endogenous TAAR1 agonists include cyclohexylamine, isoamylamine, and trimethylamine, among others.

Exogenous

2-Aminoindanes 2-Aminoindane (2-AI) – a potent TAAR1 partial or full agonist in rodents, weaker TAAR1 full agonist in humans 5-Iodo-2-aminoindane (5-IAI) – a potent TAAR1 partial or full agonist in rodents, weaker TAAR1 partial agonist in humans MDAI – a potent TAAR1 full agonist in rodents, weaker TAAR1 partial agonist in humans N-Methyl-2-AI (NM-2-AI) – a potent TAAR1 partial or full agonist in rodents, weaker TAAR1 partial agonist in humans A-77636 – an experimental dopamine agonist Amphetamines (α-methyl-β-phenethylamines) 4-Fluoroamphetamine – a potent TAAR1 partial agonist in rodents, but much less potent in humans 4-Hydroxyamphetamine – an amphetamine metabolite Amphetamine – a potent TAAR1 near-full agonist in rodents, but much less potent in humans Cathinone – weak rodent and human TAAR1 partial agonist MDA – a potent TAAR1 partial agonist in rodents, but much less potent weak partial agonist in humans MDMA – a moderate-efficacy TAAR1 partial agonist in rodents, but much less potent weak partial agonist in humans Methamphetamine – a potent TAAR1 near-full agonist in rodents, but much less potent in humans Phentermine – a weak human TAAR1 near-full agonist Selegiline (L-deprenyl) – a weak mouse TAAR1 partial agonist Solriamfetol – a wakefulness-promoting agent acting as a dual norepinephrine–dopamine reuptake inhibitor (NDRI) and human TAAR1 agonist AP163 – a TAAR1 agonist Apomorphine – a dopamine agonist and antiparkinsonian agent, potent rodent TAAR1 agonist but not in humans Asenapine – an atypical antipsychotic Chlorpromazine – a dopamine antagonist and antipsychotic Clonidine – an adrenergic agonist and antihypertensive agent, rodent and human TAAR1 agonist Cyproheptadine – a serotonin antagonist Ergolines and lysergamides Bromocriptine – a dopamine agonist and antiparkinsonian agent Dihydroergotamine – an antimigraine agent Ergometrine (ergonovine) – an obstetric drug Lisuride – a dopamine agonist and antiparkinsonian agent Lysergic acid diethylamide (LSD) – a serotonergic psychedelic and TAAR1 weak partial agonist in rodents but not in humans Metergoline – a prolactin inhibitor Fenoldopam – a dopamine agonist and antihypertensive agent Fenoterol – an adrenergic agonist Guanabenz – an adrenergic agonist and antihypertensive agent, highly potent rodent and human TAAR1 agonist Guanfacine – an adrenergic agonist and ADHD medication Idazoxan – adrenergic antagonist, potent mouse TAAR1 agonist but much weaker in humans Isoprenaline – an adrenergic agonist LK00764 – a rodent and human TAAR1 agonist LY03020 MPTP – a monoaminergic neurotoxin Naphazoline – an adrenergic agonist