Trace amine-associated receptor 1 as a monoaminergic modulator in brain

Abstract

Brain monoaminergic systems play critical roles in mood, cognition, emotion, reward, learning and attention, and aberrance in brain monoaminergic activity is associated with a variety of neuropsychiatric disorders/diseases. The present commentary focuses on trace amine-associated receptor 1 (TAAR1) and its potential regulatory roles in brain monoaminergic systems. TAAR1 was discovered in 2001 and has been established to be a G-protein-coupled receptor signaling through the cAMP pathway. This receptor is activated by a broad spectrum of agonists, although there are notable species differences in ligand efficacy and potency. TAAR1 is expressed and widely distributed in brain monoaminergic systems and co-localized with the dopamine transporter in a subset of dopaminergic neurons in rhesus monkey and mouse brain substantia nigra. TAAR1 activation by the common biogenic amines, the trace amine beta-phenylethylamine and methamphetamine alters the monoamine transporter function in both mouse and rhesus monkey brain synaptosomes, suggesting a modulatory role for this receptor in the presynaptic regulation of monoaminergic activity. However, little is known about other functional roles of TAAR1 in the brain. With a purpose to promote further studies on this receptor, we herein discuss the recent findings that provide insights into the functional significance and biological relevance of this receptor as a modulator in brain monoaminergic systems.

Fig. 1

TAAR1: from gene to protein. (A) Chromosomal localization of TAAR genes in human. The TAAR1 gene along with the genes for other TAAR members is located on the chromosomal region of 6q23.1. The boxes indicate the positions of the genes but the width of the boxes is not representative of the length of the respective coding sequences. Arrows on top of the boxes indicate the reading orientation of the TAAR genes. (B) Analysis of amino acid sequences of TAAR1 from different species. The Identity (%) represents the percentage values defined as the result of the amino acids identical to human TAAR1 divided by the total amino acids numerically. Note the high Identity (%) among primates and the large divergence between primates and rodents. (C) Comparison of rhesus and rat TAAR1 to human TAAR1 by domains. The number of the amino acids identical to human TAAR1 (I) and the total amino acids (T) and the percentage values of I/T are shown.

Fig. 2

Brain monoaminergic systems include the dopaminergic system, the noradrenergic system and the serotonergic system. (A) The dopaminergic system refers to the brain regions that dopaminergic neurons originate from and project to and include four major pathways. The mesocortical pathway runs from the ventral tegmental area to prefrontal cortex, the mesolimbic pathway runs from the ventral tegmental area to limbic nuclei (nucleus accumbens, amygdala, hippocampus), the nigrostriatal pathway runs from the substantia nigra to the striatum (caudate and putamen), and the tuberoinfundibular pathway runs from the arcuate nucleus in the mediobasal hypothalamus to the median eminence. (B) The noradrenergic system comprises the brain regions that the noradrenergic neurons reside in and extend to. Most of the noradrenergic neurons reside in the locus ceruleus and project to various distant brain areas. (C) The serotonergic system consists of the brain regions that the serotonergic neurons start from and project to. Most of the serotonergic neurons start from the raphe nuclei and project to various distant brain areas.

Fig. 3

Activation of rhesus monkey TAAR1 and the ligands. (A) Rhesus monkey TAAR1 (rhTAAR1) activation by different ligands. Reporter-transfected HEK293 cells with or without rhTAAR1 expression (labeled as rhTAAR1 and HEK, respectively) were treated with 10 µM of each drug for 18 h, and the cAMP production following drug treatment was determined by measurement of the expression level of CRE-Luc (a cAMP sensitive reporter). Data shown are values of mean ± SEM for three independent experiments performed in triplicate, ** p < 0.01. See [9] for detail. (B) Structure of TAAR1 agonists.

Fig. 4

Schematic model for monoamine transporter regulation by receptors. TAAR1 and monoamine autoreceptors (AR) are located in presynaptic monoaminergic neurons and are implicated in monoamine transporter (MAT) regulation. Common biogenic amines regulate monoamine transporter function by interaction with both TAAR1 and the specific autoreceptors, but trace amines and psychostimulant amphetamines only interact with TAAR1. Monoamine autoreceptor inhibitors block the autoreceptor signaling and consequently silence its influence on the monoamine transporter.