Non-Functional Trace Amine-Associated Receptor 1 Variants in Patients With Mental Disorders

Abstract

Background: The G protein–coupled receptor (GPCR) trace amine-associated receptor 1 (TAAR1) is expressed across brain areas involved in emotions, reward and cognition, and modulates monoaminergic and glutamatergic neurotransmissions. TAAR1 is stimulated with nanomolar affinity by 3-iodothyronamine (T1AM), an endogenous messenger considered a novel branch of thyroid hormone signaling. The human gene for TAAR1 maps to locus 6q23, within a region associated with major mental disorders. Materials and Methods: We screened a cohort of patients with major mental disorders (n = 104) and a group of healthy controls (n = 130) for TAAR1 variants. HEK293 cells were transiently transfected with: i) wild-type TAAR1 and ii) mutated TAAR1, either in homozygous or heterozygous state. Cell surface expression and Gs/adenylyl cyclase activation upon administration of β-phenylethylamine (PEA), T1AM, and RO5166017, were assessed. Results: We detected 13 missense variants in TAAR1 coding region, with a significant enrichment in patients as compared to healthy controls (11 vs. 1, 1 variant in both groups, p < 0.01). In silico analysis identified four dysfunctional variants, all in patients. Three of these—R23C, Y131C, and C263R—were functionally characterized. In cells co-transfected with wild-type and mutated TAAR1, we observed a significant reduction of cell surface expression. In heterozygosity, the three TAAR1 variants substantially dampened Gs signaling in response to PEA, and, more robustly, to T1AM. Co-stimulation with PEA and RO5166017 did not yield any improvement in Gs signaling. R23C, Y131C, and C263R are rare in the general population and map in functionally important highly conserved positions across TAAR1 orthologous and paralogous genes. Conclusions: Our findings suggest that disruptions of TAAR1 activity may be relevant to the pathophysiology of mental disorders, thereby providing a promising target for novel psychopharmacological interventions.

Therapeutic Potential of TAAR1 Agonists in Schizophrenia: Evidence from Preclinical Models and Clinical Studies

“…The TAAR family consist of 6 functional members in humans, with TAAR1 being the most studied [67,68]. All human TAAR genes cluster to a small genomic region of 108 kb located in chromosome 6q23, which has been consistently identified as a susceptibility locus for schizophrenia and affective disorders [69]. Although several groups have attempted to identify susceptibility loci for mental disorders in TAARs, none of the reports received sufficient replication and the detected variants were not genome-wide significant.…”

“…In contrast, several rare variants in TAAR genes (particularly TAAR1) have been detected in patients with mental and metabolic disorders (reviewed by Rutigliano and Zucchi) [66]. Some of the variants have demonstrated altered receptor function in vitro [69,70], warranting further assessment of naturally occurring TAAR1 variants in both brain and metabolic disorders. Endogenous TAs exert effects at targets other than TAAR1, including aminergic and non-GPRC receptors as well as transporters [65,86,97].…”

Differential Signaling Profiles of MC4R Mutations with Three Different Ligands

“…In case of reporter gene assays, the transfection included an additional 45 ng of reporter DNA per well in MEM without supplements. For the HiBiT assay, transfection was performed as described previously [67].…”

Methamphetamine Activates Trace Amine Associated Receptor 1 to Regulate Astrocyte Excitatory Amino Acid Transporter-2 via Differential CREB Phosphorylation During HIV-Associated Neurocognitive Disorders

“…Non-functional mutations in mouse TAAR1 affect METH intake, hypothermia and conditioned taste aversion (82,83). Humans possess many TAAR1 variants with sensitivity to ligands (84)(85)(86)(87). However, the effects of TAAR1 variants on signaling cascades and risk for MUD, HAND, and neuropsychological disease will need to be evaluated.…”