Striatal Tyrosine Hydroxylase Is Stimulated via TAAR1 by 3-Iodothyronamine, But Not by Tyramine or β-Phenylethylamine

Abstract

The trace amine-associated receptor 1 (TAAR1) is expressed by dopaminergic neurons, but the precise influence of trace amines upon their functional activity remains to be fully characterized. Here, we examined the regulation of tyrosine hydroxylase (TH) by tyramine and beta-phenylethylamine (β-PEA) compared to 3-iodothyronamine (T1AM). Immunoblotting and amperometry were performed in dorsal striatal slices from wild-type (WT) and TAAR1 knockout (KO) mice. T1AM increased TH phosphorylation at both Ser19 and Ser40, actions that should promote functional activity of TH. Indeed, HPLC data revealed higher rates of L-dihydroxyphenylalanine (DOPA) accumulation in WT animals treated with T1AM after the administration of a DOPA decarboxylase inhibitor. These effects were abolished both in TAAR1 KO mice and by the TAAR1 antagonist, EPPTB. Further, they were specific inasmuch as Ser845 phosphorylation of the post-synaptic GluA1 AMPAR subunit was unaffected. The effects of T1AM on TH phosphorylation at both Ser19 (CamKII-targeted), and Ser40 (PKA-phosphorylated) were inhibited by KN-92 and H-89, inhibitors of CamKII and PKA respectively. Conversely, there was no effect of an EPAC analog, 8-CPT-2Me-cAMP, on TH phosphorylation. In line with these data, T1AM increased evoked striatal dopamine release in TAAR1 WT mice, an action blunted in TAAR1 KO mice and by EPPTB. Mass spectrometry imaging revealed no endogenous T1AM in the brain, but detected T1AM in several brain areas upon systemic administration in both WT and TAAR1 KO mice. In contrast to T1AM, tyramine decreased the phosphorylation of Ser40-TH, while increasing Ser845-GluA1 phosphorylation, actions that were not blocked in TAAR1 KO mice. Likewise, β-PEA reduced Ser40-TH and tended to promote Ser845-GluA1 phosphorylation. The D1 receptor antagonist SCH23390 blocked tyramine-induced Ser845-GluA1 phosphorylation, but had no effect on tyramine- or β-PEA-induced Ser40-TH phosphorylation. In conclusion, by intracellular cascades involving CaMKII and PKA, T1AM, but not tyramine and β-PEA, acts via TAAR1 to promote the phosphorylation and functional activity of TH in the dorsal striatum, supporting a modulatory influence on dopamine transmission.

TAAR1-Dependent and -Independent Actions of Tyramine in Interaction With Glutamate Underlie Central Effects of Monoamine Oxidase Inhibition

“…We propose that TAAR1 is strategically positioned intracellularly to sense increases of tyramine concentration and suppress the further and potentially disruptive accumulation of this TA. Further supporting this hypothesis, we have previously found that TAAR1 increases TH activity through phosphorylation of serine 19 and 40 (16). In the literature, a heightened firing rate of DA neurons in TAAR1-KO mice is reported (24,(26)(27)(28), which is consistent with the accumulation of tyramine upon MAOI found here.…”

“…interestingly, this can occur with the TA localized intracellular rather than on the surface membrane (16)(17)(18)(19). In addition to binding TAs, such as tyramine, TAAR1 is activated by several classes of psychoactive agents employed for both therapeutic and recreational purposes, notably amphetamine, methamphetamine and methylenedioxymethamphetamine (MDMA) (6,20).…”

N-(3-Ethoxy-phenyl)-4-pyrrolidin-1-yl-3-trifluoromethyl-benzamide (EPPTB) prevents 3-iodothyronamine (T1AM)-induced neuroprotection against kainic acid toxicity

“…From the pharmacodynamics point of view, T1AM is indicated as a multi-targets molecule able to interact at several G-protein coupled receptors, including the ex-orphan trace amine associated receptor isoform 1 (TAAR1). T1AM is considered an agonist of TAAR1 (Scanlan et al, 2004) but also a biased agonist at dopaminergic type 2 (D2R; Zhang et al, 2018) and serotoninergic type 1B (5HT1BR; Bräunig et al, 2018) receptors which can be found heterodimerized with TAAR1.Indeed, if we exclude the effect of T1AM on the reduction of spinal cord injury (Lv et al, 2018), few of the pharmacological effects reported for T1AM may be attributed unequivocally to TAAR1 activation. Overall, irrespective of which is the plasma membrane receptor recognized, T1AM may also generate, inside cells TA1, a metabolite endowed of an its own signaling capacity and pharmacological activities.…”

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

“…In detail, T1AM, but not trace amines, was found to increase the activity of the tyrosine hydroxylase in the dorsal striatum, through a TAAR1-dependent phosphorylation of key regulatory sites (Ser19, Ser31, and Ser40). Therefore, disrupting the T1AM-TAAR1 interplay could specifically affect dopamine release, in brain areas involved in mood and psychotic disorders (Zhang et al, 2018a).…”