T1AM has been found to produce TAAR1-dependenttyrosine hydroxylase (TH)phosphorylation in mousedorsal striatumslices.[10][6] This phosphorylation would be expected to promote thefunctional activity of TH.[10][6] Accordingly, higher rates ofL-DOPA accumulation were observed after administration of T1AM in mice treated with aDOPA decarboxylase inhibitor.[10][6] The preceding effects were absent with TAAR1knockout mice or with the TAAR1antagonistEPPTB.[6] In addition, T1AM-mediated TH phosphorylation appeared to be mediated byCaMKII andprotein kinase A (PKA) signaling.[10][6] T1AM was also found to increase electrically evokeddopamine release in striatal slices, which was blunted in TAAR1 knockout mice and in mice treated with EPPTB, indicating partial mediation by the TAAR1.[6] In contrast to T1AM, thetrace aminesβ-phenethylamine andtyramine reduced TH phosphorylation, which was independent of the TAAR1, and hence do not appear to augment TH functional activity.[10][6]
^Scanlan T, Suchland K, Hart M, Chiellini G, Huang Y, Kruzich P, Frascarelli S, Crossley D, Bunzow J, Ronca-Testoni S, Lin E, Hatton D, Zucchi R, Grandy D (2004). "3-Iodothyronamine is an endogenous and rapid-acting derivative of thyroid hormone".Nat. Med.10 (6):638–42.doi:10.1038/nm1051.PMID15146179.S2CID2389946.
^Hart M, Suchland K, Miyakawa M, Bunzow J, Grandy D, Scanlan T (2006). "Trace amine-associated receptor agonists: synthesis and evaluation of thyronamines and related analogues".J. Med. Chem.49 (3):1101–12.doi:10.1021/jm0505718.PMID16451074.
^abWu SY, Green WL, Huang WS, Hays MT, Chopra IJ (2005). "Alternate Pathways of Thyroid Hormone Metabolism".Thyroid.15 (8):943–958.doi:10.1089/thy.2005.15.943.PMID16131336.
^abKhan MZ, Nawaz W (October 2016). "The emerging roles of human trace amines and human trace amine-associated receptors (hTAARs) in central nervous system".Biomed Pharmacother.83:439–449.doi:10.1016/j.biopha.2016.07.002.PMID27424325.
^abcdefghZhang X, Mantas I, Alvarsson A, Yoshitake T, Shariatgorji M, Pereira M, Nilsson A, Kehr J, Andrén PE, Millan MJ, Chergui K, Svenningsson P (2018)."Striatal Tyrosine Hydroxylase Is Stimulated via TAAR1 by 3-Iodothyronamine, But Not by Tyramine or β-Phenylethylamine".Front Pharmacol.9: 166.doi:10.3389/fphar.2018.00166.PMC5837966.PMID29545750.In this study, we investigated the action of T1AM at TAAR1 on dopaminergic terminals as compared to those of TAs. However, T1AM is also known to be an agonist of TAAR5 (Dinter et al., 2015c). Moreover, the β-phenylethylamine-like structure affords T1AM the ability to bind with various members of GPCR superfamily and ion channels (Chiellini et al., 2017; Khajavi et al., 2017). It is indeed claimed that T1AM interacts with α2a adrenergic receptors, β2-adrenergic receptors and muscarinic receptors (Kleinau et al., 2011; Dinter et al., 2015a,b; Laurino et al., 2016, 2017). Notably, outside the CNS, T1AM has been found to differentially regulate insulin secretion through actions at TAAR1 and α2a adrenergic receptor (Chiellini et al., 2017; Lehmphul et al., 2017). Hence, despite blockade of the actions of T1AM in KO mice and by pharmacological antagonist, the possibility that it exerts actions via other mechanisms should not be excluded.
^abcdeHalff EF, Rutigliano G, Garcia-Hidalgo A, Howes OD (January 2023)."Trace amine-associated receptor 1 (TAAR1) agonism as a new treatment strategy for schizophrenia and related disorders".Trends Neurosci.46 (1):60–74.doi:10.1016/j.tins.2022.10.010.PMID36369028.One way in which TAAR1 regulates presynaptic dopamine function is by modulating phosphorylation levels of tyrosine hydroxylase (TH), the rate-limiting enzyme for dopamine synthesis [59]. TH phosphorylation on serine (Ser) residues Ser19 [calmodulin-dependent protein kinase II (CaMKII)-targeted], Ser31 and Ser40 (PKA-targeted) determines its activity, and Ser40 phosphorylation is thought to be the main contributor to increasing TH activity and consequently dopamine production [60,61]. [...] TAAR1-KO mice display increased levels of phosphorylated TH at all three sites as well as elevated TH activity in the striatum, despite no change in overall TH protein or mRNA levels in this region [41]. [...] The TAs tyramine and PEA decrease Ser40 phosphorylation in mouse dorsal striatum, whereas 3-iodothyronamine (T1AM) increases TH phosphorylation at Ser19 and Ser40, as well as the production of the dopamine precursor l-dihydroxyphenylalanine (l-DOPA) [63]. Endogenous T1AM, however, is only found in the periphery, and its role in TAAR1 function in the brain is therefore unclear [63]. The TAAR1 antagonist EPPTB reduces CaMKII activity in the nucleus accumbens (NAc), but TH phosphorylation was not investigated in this study, and it therefore remains unclear what effect antagonism has on TH [64].
^Piehl S, Hoefig CS, Scanlan TS, Köhrle J (February 2011). "Thyronamines--past, present, and future".Endocr Rev.32 (1):64–80.doi:10.1210/er.2009-0040.PMID20880963.Intraperitoneal or icv injection of low doses of 3-T1AM (4 and 1.2 mol/kg body weight, respectively) into rats or mice caused a significant increase in food intake without affecting oxygen consumption and locomotor activity. However, at high 3-T1AM doses (50 mg/kg body weight, 127 mol), the authors confirmed the previously reported reduction of oxygen consumption and locomotor activity (3).
^Dhillo WS, Bewick GA, White NE, Gardiner JV, Thompson EL, Bataveljic A, Murphy KG, Roy D, Patel NA, Scutt JN, Armstrong A, Ghatei MA, Bloom SR (March 2009). "The thyroid hormone derivative 3-iodothyronamine increases food intake in rodents".Diabetes Obes Metab.11 (3):251–260.doi:10.1111/j.1463-1326.2008.00935.x.PMID18671794.
Notes: (1) TAAR1 activity of ligands varies significantly between species. Some agents that are TAAR1 ligands in some species are not in other species. This navbox includes all TAAR1 ligands regardless of species. (2) See the individual pages for references, as well as theList of trace amines,TAAR, andTAAR1 pages.See also:Receptor/signaling modulators
