TAAR1 Regulates Purinergic-induced TNF Secretion from Peripheral, But Not CNS-resident, Macrophages

Barnes, David A.; Hoener, Marius C.; Moore, Craig S.; Berry, Mark D.

doi:10.1007/s11481-022-10053-8

Cited by 4 publications

(6 citation statements)

References 41 publications

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“…To elucidate the role of TAAR1 in olfactory dysfunction in PD, some limitations in our study should be solved by further studies since TAAR1 might play multiple roles in different cells. It has been reported that the functions of TAAR1 in glial cells and neurons may differ or even be diametrically opposed [41,65,66]; we did not detect changes in TAAR1 within microglia. Due to these reasons, the link between TAAR1 and PD pathology is still not clear in the present study.…”

Section: Discussioncontrasting

confidence: 77%

“…However, we obtained some new findings, which might be a clue for olfactory dysfunction in PD. It has been reported that TAAR1 is expressed in immune cells, including macrophages [37,38], astrocytes [39], and microglia [40], where it plays roles in inflammation [41]. TAAR1 has been identified as a regulator of apoptosis, exerting influence through the modulation of anti-apoptotic protein Bcl-2 levels [42].…”

Section: Introductionmentioning

confidence: 99%

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A Pilot Study on a Possible Mechanism behind Olfactory Dysfunction in Parkinson’s Disease: The Association of TAAR1 Downregulation with Neuronal Loss and Inflammation along Olfactory Pathway

Zhang,

Hong,

Shi

et al. 2024

Brain Sciences

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Parkinson’s disease (PD) is characterized not only by motor symptoms but also by non-motor dysfunctions, such as olfactory impairment; the cause is not fully understood. Our study suggests that neuronal loss and inflammation in brain regions along the olfactory pathway, such as the olfactory bulb (OB) and the piriform cortex (PC), may contribute to olfactory dysfunction in PD mice, which might be related to the downregulation of the trace amine-associated receptor 1 (TAAR1) in these areas. In the striatum, although only a decrease in mRNA level, but not in protein level, of TAAR1 was detected, bioinformatic analyses substantiated its correlation with PD. Moreover, we discovered that neuronal death and inflammation in the OB and the PC in PD mice might be regulated by TAAR through the Bcl-2/caspase3 pathway. This manifested as a decrease of anti-apoptotic protein Bcl-2 and an increase of the pro-apoptotic protein cleaved caspase3, or through regulating astrocytes activity, manifested as the increase of TAAR1 in astrocytes, which might lead to the decreased clearance of glutamate and consequent neurotoxicity. In summary, we have identified a possible mechanism to elucidate the olfactory dysfunction in PD, positing neuronal damage and inflammation due to apoptosis and astrocyte activity along the olfactory pathway in conjunction with the downregulation of TAAR1.

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Section: Discussioncontrasting

confidence: 77%

Section: Introductionmentioning

confidence: 99%

A Pilot Study on a Possible Mechanism behind Olfactory Dysfunction in Parkinson’s Disease: The Association of TAAR1 Downregulation with Neuronal Loss and Inflammation along Olfactory Pathway

Zhang,

Hong,

Shi

et al. 2024

Brain Sciences

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“…Furthermore, inn mouse bone marrow macrophages, selective TAAR agonist RO5256390 inhibited tumor necrosis factor (TNF) synthesis following ATP stimulation. However, this TAAR1 agonist did not affect the ADP-induced secretion of TNF and IL-6 in microglial cells in the mouse CNS [41].…”

Section: Monocytes and Macrophagesmentioning

confidence: 75%

A role of trace amine-associated receptors in the immune system function

Moiseenko,

Apryatina,

Gainetdinov

et al. 2024

Preprint

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Trace amines are a separate, independent group of biogenic amines, close in structure to classical monoamine neurotransmitters such as dopamine, serotonin and norepinephrine. G protein-coupled Trace Amine-Associated Receptors (TAAR) are mostly investigated for their involvement in the pathogenesis of neuropsychiatric disorders, but expression of TAAR family receptors is observed also in various populations of cells of the immune system. The review is focused on the basic information on the interaction of trace amines and their receptors with cells of the general immune system of humans and other mammals, as well as on data on TAARs role in the function of individual populations of myeloid and lymphoid cells. With further research on the regulatory role of the trace amine system in the pathogenesis of the immune response and determination of the biological mechanisms for their action it would be possible to develop new methods for treating diseases related to immune system dysfunctions.

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“…PLS regression was performed on these two reduced data matrices, and the results were obtained in terms of predictive ability of the biological data (TAAR1 pKi and α 2 pKi). Regarding test set compounds, the predictive ability of the two models A and B was expressed as r 2 pred by applying the following equation Equation ( 4):…”

Section: Qsar Analysesmentioning

confidence: 99%

“…Trace amine-associated receptor 1 (TAAR1) is a promising target for the development of innovative therapies for many diseases, in virtue of its wide distribution in the brain and in diverse peripheral tissues [1][2][3][4][5]. TAAR1 is responsive to a class of biogenic compounds called trace amines (TAs), such as tyramine (TYR), β-phenylethylamine (β-PEA), and 3iodothyronamine (T1AM), whose dysregulation was correlated to the etiology of various diseases, like schizophrenia, depression, attention deficit hyperactivity disorder, substance abuse, metabolic syndrome, and Parkinson's disease [3,[6][7][8][9][10][11].…”

Section: Introductionmentioning

confidence: 99%

Discovery of Guanfacine as a Novel TAAR1 Agonist: A Combination Strategy through Molecular Modeling Studies and Biological Assays

Cichero,

Francesconi,

Casini

et al. 2023

Pharmaceuticals

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Trace amine-associated receptor 1 (TAAR1) is an attractive target for the design of innovative drugs to be applied in diverse pharmacological settings. Due to a non-negligible structural similarity with endogenous ligands, most of the agonists developed so far resulted in being affected by a low selectivity for TAAR1 with respect to other monoaminergic G protein-coupled receptors, like the adrenoreceptors. This study utilized comparative molecular docking studies and quantitative–structure activity relationship (QSAR) analyses to unveil key structural differences between TAAR1 and alpha2-adrenoreceptor (α2-ADR), with the aim to design novel TAAR1 agonists characterized by a higher selectivity profile and reduced off-target effects. While the presence of hydrophobic motives is encouraged towards both the two receptors, the introduction of polar/positively charged groups and the ligand conformation deeply affect the TAAR1 or α2-ADR putative selectivity. These computational methods allowed the identification of the α2A-ADR agonist guanfacine as an attractive TAAR1-targeting lead compound, demonstrating nanomolar activity in vitro. In vivo exploration of the efficacy of guanfacine showed that it is able to decrease the locomotor activity of dopamine transporter knockout (DAT-KO) rats. Therefore, guanfacine can be considered as an interesting template molecule worthy of structural optimization. The dual activity of guanfacine on both α2-ADR and TAAR1 signaling and the related crosstalk between the two pathways will deserve more in-depth investigation.

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TAAR1 Regulates Purinergic-induced TNF Secretion from Peripheral, But Not CNS-resident, Macrophages

Cited by 4 publications

References 41 publications

A Pilot Study on a Possible Mechanism behind Olfactory Dysfunction in Parkinson’s Disease: The Association of TAAR1 Downregulation with Neuronal Loss and Inflammation along Olfactory Pathway

A Pilot Study on a Possible Mechanism behind Olfactory Dysfunction in Parkinson’s Disease: The Association of TAAR1 Downregulation with Neuronal Loss and Inflammation along Olfactory Pathway

A role of trace amine-associated receptors in the immune system function

Discovery of Guanfacine as a Novel TAAR1 Agonist: A Combination Strategy through Molecular Modeling Studies and Biological Assays

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