Plasma .BETA.-phenylethylamine in Parkinson's Disease.

Miura, Yumiko

doi:10.2739/kurumemedj.47.267

Cited by 9 publications

(5 citation statements)

References 26 publications

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“…For human TAAR, however, ligands have been described only for TAAR1 [9,22] but not for the other five putative functional human TAAR, probably as a result of their suboptimal plasma membrane expression in heterologous cell systems [6,8]. In our study with PMN and T and B cells, the TAAR1 agonists 2-PEA, TYR, and T1AM displayed EC 50 values in a similar nanomolar range as the previously reported plasma concentrations in healthy individuals [10][11][12]. However, any amine-induced function in our study was knocked down with the same efficiency by siRNA for TAAR1 or TAAR2, despite the fact that each siRNA selectively targeted and knocked down its own complementary mRNA.…”

Section: Discussionsupporting

confidence: 79%

Biogenic amines activate blood leukocytes via trace amine-associated receptors TAAR1 and TAAR2

Babušytė

Kotthoff

Fiedler

et al. 2013

Journal of Leukocyte Biology

110

148

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Certain biogenic amines, such as 2-PEA, TYR, or T1AM, modulate blood pressure, cardiac function, brain monoaminergic systems, and olfaction-guided behavior by specifically interacting with members of a group of rhodopsin-like receptors, TAAR. A receptor that is absent from olfactory epithelia but had long been identified in the brain and a variety of peripheral tissues, TAAR1 has been found recently in blood B cells, suggesting a functional role of TAAR1 in these cells. With the present study, we have set out to clarify the expression and functional roles of TAAR in different isolated human blood leukocyte types. Here, we report the functional expression of TAAR1 and its closest relative TAAR2 in blood PMN and T and B cells. Both receptors are coexpressed in a subpopulation of PMN, where they are necessary for the chemosensory migration toward the TAAR1 ligands 2-PEA, TYR, and T1AM, with EC50 values of 0.43 ± 0.05 nM, 0.52 ± 0.05 nM, and 0.25 ± 0.04 nM, respectively. The same amines, with similar potencies, triggered cytokine or Ig secretion, in purified blood T or B cells, respectively. Notably, 2-PEA regulated mRNA expression of 28 T cell function-related genes, above all of the CCL5. In siRNA-guided experiments, TAAR1 and TAAR2 proved to be necessary for amine-induced blood leukocyte functions. In summary, our results demonstrate that biogenic amines potently regulate blood cell functions via TAAR1 and TAAR2 and open the perspective of their specific pharmacological modulation.

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Section: Discussionsupporting

confidence: 79%

Biogenic amines activate blood leukocytes via trace amine-associated receptors TAAR1 and TAAR2

Babušytė

Kotthoff

Fiedler

et al. 2013

Journal of Leukocyte Biology

110

148

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“…In a similar percentage of PMN, 2-PEA or saccharin activated chemotactic migration, which was largely attenuated by PTX or by siRNA knockdown of a-gustducin, suggesting a role of at least G i -type proteins in the activation of chemotactic migration by physiologic concentrations of these foodborne chemosensory receptor agonists. Indeed, the plasma concentrations of 2-PEA have been published to be in the nanomolar range [79], and plasma concentrations for saccharin were published to be in the micromolar range after typical sweetener application [11,80]. Consequently, olfactory and taste receptors, as well as their signaling components, may be considered markers for, on average, 40-60% of circulating PMN, constituting a chemosensory-type subset of PMN, which remains to be characterized by future experiments, for instance, by use of receptor-specific antibodies suitable for use in flow cytometry.…”

Section: Discussionmentioning

confidence: 99%

Class I odorant receptors, TAS1R and TAS2R taste receptors, are markers for subpopulations of circulating leukocytes

Malki

Fiedler

Fricke

et al. 2015

Journal of Leukocyte Biology

125

107

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Our cellular immune system has to cope constantly with foodborne substances that enter the bloodstream postprandially. Here, they may activate leukocytes via specific but yet mostly unknown receptors. Ectopic RNA expression out of gene families of chemosensory receptors, i.e., the ∼400 ORs, ∼25 TAS2R bitter-taste receptors, and the TAS1R umami- and sweet-taste receptor dimers by which we typically detect foodborne substances, has been reported in a variety of peripheral tissues unrelated to olfaction or taste. In the present study, we have now discovered, by gene-specific RT-PCR experiments, the mRNA expression of most of the Class I ORs (TAS1R) and TAS2R in 5 different types of blood leukocytes. Surprisingly, we did not detect Class II OR mRNA. By RT-qPCR, we show the mRNA expression of human chemosensory receptors and their cow orthologs in PMN, thus suggesting an evolutionary concept. By immunocytochemistry, we demonstrate that some olfactory and taste receptors are expressed, on average, in 40-60% of PMN and T or B cells and largely coexpress in the same subpopulation of PMN. The mRNA expression and the size of subpopulations expressing certain chemosensory receptors varied largely among individual blood samples, suggesting a regulated expression of olfactory and taste receptors in these cells. Moreover, we show mRNA expression of their downstream signaling molecules and demonstrate that PTX abolishes saccharin- or 2-PEA-induced PMN chemotactic migration, indicating a role for Gi-type proteins. In summary, our data suggest "chemosensory"-type subpopulations of circulating leukocytes.

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“…Substrates of human AOC3 also include arylamines and catecholamines, with the non-physiologic benzylamine exhibiting a low K m value (84.5 uM) and the highest k cat /K m . Adding an extra methyl group to benzylamine results in an approximately 25-fold increase in K m and a decrease in k cat /K m of approximately two orders of magnitude, indicating that the endogenous phenethylamine [48] is an unlikely substrate.…”

Section: Resultsmentioning

confidence: 99%

Implication for Functions of the Ectopic Adipocyte Copper Amine Oxidase (AOC3) from Purified Enzyme and Cell-Based Kinetic Studies

2012

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AOC3 is highly expressed in adipocytes and smooth muscle cells, but its function in these cells is currently unknown. The in vivo substrate(s) of AOC3 is/are also unknown, but could provide an invaluable clue to the enzyme's function. Expression of untagged, soluble human AOC3 in insect cells provides a relatively simple means of obtaining pure enzyme. Characterization of enzyme indicates a 6% titer for the active site 2,4,5-trihydroxyphenylalanine quinone (TPQ) cofactor and corrected k cat values as high as 7 s−1. Substrate kinetic profiling shows that the enzyme accepts a variety of primary amines with different chemical features, including nonphysiological branched-chain and aliphatic amines, with measured k cat/Km values between 102 and 104 M−1 s−1. Km(O2) approximates the partial pressure of oxygen found in the interstitial space. Comparison of the properties of purified murine to human enzyme indicates k cat/Km values that are within 3 to 4-fold, with the exception of methylamine and aminoacetone that are ca. 10-fold more active with human AOC3. With drug development efforts investigating AOC3 as an anti-inflammatory target, these studies suggest that caution is called for when screening the efficacy of inhibitors designed against human enzymes in non-transgenic mouse models. Differentiated murine 3T3-L1 adipocytes show a uniform distribution of AOC3 on the cell surface and whole cell Km values that are reasonably close to values measured using purified enzymes. The latter studies support a relevance of the kinetic parameters measured with isolated AOC3 variants to adipocyte function. From our studies, a number of possible substrates with relatively high k cat/Km have been discovered, including dopamine and cysteamine, which may implicate a role for adipocyte AOC3 in insulin-signaling and fatty acid metabolism, respectively. Finally, the demonstrated AOC3 turnover of primary amines that are non-native to human tissue suggests possible roles for the adipocyte enzyme in subcutaneous bacterial infiltration and obesity.

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Plasma .BETA.-phenylethylamine in Parkinson's Disease.

Cited by 9 publications

References 26 publications

Biogenic amines activate blood leukocytes via trace amine-associated receptors TAAR1 and TAAR2

Biogenic amines activate blood leukocytes via trace amine-associated receptors TAAR1 and TAAR2

Class I odorant receptors, TAS1R and TAS2R taste receptors, are markers for subpopulations of circulating leukocytes

Implication for Functions of the Ectopic Adipocyte Copper Amine Oxidase (AOC3) from Purified Enzyme and Cell-Based Kinetic Studies

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