l-DOPA and Its Receptor GPR143: Implications for Pathogenesis and Therapy in Parkinson’s Disease

Goshima, Yoshio; Masukawa, Daiki; Kasahara, Yuka; Hashimoto, Tatsuo

doi:10.3389/fphar.2019.01119

Cited by 27 publications

(27 citation statements)

References 69 publications

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“…Some strong arguments support the idea that L-DOPA itself can be a neurotransmitter [99][100][101]. Numerous groups of neurons express tyrosine hydroxylase without expressing the AADC while several cells can express AADC without tyrosine hydroxylase [102,103].…”

Section: L-dopa Its Own False Neurotransmitter?mentioning

confidence: 99%

“…L-DOPA has an affinity in the micromolar range for GPR143, which promotes cytosolic Ca 2+ enhancement upon L-DOPA stimulation in the retina [107]. GPR143 has a widespread distribution and could therefore mediate some of the actions of exogenous L-DOPA [99], at least at moderate doses. Thus, it is not a clear "false neurotransmitter" situation as L-DOPA would be one natural ligand of this receptor.…”

Section: L-dopa Its Own False Neurotransmitter?mentioning

confidence: 99%

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L-DOPA in Parkinson’s Disease: Looking at the “False” Neurotransmitters and Their Meaning

Chagraoui

Boulain

Juvin

et al. 2019

IJMS

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L-3,4-dihydroxyphenylalanine (L-DOPA) has been successfully used in the treatment of Parkinson’s disease (PD) for more than 50 years. It fulfilled the criteria to cross the blood–brain barrier and counteract the biochemical defect of dopamine (DA). It remarkably worked after some adjustments in line with the initial hypothesis, leaving a poor place to the plethora of mechanisms involving other neurotransmitters or mechanisms of action beyond newly synthesized DA itself. Yet, its mechanism of action is far from clear. It involves numerous distinct cell populations and does not mimic the mechanism of action of dopaminergic agonists. L-DOPA-derived DA is mainly released by serotonergic neurons as a false neurotransmitter, and serotonergic neurons are involved in L-DOPA-induced dyskinesia. The brain pattern and magnitude of DA extracellular levels together with this status of false neurotransmitters suggest that the striatal effects of DA via this mechanism would be minimal. Other metabolic products coming from newly formed DA or through the metabolism of L-DOPA itself could be involved. These compounds can be trace amines and derivatives. They could accumulate within the terminals of the remaining monoaminergic neurons. These “false neurotransmitters,” also known for some of them as inducing an “amphetamine-like” mechanism, could reduce the content of biogenic amines in terminals of monoaminergic neurons, thereby impairing the exocytotic process of monoamines including L-DOPA-induced DA extracellular outflow. The aim of this review is to present the mechanism of action of L-DOPA with a specific attention to “false neurotransmission.”

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Section: L-dopa Its Own False Neurotransmitter?mentioning

confidence: 99%

Section: L-dopa Its Own False Neurotransmitter?mentioning

confidence: 99%

L-DOPA in Parkinson’s Disease: Looking at the “False” Neurotransmitters and Their Meaning

Chagraoui

Boulain

Juvin

et al. 2019

IJMS

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“…In fact, L-Dopa was reported to have binding activity for the gene product of ocular albinism 1 (OA1), GPR143, a G protein-coupled receptor (GPCR). Moreover, L-Dopa induced intracellular Ca2 + response in cell lines that express GPR143 (55). While GPR143 is expressed in the central and peripheral nervous system, its expression in the anterior pituitary has not been explored yet.…”

Section: Accepted Articlementioning

confidence: 99%

“…All rights reserved Although the conclusions that can be drawn from the experiments carried out with cell lines are limited, our results suggest that corticotrophs could exert a paracrine function producing DA and contributing in this way to the inhibition of PRL secretion. The role of L-Dopa in apoptosis and survival of dopaminergic neurons has been widely studied (55)(56)(57)(58)(59)(60)(61), but such effects remain unexplored in corticotrophs. Based on this premise, we investigated the effect of L-Dopa in apoptosis and proliferation of AtT20 cells.…”

Section: Accepted Articlementioning

confidence: 99%

Anterior pituitary gland synthesises dopamine from l‐3,4‐dihydroxyphenylalanine (l‐dopa)

Orrillo

Dios

Asad

et al. 2020

J Neuroendocrinology

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Prolactin (PRL) is a hormone principally secreted by lactotrophs of the anterior pituitary gland. Although the synthesis and exocytosis of this hormone are mainly under the regulation of hypothalamic dopamine (DA), the possibility that the anterior pituitary synthesizes this catecholamine remains unclear. In this study, our aim was to determine if the anterior pituitary produces DA from the precursor L-Dopa. To this purpose, we studied the expression of aromatic L-amino acid decarboxylase (AADC) enzyme and the transporter VMAT2 in the anterior pituitary, AtT20 and GH3 cells by immunofluorescence and western blot. Moreover, we investigated the production of DA Accepted Article This article is protected by copyright. All rights reserved from L-Dopa and its release in vitro. Then, we explored the effects of L-Dopa in the secretion of PRL from anterior pituitary fragments. We observed that the anterior pituitary, AtT20 and GH3 cells express both AADC and VMAT2. Next, we detected an increase in DA content after anterior pituitary fragments were incubated with L-Dopa. Also, the presence of L-Dopa increased DA levels in incubation media and reduced PRL secretion. Likewise, the content of cellular DA increased after AtT20 cells were incubated with L-Dopa. In addition, L-Dopa reduced CRH-stimulated ACTH release from these cells after AADC activity was inhibited by NSD-1015. Moreover, DA formation from L-Dopa increased apoptosis and decreased proliferation. However, in the presence of NSD-1015, L-Dopa decreased apoptosis and increased proliferation rates. These results suggest that the anterior pituitary synthesizes DA from L-Dopa by AADC and this catecholamine can be released from this gland contributing to the control of PRL secretion. In addition, our results suggest that L-Dopa exerts direct actions independently from its metabolization to DA.

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“…L-Dopa (l-3,4 dihydroxyphenylalanine) is the precursor for Dopamine. Although L-Dopa itself is a neurotransmitter/modulator with receptors in the central and peripheral nervous system [5], its role as a signaling molecule per se in inter-kingdom communication is unclear. Mutualistic bacteria have been found responding to L-Dopa variation, e.g., Enterobacteriaceae and Pseudomonadaceae increase their growth in-vitro when supplemented with L-Dopa [6].…”

Section: Introductionmentioning

confidence: 99%

Microbiota-dependent and independent production of L-dopa in the gut of Daphnia magna

El-Shehawy

Luecke-Johansson

Ribbenstedt

et al. 2021

Preprint

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The host-microbiome interactions are essential for the physiological and ecological performance of the host, yet these interactions are challenging to identify. Neurotransmitters are commonly implicated in these interactions, but we know very little about the mechanisms of their involvement, especially in invertebrates. Here, we report a peripheral Catecholamine (CA) pathway involving the gut microbiome of the model species Daphnia magna. We demonstrate that: (1) tyrosine hydroxylase and dopa decarboxylase enzymes are present in the gut wall; (2) DOPA decarboxylase gene is expressed in the gut by the host, and its expression follows the molt cycle peaking after ecdysis; (3) biologically active L-Dopa, but not Dopamine, is present in the gut lumen; and (4) gut bacteria produce L-Dopa in a concentration-dependent manner when provided L-Tyrosine as a substrate. Impinging on gut bacteria involvement in host physiology and ecologically relevant traits, we suggest L-Dopa as a communication agent in the host-microbiome interactions in daphnids and, possibly, other crustaceans.

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l-DOPA and Its Receptor GPR143: Implications for Pathogenesis and Therapy in Parkinson’s Disease

Cited by 27 publications

References 69 publications

L-DOPA in Parkinson’s Disease: Looking at the “False” Neurotransmitters and Their Meaning

L-DOPA in Parkinson’s Disease: Looking at the “False” Neurotransmitters and Their Meaning

Anterior pituitary gland synthesises dopamine from l‐3,4‐dihydroxyphenylalanine (l‐dopa)

Microbiota-dependent and independent production of L-dopa in the gut of Daphnia magna

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