Zinc antagonizes iron-regulation of tyrosine hydroxylase activity and dopamine production in Drosophila melanogaster

Abstract Background Dopamine (DA) is a neurotransmitter that plays roles in movement, cognition, attention, and reward responses, and deficient DA signaling is associated with the progression of a number of neurological diseases, such as Parkinson’s disease. Due to its critical functions, DA express...

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Autores principales:	Guiran Xiao, Mengran Zhao, Zhihua Liu, Fan Du, Bing Zhou
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	Catecholamines up Zinc Iron Tyrosine hydroxylase Parkinson’s disease Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/dc67f011dedc4e549b0991570619c048
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spelling	oai:doaj.org-article:dc67f011dedc4e549b0991570619c0482021-11-08T11:17:41ZZinc antagonizes iron-regulation of tyrosine hydroxylase activity and dopamine production in Drosophila melanogaster10.1186/s12915-021-01168-01741-7007https://doaj.org/article/dc67f011dedc4e549b0991570619c0482021-11-01T00:00:00Zhttps://doi.org/10.1186/s12915-021-01168-0https://doaj.org/toc/1741-7007Abstract Background Dopamine (DA) is a neurotransmitter that plays roles in movement, cognition, attention, and reward responses, and deficient DA signaling is associated with the progression of a number of neurological diseases, such as Parkinson’s disease. Due to its critical functions, DA expression levels in the brain are tightly controlled, with one important and rate-limiting step in its biosynthetic pathway being catalyzed by tyrosine hydroxylase (TH), an enzyme that uses iron ion (Fe2+) as a cofactor. A role for metal ions has additionally been associated with the etiology of Parkinson’s disease. However, the way dopamine synthesis is regulated in vivo or whether regulation of metal ion levels is a component of DA synthesis is not fully understood. Here, we analyze the role of Catsup, the Drosophila ortholog of the mammalian zinc transporter SLC39A7 (ZIP7), in regulating dopamine levels. Results We found that Catsup is a functional zinc transporter that regulates intracellular zinc distribution between the ER/Golgi and the cytosol. Loss-of-function of Catsup leads to increased DA levels, and we showed that the increased dopamine production is due to a reduction in zinc levels in the cytosol. Zinc ion (Zn2+) negatively regulates dopamine synthesis through direct inhibition of TH activity, by antagonizing Fe2+ binding to TH, thus rendering the enzyme ineffective or non-functional. Conclusions Our findings uncovered a previously unknown mechanism underlying the control of cellular dopamine expression, with normal levels of dopamine synthesis being maintained through a balance between Fe2+ and Zn2+ ions. The findings also provide support for metal modulation as a possible therapeutic strategy in the treatment of Parkinson’s disease and other dopamine-related diseases.Guiran XiaoMengran ZhaoZhihua LiuFan DuBing ZhouBMCarticleCatecholamines upZincIronTyrosine hydroxylaseParkinson’s diseaseBiology (General)QH301-705.5ENBMC Biology, Vol 19, Iss 1, Pp 1-16 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Catecholamines up Zinc Iron Tyrosine hydroxylase Parkinson’s disease Biology (General) QH301-705.5
spellingShingle	Catecholamines up Zinc Iron Tyrosine hydroxylase Parkinson’s disease Biology (General) QH301-705.5 Guiran Xiao Mengran Zhao Zhihua Liu Fan Du Bing Zhou Zinc antagonizes iron-regulation of tyrosine hydroxylase activity and dopamine production in Drosophila melanogaster
description	Abstract Background Dopamine (DA) is a neurotransmitter that plays roles in movement, cognition, attention, and reward responses, and deficient DA signaling is associated with the progression of a number of neurological diseases, such as Parkinson’s disease. Due to its critical functions, DA expression levels in the brain are tightly controlled, with one important and rate-limiting step in its biosynthetic pathway being catalyzed by tyrosine hydroxylase (TH), an enzyme that uses iron ion (Fe2+) as a cofactor. A role for metal ions has additionally been associated with the etiology of Parkinson’s disease. However, the way dopamine synthesis is regulated in vivo or whether regulation of metal ion levels is a component of DA synthesis is not fully understood. Here, we analyze the role of Catsup, the Drosophila ortholog of the mammalian zinc transporter SLC39A7 (ZIP7), in regulating dopamine levels. Results We found that Catsup is a functional zinc transporter that regulates intracellular zinc distribution between the ER/Golgi and the cytosol. Loss-of-function of Catsup leads to increased DA levels, and we showed that the increased dopamine production is due to a reduction in zinc levels in the cytosol. Zinc ion (Zn2+) negatively regulates dopamine synthesis through direct inhibition of TH activity, by antagonizing Fe2+ binding to TH, thus rendering the enzyme ineffective or non-functional. Conclusions Our findings uncovered a previously unknown mechanism underlying the control of cellular dopamine expression, with normal levels of dopamine synthesis being maintained through a balance between Fe2+ and Zn2+ ions. The findings also provide support for metal modulation as a possible therapeutic strategy in the treatment of Parkinson’s disease and other dopamine-related diseases.
format	article
author	Guiran Xiao Mengran Zhao Zhihua Liu Fan Du Bing Zhou
author_facet	Guiran Xiao Mengran Zhao Zhihua Liu Fan Du Bing Zhou
author_sort	Guiran Xiao
title	Zinc antagonizes iron-regulation of tyrosine hydroxylase activity and dopamine production in Drosophila melanogaster
title_short	Zinc antagonizes iron-regulation of tyrosine hydroxylase activity and dopamine production in Drosophila melanogaster
title_full	Zinc antagonizes iron-regulation of tyrosine hydroxylase activity and dopamine production in Drosophila melanogaster
title_fullStr	Zinc antagonizes iron-regulation of tyrosine hydroxylase activity and dopamine production in Drosophila melanogaster
title_full_unstemmed	Zinc antagonizes iron-regulation of tyrosine hydroxylase activity and dopamine production in Drosophila melanogaster
title_sort	zinc antagonizes iron-regulation of tyrosine hydroxylase activity and dopamine production in drosophila melanogaster
publisher	BMC
publishDate	2021
url	https://doaj.org/article/dc67f011dedc4e549b0991570619c048
work_keys_str_mv	AT guiranxiao zincantagonizesironregulationoftyrosinehydroxylaseactivityanddopamineproductionindrosophilamelanogaster AT mengranzhao zincantagonizesironregulationoftyrosinehydroxylaseactivityanddopamineproductionindrosophilamelanogaster AT zhihualiu zincantagonizesironregulationoftyrosinehydroxylaseactivityanddopamineproductionindrosophilamelanogaster AT fandu zincantagonizesironregulationoftyrosinehydroxylaseactivityanddopamineproductionindrosophilamelanogaster AT bingzhou zincantagonizesironregulationoftyrosinehydroxylaseactivityanddopamineproductionindrosophilamelanogaster
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Zinc antagonizes iron-regulation of tyrosine hydroxylase activity and dopamine production in Drosophila melanogaster

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