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

• Published in: BMC biology Vol. 19; no. 1; p. 236
• Main Authors: Xiao, Guiran, Zhao, Mengran, Liu, Zhihua, Du, Fan, Zhou, Bing
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 03-11-2021; BioMed Central; BMC
• Subjects: Animals; Apoptosis; Catecholamines up; Cation Transport Proteins - genetics; Cellular signal transduction; Cognition; Cytosol; Development and progression; Dopamine; Drosophila melanogaster - genetics; Drosophila melanogaster - metabolism; Endoplasmic Reticulum - metabolism; Enzymes; Etiology; Ferrous ions; Fruit flies; Golgi apparatus; Health aspects; Homeostasis; Hydroxylase; Hydroxylases; Insects; Iron; Metal ions; Movement disorders; Neurodegenerative diseases; Neurological diseases; Neurons; Neurotransmitters; Parkinson's disease; Physiological aspects; Proteins; Reinforcement; Tyrosine; Tyrosine 3-monooxygenase; Tyrosine 3-Monooxygenase - genetics; Tyrosine 3-Monooxygenase - metabolism; Tyrosine hydroxylase; Zinc; Zinc transporter; China; Iron; Tyrosine hydroxylase; Catecholamines up; Parkinson’s disease; Zinc
• ISSN: 1741-7007; 1741-7007
• DOI: 10.1186/s12915-021-01168-0

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 (Fe
) 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.
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 (Zn
) negatively regulates dopamine synthesis through direct inhibition of TH activity, by antagonizing Fe
binding to TH, thus rendering the enzyme ineffective or non-functional.
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 Fe
and Zn
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.