Catecholamines up integrates dopamine synthesis and synaptic trafficking

Wang, Zhe; Ferdousy, Faiza; Lawal, Hakeem O.; Huang, Zhu; Daigle, J. Gavin; Izevbaye, Iyare; Doherty, Olugbenga M.; Thomas, Jerrad; Stathakis, Dean G.; O’Donnell, Janis M.

doi:10.1111/j.1471-4159.2011.07517.x

Cited by 40 publications

(35 citation statements)

References 54 publications

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“…As noted above, previous studies of ZIP7 activity have implicated this family of zinc transporters in rather disparate physiological processes, ranging from catecholamine biosynthesis, synaptic vesicle loading and release of dopamine, and sleep behavior in Drosophila (Stathakis et al, 1999;Harbison et al, 2009;Wang et al, 2011) to inhibition of tyrosine kinase-mediated cell proliferation in mammalian cells (Murakami and Hirano, 2008;Taylor et al, 2008;Hogstrand et al, 2009). The requirement for ZIP7 activity for normal trafficking of Notch, EGFR and the fly APP ortholog in Drosophila tissues suggests that ZIP7 might have pleiotropic roles in other cellular processes that depend upon proper Zn 2+ homeostasis in the ER and Golgi compartments, as well as regulation of cytosolic Zn 2+ by release of ER/Golgi zinc ion stores.…”

Section: Discussionmentioning

confidence: 94%

“…In Drosophila, Catsup has been shown to act as a negative regulator of catecholamine biosynthesis (Stathakis et al, 1999), and in synaptic transport and release of dopamine in (Wang et al, 2011). Molecular polymorphisms in the Catsup locus are associated with genetic variation in Drosophila sleep patterns, linking ZIP7 function to neurophysiological processes that regulate behavior in flies (Harbison et al, 2009).…”

Section: Discussionmentioning

confidence: 99%

“…Two new mutant alleles of the Drosophila Catsup gene (Stathakis et al, 1999;Harbison et al, 2009;Wang et al, 2011) were recovered that display an abnormal pattern of Notch accumulation in homozygous mutant clones. In both mutants, Notch accumulates within the cytoplasm of wing disc mutant clone cells, leading to abnormally high levels of Notch through the entire apicobasal profile of the polarized columnar epithelium (Fig.…”

Section: Abnormal Subcellular Accumulation Of the Notch Receptor In Dmentioning

confidence: 99%

“…Among the ~40 new mutants recovered, we obtained two new alleles of the Catecholamines up (Catsup) gene, which has previously been implicated as a negative regulator of tyrosine hydroxylase activity during catecholamine biosynthesis (Stathakis et al, 1999), in synaptic vesicle loading and release of dopamine (Wang et al, 2011), and in the control of sleep behavior (Harbison et al, 2009) in Drosophila. The Catsup gene encodes the Drosophila ortholog of the mammalian ZIP7 protein (also known as SLC39A7), a zinc transporter belonging to the ZIP (Zrt/Irt-like protein) family.…”

Section: Introductionmentioning

confidence: 99%

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Protein trafficking abnormalities inDrosophilatissues with impaired activity of the ZIP7 zinc transporter Catsup

et al. 2013

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Developmental patterning requires the precise interplay of numerous intercellular signaling pathways to ensure that cells are properly specified during tissue formation and organogenesis. The spatiotemporal function of the Notch signaling pathway is strongly influenced by the biosynthesis and intracellular trafficking of signaling components. Receptors and ligands must be trafficked to the cell surface where they interact, and their subsequent endocytic internalization and endosomal trafficking is crucial for both signal propagation and its down-modulation. In a forward genetic screen for mutations that alter intracellular Notch receptor trafficking in Drosophila epithelial tissues, we recovered mutations that disrupt the Catsup gene, which encodes the Drosophila ortholog of the mammalian ZIP7 zinc transporter. Loss of Catsup function causes Notch to accumulate abnormally in the endoplasmic reticulum (ER) and Golgi compartments, resulting in impaired Notch signaling. In addition, Catsup mutant cells exhibit elevated ER stress, suggesting that impaired zinc homeostasis causes increased levels of misfolded proteins within the secretory compartment.

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Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Section: Abnormal Subcellular Accumulation Of the Notch Receptor In Dmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Protein trafficking abnormalities inDrosophilatissues with impaired activity of the ZIP7 zinc transporter Catsup

et al. 2013

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“…Although these studies did not explore the subcellular location of the GCH1 interactions, it is tempting to speculate that GCH1 also participates in the Hsc70-TH-AADC-VMAT2 complex as a critical enzyme necessary for DA synthesis. More recently, a functional interaction between VMAT2 and the DA biosynthetic complex through the Cathecolamines up (Catsup) gene was identified in Drosophila DA neurons (31). A complex network of proteins linking DA synthesis and synaptic vesicle refilling might require highly regulated mechanistic steps involving assembly/disassembly and conformational changes that promote correct protein folding, localization, and activity.…”

Section: Discussionmentioning

confidence: 99%

The Molecular Chaperone Hsc70 Interacts with Tyrosine Hydroxylase to Regulate Enzyme Activity and Synaptic Vesicle Localization

Parra¹,

Baust²,

Smith

et al. 2016

Journal of Biological Chemistry

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We previously reported that the vesicular monoamine transporter 2 (VMAT2) is physically and functionally coupled with Hsc70 as well as with the dopamine synthesis enzymes tyrosine hydroxylase (TH) and aromatic amino acid decarboxylase, providing a novel mechanism for dopamine homeostasis regulation. Here we expand those findings to demonstrate that Hsc70 physically and functionally interacts with TH to regulate the enzyme activity and synaptic vesicle targeting. Co-immunoprecipitation assays performed in brain tissue and heterologous cells demonstrated that Hsc70 interacts with TH and aromatic amino acid decarboxylase. Furthermore, in vitro binding assays showed that TH directly binds the substrate binding and carboxyl-terminal domains of Hsc70. Immunocytochemical studies indicated that Hsc70 and TH co-localize in midbrain dopaminergic neurons. The functional significance of the Hsc70-TH interaction was then investigated using TH activity assays. In both dopaminergic MN9D cells and mouse brain synaptic vesicles, purified Hsc70 facilitated an increase in TH activity. Neither the closely related protein Hsp70 nor the unrelated Hsp60 altered TH activity, confirming the specificity of the Hsc70 effect. Overexpression of Hsc70 in dopaminergic MN9D cells consistently resulted in increased TH activity whereas knockdown of Hsc70 by short hairpin RNA resulted in decreased TH activity and dopamine levels. Finally, in cells with reduced levels of Hsc70, the amount of TH associated with synaptic vesicles was decreased. This effect was rescued by addition of purified Hsc70. Together, these data demonstrate a novel interaction between Hsc70 and TH that regulates the activity and localization of the enzyme to synaptic vesicles, suggesting an important role for Hsc70 in dopamine homeostasis.Dopaminergic neurons within the substantia nigra and ventral tegmental area are the primary sources of the catecholamine neurotransmitter dopamine (DA).2 Despite the fact that dopaminergic neurons account for less than 0.01% of all neurons, they play a significant role in brain function (1-3). Consequently, DA homeostasis is crucial for the preservation and regulation of physiological functions such as locomotion, cognition, neuroendocrine secretion, and motivated behaviors (4). Thus, it is not surprising that disruptions in the DA system have been implicated in several neurological and psychiatric disorders, including Parkinson disease, depression, schizophrenia, attention deficit hyperactivity disorder, Tourette syndrome, and drug addiction (4 -8).The DA life cycle consists of a series of highly regulated molecular events that are ultimately responsible for controlling DA homeostasis. Synthesis of DA occurs in the presynaptic terminals via two enzymatic reactions. First, tyrosine is converted into L-3,4-dihydroxyphenylalanine through the actions of the rate-limiting enzyme tyrosine hydroxylase (TH) (9, 10). Subsequently, aromatic amino acid decarboxylase (AADC) converts L-DOPA into DA (11). When synthesized, DA is packaged and stored withi...

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Drosophila as a Neurotoxicological Model

Lawal

Krantz²

2018

Methods in Pharmacology and Toxicology

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Catecholamines up integrates dopamine synthesis and synaptic trafficking

Cited by 40 publications

References 54 publications

Protein trafficking abnormalities inDrosophilatissues with impaired activity of the ZIP7 zinc transporter Catsup

Protein trafficking abnormalities inDrosophilatissues with impaired activity of the ZIP7 zinc transporter Catsup

The Molecular Chaperone Hsc70 Interacts with Tyrosine Hydroxylase to Regulate Enzyme Activity and Synaptic Vesicle Localization

Drosophila as a Neurotoxicological Model

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