Catecholamines up

Catecholamines up (Catsup) is a dopamine regulatory membrane protein that functions as a zinc ion transmembrane transporter (orthologous to ZIP7), and a negative regulator of rate-limiting enzymes involved in dopamine synthesis and transport: Tyrosine hydroxylase (TH), GTP Cyclohydrolase I (GTPCH), and Vesicular Monoamine Transporter (VMAT) in Drosophila melanogaster.[1][2][3][4]

Catecholamines up
Identifiers
OrganismDrosophila melanogaster (Fruit fly)
SymbolCatsup
Entrez48805
HomoloGene137786
RefSeq (mRNA)NM_080192
RefSeq (Prot)NP_524931
UniProtQ9V3A4

Catsup plays a significant role in zinc ion transmembrane transport, and the mutations in Catsup gene can lead to abnormal accumulation of membrane proteins, such as Notch, decreased Notch signalling, increase in levels of apoptosis, and induce of ER stress response.[4] Additionally, Catsup plays an important role in regulation of dopamine synthesis, and the mutations in Catsup gene can lead to hyperactivity of Catsup-regulated enzymes TH, GTPCH, and VMAT, as well as to increases in dopamine (DA) and tetrahydrobiopterin (BH4) levels.[1][3]

Gene structure and function

Catsup is a pleiotropic quantitative trait gene that encodes a negative regulator of dopamine (DA) and tetrahydrobiopterin (BH4) synthesis, as well as synaptic vesicle uptake in Drosophila melanogaster.[3] In dopamine synthesis, Catsup functions to inhibit Tyrosine hydroxylase (TH), GTP Cyclohydrolase I (GTPCH), and Vesicular Monoamine Transporter (VMAT) enzyme activity.[5] Various molecular polymorphisms of Catsup are associated with variations in quantitative traits, such as locomotor behavior, lifespan, and sensory bristle number.[3] Catsup protein is composed of seven transmembrane helices that induce post-translational modification of both enzymes TH and GTPCH, and two conserved extracellular ZIP Zinc transporter domains that possess zinc ion transmembrane transport activity.[3][4][6]

Catsup co-localizes with enzymes TH and VMAT to dopaminergic neuron cell bodies and synaptic termini.[3] Additionally, Catsup gene encodes Drosophila ortholog to ZIP7 zinc transporter protein, which is part of ZIP (Zrt/Irt-like protein) family in mammals.[4]

Role in regulation of dopamine biosynthesis

Catsup regulates production of dopamine by serving as a negative regulator of rate-limiting enzymes in dopamine and pteridine synthesis pathways, both of which are required to occur for production of dopamine.[6]

In dopamine synthesis pathway, Catsup negatively regulates Tyrosine hydroxylase (TH) activity, preventing TH catalyzed conversion of tyrosine to the precursor of dopamine, L-Dopa.[3]

In pteridine biosynthesis pathway, Catsup negatively regulates the activity of GTP Cyclohydrolase I (GTPCH), preventing GTPCH catalyzed biosynthesis of TH cofactor required for TH catalytic activity and regulation, tetrahydrobiopterin (BH4).[6]

Role in zinc ion transmembrane transport

Catsup gene encodes Drosophila ortholog to ZIP7 zinc transporter protein in mammals, which controls zinc homeostasis and maintains concentrations of free zinc low in cells.[4] Zinc transporters allow zinc transport into the cytoplasm of the cell, and disruptions to zinc transporters can lead to neurodevelopmental damages.[7]

Mutations

As the zinc ion transmembrane transporter, Catsup mutations can lead to abnormal accumulation of membrane proteins, such as Notch, decreased Notch signalling, increase in levels of apoptosis, and induce of ER stress response.[4]

As the regulator of dopamine biosynthesis, Catsup mutations can lead to hyperactivity of Catsup-regulated enzymes TH, GTPCH, and VMAT, as well as to increases in dopamine (DA) and tetrahydrobiopterin (BH4) levels.[1][3]

References
  1. Stathakis DG, Burton DY, McIvor WE, Krishnakumar S, Wright TR, O'Donnell JM (September 1999). "The catecholamines up (Catsup) protein of Drosophila melanogaster functions as a negative regulator of tyrosine hydroxylase activity". Genetics. 153 (1): 361–82. PMC 1460756. PMID 10471719.
  2. O’Donnell, Janis M.; Stathakis, Dean G.; Burton, Denise; Chen, Zuomin (2002). Chemistry and Biology of Pteridines and Folates. Springer, Boston, MA. pp. 211–215. doi:10.1007/978-1-4615-0945-5_35. ISBN 9781461353171.
  3. Wang Z, Ferdousy F, Lawal H, Huang Z, Daigle JG, Izevbaye I, Doherty O, Thomas J, Stathakis DG, O'Donnell JM (December 2011). "Catecholamines up integrates dopamine synthesis and synaptic trafficking". Journal of Neurochemistry. 119 (6): 1294–305. doi:10.1111/j.1471-4159.2011.07517.x. PMC 3233821. PMID 21985068.
  4. Groth C, Sasamura T, Khanna MR, Whitley M, Fortini ME (July 2013). "Protein trafficking abnormalities in Drosophila tissues with impaired activity of the ZIP7 zinc transporter Catsup". Development. 140 (14): 3018–27. doi:10.1242/dev.088336. PMC 3699284. PMID 23785054.
  5. Carbone MA, Jordan KW, Lyman RF, Harbison ST, Leips J, Morgan TJ, DeLuca M, Awadalla P, Mackay TF (May 2006). "Phenotypic variation and natural selection at catsup, a pleiotropic quantitative trait gene in Drosophila". Current Biology. 16 (9): 912–9. doi:10.1016/j.cub.2006.03.051. PMID 16682353.
  6. Hsouna A, Lawal HO, Izevbaye I, Hsu T, O'Donnell JM (August 2007). "Drosophila dopamine synthesis pathway genes regulate tracheal morphogenesis". Developmental Biology. 308 (1): 30–43. doi:10.1016/j.ydbio.2007.04.047. PMC 1995089. PMID 17585895.
  7. Jeong J, Eide DJ (2013). "The SLC39 family of zinc transporters". Molecular Aspects of Medicine. 34 (2–3): 612–9. doi:10.1016/j.mam.2012.05.011. PMC 3602797. PMID 23506894.
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