title: Catecholamines up integrates dopamine synthesis and synaptic trafficking.
abstract: The highly reactive nature of dopamine renders dopaminergic neurons vulnerable to oxidative damage. We recently demonstrated that loss-of-function mutations in the Drosophila gene Catecholamines up (Catsup) elevate dopamine pools but, paradoxically, also confer resistance to paraquat, an herbicide that induces oxidative stress-mediated toxicity in dopaminergic neurons. We now report a novel association of the membrane protein, Catsup, with GTP cyclohydrolase rate-limiting enzyme for tetrahydrobiopterin (BH(4)) biosynthesis and tyrosine hydroxylase, rate-limiting enzyme for dopamine biosynthesis, which requires BH(4) as a cofactor. Loss-of-function Catsup mutations cause dominant hyperactivation of both enzymes. Elevated dopamine levels in Catsup mutants coincide with several distinct characteristics, including hypermobility, minimal basal levels of 3,4-dihydroxy-phenylacetic acid, an oxidative metabolite of dopamine, and resistance to the vesicular monoamine transporter inhibitor, reserpine, suggesting that excess dopamine is synaptically active and that Catsup functions in the regulation of synaptic vesicle loading and release of dopamine. We conclude that Catsup regulates and links the dopamine synthesis and transport networks.
authors: Department of Biological Sciences, University of Alabama, Tuscaloosa, Alabama 35487, USA.
authors: Zhe
authors: Z
authors: Wang
authors: Faiza
authors: F
authors: Ferdousy
authors: Hakeem
authors: H
authors: Lawal
authors: Zhinong
authors: Z
authors: Huang
authors: J Gavin
authors: JG
authors: Daigle
authors: Iyare
authors: I
authors: Izevbaye
authors: Olugbenga
authors: O
authors: Doherty
authors: Jerrad
authors: J
authors: Thomas
authors: Dean G
authors: DG
authors: Stathakis
authors: Janis M
authors: JM
authors: O'Donnell
mesh_terms: D000284:Administration, Oral; D000818:Animals; D030801:Animals, Genetically Modified; D014150:Antipsychotic Agents / Q000008:administration & dosage; D004298:Dopamine / Q000378:metabolism*; D015259:Dopamine Agents / Q000008:administration & dosage; D059290:Dopaminergic Neurons / Q000378:metabolism*; D004330:Drosophila; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004563:Electrochemistry; D005260:Female; D006136:GTP Cyclohydrolase / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics; D006540:Herbicides / Q000008:administration & dosage; D047468:Immunoprecipitation; D007980:Levodopa / Q000008:administration & dosage; D008124:Locomotion / Q000187:drug effects / Q000502:physiology; D008297:Male; D007470:Monoiodotyrosine / Q000008:administration & dosage; D010269:Paraquat / Q000008:administration & dosage; D021381:Protein Transport / Q000187:drug effects / Q000235:genetics; D012110:Reserpine / Q000008:administration & dosage; D013569:Synapses / Q000187:drug effects / Q000235:genetics*; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics; D050493:Vesicular Monoamine Transport Proteins / Q000235:genetics
chemical_list: C523964:3-iodotyrosine; D014150:Antipsychotic Agents; D015259:Dopamine Agents; D029721:Drosophila Proteins; D006540:Herbicides; D050493:Vesicular Monoamine Transport Proteins; C511455:catsup protein, Drosophila; D049452:Green Fluorescent Proteins; D007980:Levodopa; D012110:Reserpine; D014446:Tyrosine 3-Monooxygenase; D006136:GTP Cyclohydrolase; D007470:Monoiodotyrosine; D010269:Paraquat; D004298:Dopamine