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Catecholamines up integrates dopamine synthesis and synaptic trafficking
Author(s) -
Wang Zhe,
Ferdousy Faiza,
Lawal Hakeem,
Huang Zhig,
Daigle J. Gavin,
Izevbaye Iyare,
Doherty Olugbenga,
Thomas Jerrad,
Stathakis Dean G,
O’Donnell Janis M.
Publication year - 2011
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2011.07517.x
Subject(s) - dopamine , dopaminergic , tetrahydrobiopterin , tyrosine hydroxylase , dopamine transporter , vesicular monoamine transporter , chemistry , reserpine , monoamine neurotransmitter , biology , biochemistry , endocrinology , enzyme , serotonin , cofactor , receptor
J. Neurochem. (2011) 10.1111/j.1471‐4159.2011.07517.x 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.