title: Dopamine release via the vacuolar ATPase V0 sector c-subunit, confirmed in N18 neuroblastoma cells, results in behavioral recovery in hemiparkinsonian mice.
abstract: A 16-kDa proteolipid, mediatophore, in Torpedo electric organs mediates Ca(2+)-dependent acetylcholine release. Mediatophore is identical to the pore-forming stalk c-subunit of the V0 sector of vacuolar proton ATPase (ATP6V0C). The function of ATP6V0C in the mammalian central nervous system is not clear. Here, we report transfection of adeno-associated viral vectors harboring rat ATP6V0C into the mouse substantia nigra, in which high potassium stimulation increased overflow of endogenous dopamine (DA) measured in the striatum by in vivo microdialysis. Next, in the striatum of 6-hydroxydopamine-lesioned mice, a model of Parkinson's disease (PD), human tyrosine hydroxylase, aromatic l-amino-acid decarboxylase and guanosine triphosphate cyclohydrolase 1, together with or without ATP6V0C, were expressed in the caudoputamen for rescue. Motor performance on the accelerating rotarod test and amphetamine-induced ipsilateral rotation were improved in the rescued mice coexpressing ATP6V0C. [(3)H]DA, taken up into cultured N18 neuronal tumor cells transformed to express ATP6V0C, was released by potassium stimulation. These results indicated that ATP6V0C mediates DA release from nerve terminals in the striatum of DA neurons of normal mice and from gene-transferred striatal cells of parkinsonian mice. The results suggested that ATP6V0C may be useful as a rescue molecule in addition to DA-synthetic enzymes in the gene therapy of PD.
authors.affiliation: Kanazawa University, 21st Century Center of Excellence Program on Innovative Brain Science on Development, Learning and Memory, Kanazawa 920-8640, Japan.
authors.forename: Duo
authors.initials: D
authors.lastname: Jin
authors.forename: Shin-Ichi
authors.initials: S
authors.lastname: Muramatsu
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Shimizu
authors.forename: Shigeru
authors.initials: S
authors.lastname: Yokoyama
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Hirai
authors.forename: Kiyofumi
authors.initials: K
authors.lastname: Yamada
authors.forename: Hong-Xiang
authors.initials: HX
authors.lastname: Liu
authors.forename: Chiharu
authors.initials: C
authors.lastname: Higashida
authors.forename: Minako
authors.initials: M
authors.lastname: Hashii
authors.forename: Akihiko
authors.initials: A
authors.lastname: Higashida
authors.forename: Masahide
authors.initials: M
authors.lastname: Asano
authors.forename: Shoji
authors.initials: S
authors.lastname: Ohkuma
authors.forename: Haruhiro
authors.initials: H
authors.lastname: Higashida
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D045744:Cell Line, Tumor; D004298:Dopamine / Q000378:metabolism*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D017551:Microdialysis; D009447:Neuroblastoma / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D010300:Parkinson Disease / Q000503:physiopathology*; D025262:Vacuolar Proton-Translocating ATPases / Q000378:metabolism*
chemical_list: D025262:Vacuolar Proton-Translocating ATPases; D004298:Dopamine