Advanced research on dopamine signaling to develop drugs for the treatment of mental disorders: regulation of dopaminergic neural transmission by tyrosine hydroxylase protein at nerve terminals.
5R-L-Erythro-5,6,7,8-tetrahydrobiopterin (BH(4)) is an essential cofactor for tyrosine hydroxylase (TH). Recently, a type of dopa-responsive dystonia (DRD) (DYT5, Segawa's disease) was revealed to be caused by dominant mutations of the gene encoding GTP cyclohydrolase I (GCHI), which is the rate-limiting enzyme of BH(4) biosynthesis. In order to probe the role of BH(4) in vivo, we established BH(4)-depleted mice by disrupting the 6-pyruvoyltetrahydropterin synthase (PTS) gene (Pts(-/-)) and rescued them by introducing human PTS cDNA under the control of the human dopamine β-hydroxylase (DBH) promoter (Pts(-/-)-DPS). The Pts(-/-)-DPS mice developed hyperphenylalaninemia. Interestingly, tyrosine hydroxylase protein was dramatically reduced in the dopaminergic nerve terminals of these mice, and they developed abnormal posture and motor disturbance. We propose that the biochemical and pathologic changes of Pts(-/-)-DPS mice are caused by mechanisms common to human DRD, and understanding these mechanisms could give us insight into other movement disorders.
Sumi-Ichinose
Chiho
C
Department of Pharmacology, School of Medicine, Fujita Health University, Toyoake, Aichi, Japan. csichino@fujita-hu.ac.jp
Ichinose
Hiroshi
H
Ikemoto
Kazuhisa
K
Nomura
Takahide
T
Kondo
Kazunao
K
D000818:Animals; D004298:Dopamine / Q000502:physiology*; D055808:Drug Discovery / Q000379:methods*; D006801:Humans; D001523:Mental Disorders / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology; D009411:Nerve Endings / Q000187:drug effects / Q000201:enzymology*; D004364:Pharmaceutical Preparations / Q000008:administration & dosage / Q000737:chemistry; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D016896:Treatment Outcome; D014446:Tyrosine 3-Monooxygenase / Q000502:physiology*
D004364:Pharmaceutical Preparations; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine