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

Journal of Pharmacological Sciences

Chiho Sumi-Ichinose²  Hiroshi Ichinose¹  Takahide Nomura²  Kazuhisa Ikemoto²  Kazunao Kondo² 

[1] Department of Life Science, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Japan;Department of Pharmacology, School of Medicine, Fujita Health University, Japan

关键词: tetrahydrobiopterin;    dystonia;    tyrosine hydroxylase;    striatum;    dopamine;   

DOI  :  10.1254/jphs.09R28FM

学科分类：药学

来源: Nihon Yakuri Gakkai Henshuubu / Japanese Pharmacological Society

【 摘 要 】

References(38)Cited-By(4)5R-L-Erythro-5,6,7,8-tetrahydrobiopterin (BH4) 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 BH4 biosynthesis. In order to probe the role of BH4 in vivo, we established BH4-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.

【 授权许可】

Unknown