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

Chiho Sumi-Ichinose, Hiroshi Ichinose, Kazuhisa Ikemoto, Takahide Nomura, Kazunao Kondo

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)17-24
Number of pages8
JournalJournal of Pharmacological Sciences
Volume114
Issue number1
DOIs
Publication statusPublished - 21-10-2010

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

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