Regulation of Tyrosine Hydroxylase Expression and Phosphorylation in Dopamine Transporter-Deficient Mice
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Tyrosine hydroxylase (TH) and dopamine transporters (DATs) regulate dopamine (DA) neurotransmission at the biosynthesis and reuptake steps, respectively. Dysfunction or loss of these proteins occurs in impaired locomotor or addictive behavior, but little is known about the influence of DAT expression on TH function. Differences in TH phosphorylation, DA tissue content, l-DOPA biosynthesis, and DA turnover exist between the somatodendritic and terminal field compartments of nigrostriatal and mesoaccumbens pathways. We examined whether differential DAT expression affects these compartmental differences in DA regulation by comparing TH expression and phosphorylation at ser31 and ser40. In heterozygous DAT knockout (KO) (+/-) mice, DA tissue content and DA turnover were unchanged relative to wild-type mice, despite a 40% reduction in DAT protein expression. In DAT KO (-/-) mice, DA turnover increased in all DA compartments, but DA tissue content decreased (90-96%) only in terminal fields. TH protein expression and phosphorylation were differentially affected within DA pathway compartments by relative expression of DAT. TH protein decreased (∼74%), though to a significantly lesser extent than DA, in striatum and nucleus accumbens (NAc) in DAT -/- mice, with no decrease in substantia nigra or ventral tegmental area. Striatal ser31 TH phosphorylation and recovery of DA relative to TH protein expression in DAT +/- and DAT -/- mice decreased, whereas ser40 TH phosphorylation increased ∼2- to 3-fold in striatum and NAc of DAT -/- mice. These results suggest that DAT expression affects TH expression and phosphorylation largely in DA terminal field compartments, further corroborating evidence for dichotomous regulation of TH between somatodendritic and terminal field compartments of the nigrostriatal and mesoaccumbens pathways.
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Knockout of dopamine transporter decreases dopamine content in terminals of dopaminergic neurons, accompanied by elevation of pSer40-TH and reduction of total TH protein.
“Salvatore et al. further revealed that knockout of dopamine transporter decreased dopamine content in the terminals of dopaminergic neurons, and this phenomenon was accompanied by the elevation of pSer40-TH and reduction of total TH protein [103].”
From Degradation of Tyrosine Hydroxylase by the Ubiquitin-Proteasome System in the Pathogenesis of Parkinson’s Disease and Dopa-Responsive Dystonia (2020) · cites this paper as [103]
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- Authors
- Salvatore, M. F., Calipari, E. S., & Jones, S. R.
- Affiliations
- Louisiana State University Health Sciences Center Shreveport (US)
- Wake Forest University Health Sciences (US)
- Corresponding author
- Salvatore, Michael F.
- Venue
- ACS Chemical Neuroscience
- Publisher
- American Chemical Society (ACS)
- Published
- 2016-05-10
- Volume
- 7
- Issue
- 7
- Pages
- 941-951
- ISSN
- 1948-7193 (ISSN-L)
- PMC
- PMC4956566
- OpenAlex
- W2345124641
- Cited by
- 72
- References
- 57
- Citations by year
- 2026: 7 · 2025: 8 · 2024: 4 · 2023: 8 · 2022: 8 · 2021: 7 · 2020: 5 · 2019: 12 · 2018: 9 · 2017: 4
- FWCI
- 4.67
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- ACS Chemical Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute on Aging (R01AG040261)
- National Institute on Drug Abuse (R01DA030161)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- tyrosine hydroxylase, dopamine transporter, dopamine transporter knockout mice, tyrosine hydroxylase phosphorylation, dopamine turnover, nigrostriatal pathway, striatum, nucleus accumbens, dopamine reuptake, dopamine synthesis
- MeSH terms
- Animals, Brain, Dopamine, Gene Expression Regulation, Levodopa, Male, Mice, Inbred C57BL, Phosphorylation, Serine, Tyrosine 3-Monooxygenase, Mice, Knockout, Statistics, Nonparametric, Dopamine Plasma Membrane Transport Proteins, Mice
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