Ciliary neurotrophic factor stimulates tyrosine hydroxylase activity

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Abstract

Tyrosine hydroxylase (TH) is the rate-limiting enzyme in norepinephrine synthesis, and its expression and activity are regulated by many factors in sympathetic neurons. Cytokines that act through gp130, such as ciliary neurotrophic factor (CNTF) decrease norepinephrine production in sympathetic neurons by suppressing TH mRNA and stimulating degradation of TH protein, leading to the loss of enzyme. Their effect on the activity of TH is unclear, but recent in vivo observations suggest that cytokines may stimulate TH activity. We investigated this issue by quantifying TH protein levels and activity in cultured sympathetic neurons. We also examined the state of TH phosphorylation on serine 31 and 40, sites known to affect TH activity and degradation. We found that CNTF, acting through gp130, stimulated the rate of l-3,4-dihydroxyphenylalanine production while at the same time decreasing TH enzyme levels, thereby increasing the specific activity of the enzyme. We also found that phosphorylation of TH on Ser31 was increased, and phosphorylation on Ser40 was decreased, after four days of CNTF exposure. Our data are consistent with previous findings that Ser31 phosphorylation stimulates TH activity, whereas Ser40 phosphorylation can target TH for proteasomal degradation. Inflammatory cytokines have contradictory effects on tyrosine hydroxylase â€̈Inflammatory cytokines like ciliary neurotrophic factor (CNTF), suppress tyrosine hydroxylase (TH) content in sympathetic neurons, but the loss of TH in vivo is not always accompanied by a similar loss of catecholamines. We found that while CNTF decreased TH levels in sympathetic neurons, it also stimulated enzyme activity. Thus, cytokines trigger the loss of TH protein while increasing the activity of remaining enzyme.

Original languageEnglish (US)
Pages (from-to)700-704
Number of pages5
JournalJournal of Neurochemistry
Volume121
Issue number5
DOIs
StatePublished - Jun 1 2012

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Keywords

  • cytokine
  • phosphorylation
  • sympathetic
  • tyrosine hydroxylase

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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