Tyrosine hydroxylase phosphorylation: regulation and consequences

  title={Tyrosine hydroxylase phosphorylation: regulation and consequences},
  author={Peter R Dunkley and Larisa Bobrovskaya and Mark Evan Graham and Ellak I. von Nagy-Felsobuki and Phillip W Dickson},
  journal={Journal of Neurochemistry},
The rate‐limiting enzyme in catecholamine synthesis is tyrosine hydroxylase. It is phosphorylated at serine (Ser) residues Ser8, Ser19, Ser31 and Ser40 in vitro, in situ and in vivo. A range of protein kinases and protein phosphatases are able to phosphorylate or dephosphorylate these sites in vitro. Some of these enzymes are able to regulate tyrosine hydroxylase phosphorylation in situ and in vivo but the identity of the kinases and phosphatases is incomplete, especially for physiologically… 
Differential Regulation of the Human Tyrosine Hydroxylase Isoforms via Hierarchical Phosphorylation*
H hierarchical phosphorylation provides a mechanism whereby the two major human TH isoforms can be differentially regulated with only isoform 1 responding to the ERK pathway, whereas isoform 2 is more sensitive to calcium-mediated events.
Sustained phosphorylation of tyrosine hydroxylase at serine 40: a novel mechanism for maintenance of catecholamine synthesis
Sustained phosphorylation of TH at Ser40 provides a novel mechanism for increasing TH activity and this leads to increased catecholamine synthesis, a selective target for drugs or pathology in neurons that contain TH and synthesize dopamine, noradrenaline or adrenaline.
Tyrosine hydroxylase phosphorylation in vivo
This review on TH phosphorylation in vivo has three main sections focusing on: the methods used to investigate TH phosphate levels in vivo, the animals used, the sacrifice procedures, the tissue preparation, the measurement of TH protein levels and THosphorylation and the measurements of TH activation.
Tyrosine hydroxylase and regulation of dopamine synthesis.
Protein Kinase C-Dependent Dephosphorylation of Tyrosine Hydroxylase Requires the B56δ Heterotrimeric Form of Protein Phosphatase 2A
Molecular details of how protein kinase C is linked to reduced tyrosine hydroxylase activity via control of PP2A are revealed, and the complexity ofprotein kinase/protein phosphatase interactions are added.
Retinol activates tyrosine hydroxylase acutely by increasing the phosphorylation of serine40 and then serine31 in bovine adrenal chromaffin cells
The results show that retinol activates tyrosine hydroxylase via two sequential non‐genomic mechanisms, which have not previously been characterized, likely to operate in vivo to facilitate the stress response, especially when vitamin supplements are taken or when Retinol is used as a therapeutic agent.
Complex molecular regulation of tyrosine hydroxylase
The myriad mechanisms that regulate tyrosine hydroxylase expression and activity are revisited and their physiological importance in the control of catecholamine biosynthesis is highlighted.


Specificity of the MAP kinase ERK2 for phosphorylation of tyrosine hydroxylase.
Different effects on activity caused by phosphorylation of tyrosine hydroxylase at serine 40 by three multifunctional protein kinases.
Phosphorylation of tyrosine hydroxylase in situ at serine 8, 19, 31, and 40.
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  • Biology, Chemistry
    The Journal of biological chemistry
  • 1990
Depolarization‐stimulated catecholamine biosynthesis: involvement of protein kinases and tyrosine hydroxylase phosphorylation sites in situ
Investigation of the participation of extracellular signal‐regulated protein kinase (ERK) and cAMP‐dependent protein Kinase (PKA) in elevated K+‐stimulated TH phosphorylation in PC12 cells using an ERK pathway inhibitor, PD98059, and PKA‐deficient PC 12 cells suggests that ERK phosphorylates TH at Ser31 and that PKA phosphorylatedTH at Ser40 under depolarizing conditions.
Regulation of Tyrosine Hydroxylase Activity and Phosphorylation at Ser19 and Ser40 via Activation of Glutamate NMDA Receptors in Rat Striatum
Results indicate that, in the striatum, glutamate decreases tyrosine hydroxylase phosphorylation at Ser40 via activation of NMDA receptors by reducing cyclic AMP production, which provides a mechanism for the demonstrated ability ofNMDA to decrease tyrosin hydroxyase activity and dopamine synthesis.
Regulation of tyrosine hydroxylase by stress‐activated protein kinases
Recombinant human tyrosine hydroxylase (hTH1) was found to be phosphorylated by mitogen and stress‐activated protein kinase 1 (MSK1) at Ser40 and by p38 regulated/activated kinase (PRAK) on Ser19, providing new insights into the possible roles of stress‐ activated protein kinases in the regulation of catecholamine biosynthesis.
Direct phosphorylation of brain tyrosine hydroxylase by cyclic AMP-dependent protein kinase: mechanism of enzyme activation.
  • T. Joh, D. H. Park, D. Reis
  • Biology, Chemistry
    Proceedings of the National Academy of Sciences of the United States of America
  • 1978
It is proposed that the pool of native tyrosine hydroxylase is composed of a mixture of enzyme molecules in both active and probably inactive forms, that the active form is phosphorylated, and that phosphorylation produces an active form of the enzyme at the expense of an inactive one.
Phosphorylation of Ser19 Alters the Conformation of Tyrosine Hydroxylase to Increase the Rate of Phosphorylation of Ser40 *
It is suggested that phosphorylation of Ser19 alters the conformation of tyrosine hydroxylase to allow increased accessibility of Ser40 to kinases.
Phosphorylation of Ser19 increases both Ser40 phosphorylation and enzyme activity of tyrosine hydroxylase in intact cells
These data provide the first evidence that the phosphorylation of Ser19 can potentiate the phosphories of Ser40 and subsequent activation of tyrosine hydroxylase in intact cells.