Tyrosine hydroxylase phosphorylation: Regulation and consequences

Dunkley, Peter R.; Bobrovskaya, Larisa; Graham, Mark E.; Von Nagy‐Felsobuki, Ellak I.; Dickson, Phillip W.

doi:10.1111/j.1471-4159.2004.02797.x

Cited by 456Neuroscience and Neuropharmacology ResearchProtein Kinase Regulation and GTPase SignalingNeurotransmitter Receptor Influence on Behavior

Tyrosine hydroxylase phosphorylation: Regulation and consequences

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Dunkley, Peter R., Bobrovskaya, Larisa, Graham, Mark E., Von Nagy‐Felsobuki, Ellak I., Dickson, Phillip W.·2004·Journal of Neurochemistry

DOI 10.1111/j.1471-4159.2004.02797.x

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Abstract

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 relevant stimuli. The stoichiometry of tyrosine hydroxylase phosphorylation in situ and in vivo is low. The phosphorylation of tyrosine hydroxylase at Ser40 increases the enzyme's activity in vitro, in situ and in vivo. Phosphorylation at Ser31 also increases the activity but to a much lesser extent than for Ser40 phosphorylation. The phosphorylation of tyrosine hydroxylase at Ser19 or Ser8 has no direct effect on tyrosine hydroxylase activity. Hierarchical phosphorylation of tyrosine hydroxylase occurs both in vitro and in situ, whereby the phosphorylation at Ser19 increases the rate of Ser40 phosphorylation leading to an increase in enzyme activity. Hierarchical phosphorylation depends on the state of the substrate providing a novel form of control of tyrosine hydroxylase activation.

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α-Synuclein activates stress-related protein kinases to potentiate TH phosphorylation at serine 40.
“α-Synuclein activates stress-related protein kinases to potentiate TH phosphorylation at serine 40, suggesting the possible mechanism of pSer40-TH elevation by α-synuclein aggregation [52,124,125].”
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 [52]

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Thermal Stability and CD Analysis of Rat Tyrosine Hydroxylase
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Multiple Forms of Tyrosine Hydroxylase in Human Neuroblastoma Cells: Quantitation with Isoform‐Specific Antibodies
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Tyrosine Hydroxylase Dephosphorylation by Protein Phosphatase 2A in Bovine Adrenal Chromaffin Cells
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Four Forms of Tyrosine Hydroxylase Are Present in Human Adrenal Medulla
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Substrate specificity of liver calmodulin-dependent glycogen synthase kinase
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Histamine activates tyrosine hydroxylase in bovine adrenal chromaffin cells through a pathway that involves ERK1/2 but not p38 or JNK
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Tyrosine Hydroxylase in Bovine Adrenal Chromaffin Cells: Angiotensin II‐Stimulated Activity and Phosphorylation of Ser19, Ser31, and Ser40
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The biosynthesis of phosphorylated tyrosine hydroxylase by organ cultures of rat adrenal medulla and superior cervical ganglia
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Phosphorylation-induced Conformational Changes in a Mitogen-activated Protein Kinase Substrate
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Role of protein phosphatase 2C from bovine adrenal chromaffin cells in the dephosphorylation of phospho‐serine 40 tyrosine hydroxylase
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Progesterone Induces Dephosphorylation and Inactivation of Tyrosine Hydroxylase in Rat Hypothalamic Dopaminergic Neurons
Arbogast, L. A., & Voogt, J. L. (2002) · Neuroendocrinology · doi:10.1159/000057336 · Cited by 30 · see citing works
Phosphorylation of tyrosine hydroxylase in protein kinase C-deficient PC12 cells
Cahill, A. L., Horwitz, J., & Perlman, R. L. (1989) · Neuroscience · doi:10.1016/0306-4522(89)90172-3 · Cited by 29 · see citing works
Acute administration of cocaine regulates the phosphorylation of serine‐19, ‐31 and ‐40 in tyrosine hydroxylase
Jedynak, J., Ali, S. F., Haycock, J. W., et al. (2002) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2002.00982.x · Cited by 29 · see citing works
Phosphorylation of Tyrosine Hydroxylase by cGMP-Dependent Protein Kinase in Intact Bovine Chromaffin Cells
Rodríguez‐Pascual, F., Ferrero, R., Miras‐Portugal, M. T., & Torres, M. (1999) · Archives of Biochemistry and Biophysics · doi:10.1006/abbi.1999.1199 · Cited by 28 · see citing works
Influence of light and neural circuitry on tyrosine hydroxylase phosphorylation in the rat retina
Witkovsky, P., Gabriel, R., Haycock, J. W., et al. (2000) · Journal of Chemical Neuroanatomy · doi:10.1016/s0891-0618(00)00055-7 · Cited by 28 · see citing works
Immunohistochemical studies on phosphorylation of tyrosine hydroxylase in central catecholamine neurons using antibodies raised to phosphorylated forms of the enzyme
Xu, Q., Lew, J., Harada, K., Åman, K., Goldstein, M., Deutch, A. Y., Haycock, J. W., & Hökfelt, T. G. M. (1997) · Neuroscience · doi:10.1016/s0306-4522(97)00189-9 · Cited by 27 · see citing works
Regulation of Cyclic AMP Levels by Calcium in Bovine Adrenal Medullary Cells
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Dephosphorylation of tyrosine hydroxylase by brain protein phosphatases: a predominant role for type 2A
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Angiotensin II regulates tyrosine hydroxylase activity and mRNA expression in rat mediobasal hypothalamic cultures: the role of specific protein kinases
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Mutational Analysis of Substrate Inhibition in Tyrosine Hydroxylase
Quinsey, N. S., Luong, A. Q., & Dickson, P. W. (1998) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.1998.71052132.x · Cited by 24 · see citing works
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Simultaneous measurement of tyrosine hydroxylase activity and phosphorylation in bovine adrenal chromaffin cells
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A Novel Rat Tyrosine Hydroxylase mRNA Species Generated by Alternative Splicing
Lanièce, P., Hir, H. L., Bodeau‐Péan, S., Charon, Y., Valentin, L., Thermes, C., Mallet, J. J., & Dumas, S. (1996) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.1996.66051819.x · Cited by 22 · see citing works
Chronic Imipramine Administration Alters the Activity and Phosphorylation State of Tyrosine Hydroxylase in Dopaminergic Regions of Rat Brain
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Peptide substrates for ERK1/2: structure-function studies of serine 31 in tyrosine hydroxylase
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In vitro phosphorylation of a purified preparation of bovine corpus striatal tyrosine hydroxylase.
Edelman, A. M., Raese, J. D., Lazar, M. A., & Barchas, J. D. (1978) · PubMed · Cited by 19 · see citing works
Tyrosine Hydroxylase Phosphorylation in Digitonin‐Permeabilized Bovine Adrenal Chromaffin Cells: The Effect of Protein Kinase and Phosphatase Inhibitors on Ser19 and Ser40 Phosphorylation
Gonçalves, C., Hall, A. L., Sim, A. T. R., Bunn, S. J., Marley, P. D., Cheah, T. B., & Dunkley, P. R. (1997) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.1997.69062387.x · Cited by 17 · see citing works
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In situ phosphorylation of tyrosine hydroxylase in chromaffin cells: Localization to soluble compartments
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Phosphorylation of Tyrosine Hydroxylase in Isolated Mice Adrenal Glands
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Antibodies to a Segment of Tyrosine Hydroxylase Phosphorylated at Serine 40
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Activation of rat caudate tyrosine hydroxylase phosphatase by tetrahydropterins.
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Cyclin‐dependent kinase 11p110 and casein kinase 2 (CK2) inhibit the interaction between tyrosine hydroxylase and 14‐3‐3
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Phosphorylation and activation of tyrosine hydroxylase in PC18 cells: a cell line derived from rat pheochromocytoma PC12 cells
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Lack of regulation of aromatic l ‐amino acid decarboxylase in intact bovine chromaffin cells
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Specificity of the MAP kinase ERK2 for phosphorylation of tyrosine hydroxylase
Royo, M., Daubner, S. C., & Fitzpatrick, P. F. (2004) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2003.12.027 · Cited by 8 · see citing works

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Research works printed but not linked: 3

Haycock J. W., 1993, Phosphorylation of tyrosine hydroxylase isoforms in human neuroblastoma cells, Mol. Biol. Cell, 41, 406a
Waymire J., 1993, Multiple site phosphorylation and activation of tyrosine hydroxylase, Adv. Prot. Phosphatases, 7, 495
Yamauchi T., 1980, Involvement of calmodulin in the Ca2+‐dependent activation of rat brainstem tyrosine 3‐monooxygenase, Biochem. Int., 1, 98

Sorted by citations

Tyrosine hydroxylase and regulation of dopamine synthesis
Daubner, S. C., Le, T., & Wang, S. (2011) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2010.12.017 · Cited by 1,092 · see citing works
“5 to 3-fold by phosphorylation via CaMKII or ERK, respectively (13,14).”
BackgroundInfluential
Complexity of dopamine metabolism
Meiser, J., Weindl, D., & Hiller, K. (2013) · Cell Communication and Signaling · doi:10.1186/1478-811x-11-34 · Cited by 665 · see citing works
“The regulatory domain of hTH is targeted by phosphorylation at serine 19, 31 and 40 by various kinases, such as PKA, PKC CaMPKII, PKG, MPK, ERK which results in increased stability and/or activity [44].”
BackgroundInfluential
Catecholaminergic systems in stress: structural and molecular genetic approaches
Kvetnansky, R., Sabban, E. L., & Palkovits, M. (2009) · Physiological Reviews · doi:10.1152/physrev.00042.2006 · Cited by 548 · see citing works
Multi-target strategies for the improved treatment of depressive states: Conceptual foundations and neuronal substrates, drug discovery and therapeutic application
Millan, M. J. (2006) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2005.11.006 · Cited by 549 · see citing works
Interplay between Cytosolic Dopamine, Calcium, and α-Synuclein Causes Selective Death of Substantia Nigra Neurons
Mosharov, E. V., Larsen, K. E., Kanter, E., Phillips, K. A., Wilson, K., Schmitz, Y., Krantz, D. E., Kobayashi, K., Edwards, R. H., & Sulzer, D. L. (2009) · Neuron · doi:10.1016/j.neuron.2009.01.033 · Cited by 530 · see citing works
“It should also be noted that Ca 2+ dependent phosphorylation of TH (Dunkley et al., 2004) is likely to play a role in the absence of exogenously added L-DOPA.”
Comparison between proliferative and neuron-like SH-SY5Y cells as an in vitro model for Parkinson disease studies
Lopes, F. M., Schröder, R., Júnior, M. L. C. D. F., Zanotto‐Filho, A., Müller, C. B., Pires, A. S., Meurer, R. T., Colpo, G. D., Gelain, D. P., Kapczinski, F. P., et al. (2010) · Brain Research · doi:10.1016/j.brainres.2010.03.102 · Cited by 389 · see citing works
“RA treatment induces TH expression and activates phosphatase 2A, which dephosphorylates and activates TH, turning them into dopamine-producing cells (Pahlman et al., 1984; Dunkley et al., 2004).”
Background
Distinct Roles of PDE4 and PDE10A in the Regulation of cAMP/PKA Signaling in the Striatum
Nishi, A., Kuroiwa, M., Miller, D. B., O'Callaghan, J. P., Bateup, H. S., Shuto, T., Sotogaku, N., Fukuda, T., Heintz, N., Greengard, P., et al. (2008) · Journal of Neuroscience · doi:10.1523/jneurosci.2518-08.2008 · Cited by 286 · see citing works
“In mammalian striatum, the synthesis of dopamine by tyrosine hydroxylase (TH) (Harada et al., 1996; Dunkley et al., 2004) and the release of dopamine from nigrostriatal dopaminergic terminals (Zhu et al.”
BackgroundInfluential
Structural basis of 14-3-3 protein functions
Obšil, T., & Obšilová, V. (2011) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2011.09.001 · Cited by 275 · see citing works
“G e t R Ser-40 (reviewed in [102]) but only the phosphorylation of Ser19 is requited for high-affinity binding to 14-3-3.”
Background
α-Synuclein activation of protein phosphatase 2A reduces tyrosine hydroxylase phosphorylation in dopaminergic cells
Peng, X. M., Tehranian, R., Dietrich, P., Stefanis, L., & Perez, R. G. (2005) · Journal of Cell Science · doi:10.1242/jcs.02481 · Cited by 249 · see citing works
“Since it is well-documented that Ser40 dephosphorylation occurs almost exclusively by PP2A (Berresheim and Kuhn, 1994; Dunkley et al., 2004; Haavik et al., 1989; Leal et al., 2002) our findings indicate that (1) TH Ser40 is dephosphorylated by PP2A in dopaminergic cells, and (2) the Ser40 residue on TH remains accessi…”
Background
The Evolution of Dopamine Systems in Chordates
Yamamoto, K., & Vernier, P. (2011) · Frontiers in Neuroanatomy · doi:10.3389/fnana.2011.00021 · Cited by 241 · see citing works
“…March 2011 | Volume 5 | Article 21 | 2 phosphorylation sites for the MAP kinase ERK, for the protein kinase A, and protein kinase C are highly conserved, and in every species where it has been tested, TH phosphorylation is required for the enzyme to be active (Dunkley et al., 2004).”
BackgroundInfluential
The role of alpha-synuclein in neurotransmission and synaptic plasticity
Cheng, F., Vivacqua, G., & Yu, S. (2010) · Journal of Chemical Neuroanatomy · doi:10.1016/j.jchemneu.2010.12.001 · Cited by 238 · see citing works
“Previous studies showed that phosphorylation of critical serine residues (40, 31 and 19) in the N-terminus of TH was associated with activation of the enzyme (Campbell et al., 1986; Haycock, 1990), which could be reversed by protein phosphatase 2A (PP2A) (Dunkley et al., 2004), an important enzyme required for dephosp…”
Molecular hydrogen is protective against 6-hydroxydopamine-induced nigrostriatal degeneration in a rat model of Parkinson's disease
Fu, Y., Ito, M., Fujita, Y., Ito, M., Ichihara, M., Masuda, A., Suzuki, Y., Maesawa, S., Kajita, Y., Hirayama, M., et al. (2009) · Neuroscience Letters · doi:10.1016/j.neulet.2009.02.016 · Cited by 214 · see citing works
Chronic food restriction: Enhancing effects on drug reward and striatal cell signaling
Carr, K. D. (2006) · Physiology & Behavior · doi:10.1016/j.physbeh.2006.09.021 · Cited by 180 · see citing works
“Decreased DOPA synthesis, in the presence of increased levels of TH protein, may reflect the inhibitory effect of increased DA binding to TH protein or decreased concentrations of cofactor tetrahydrobiopterin [109,110].”
Background
Human tyrosine hydroxylase in Parkinson’s disease and in related disorders
Nagatsu, T., Nakashima, A., Ichinose, H., & Kobayashi, K. (2018) · Journal of Neural Transmission · doi:10.1007/s00702-018-1903-3 · Cited by 176 · see citing works
Daytime spikes in dopaminergic activity drive rapid mood-cycling in mice
Sidor, M. M., Spencer, S. M., Dzirasa, K., Parekh, P. K., Tye, K. M., Warden, M. R., Arey, R. N., Enwright, J. F., Jacobsen, J. P. R., Kumar, S., et al. (2015) · Molecular Psychiatry · doi:10.1038/mp.2014.167 · Cited by 158 · see citing works
Autism-linked dopamine transporter mutation alters striatal dopamine neurotransmission and dopamine-dependent behaviors
DiCarlo, G. E., Aguilar, J. I., Matthies, H. J. G., Harrison, F. E., Bundschuh, K. E., West, A. M., Hashemi, P., Herborg, F., Rickhag, M., Chen, H., et al. (2019) · Journal of Clinical Investigation · doi:10.1172/jci127411 · Cited by 156 · see citing works
A Synopsis on the Role of Tyrosine Hydroxylase in Parkinson’s Disease
Tabrez, S. S. M., Jabir, N. R., Shakil, S., Greig, N. H., Alam, Q., Abuzenadah, A. M., Damanhouri, G., & Kamal, M. A. (2012) · CNS & Neurological Disorders - Drug Targets · doi:10.2174/187152712800792785 · Cited by 152 · see citing works
“The N-terminal domain of TH is quite complex, with 4 to 5 phosphorylation sites [35].”
Background
Complex molecular regulation of tyrosine hydroxylase
Tekin, I., Roskoski, R., Carkaci-Salli, N., & Vrana, K. E. (2014) · Journal of Neural Transmission · doi:10.1007/s00702-014-1238-7 · Cited by 128 · see citing works
Selective cell death in neurodegeneration: Why are some neurons spared in vulnerable regions?
Double, K. L., Reyes, S., Werry, E. L., & Halliday, G. M. (2010) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2010.06.001 · Cited by 123 · see citing works
Nobiletin treatment improves motor and cognitive deficits seen in MPTP-induced Parkinson model mice
Yabuki, Y., Ohizumi, Y., Yokosuka, A., Mimaki, Y., & Fukunaga, K. (2013) · Neuroscience · doi:10.1016/j.neuroscience.2013.11.051 · Cited by 118 · see citing works
“Ser-8 is phosphorylated by ERK 1/2, but its function remains unclear (Dunkley et al., 2004, Daubner et al., 2011).”
Serine 129 Phosphorylation Reduces the Ability of α-Synuclein to Regulate Tyrosine Hydroxylase and Protein Phosphatase 2A in Vitro and in Vivo
Lou, H., Montoya, S. E., Alerte, T. N. M., Wang, J., Wu, J., Peng, X., Hong, C.-S., Friedrich, E. E., Mader, S. A., Pedersen, C. J., et al. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.100867 · Cited by 115 · see citing works
Plasticity of Hypothalamic Dopamine Neurons during Lactation Results in Dissociation of Electrical Activity and Release
Romanò, N., Yip, S. H., Hodson, D. J., Guillou, A., Parnaudeau, S., Kirk, S. E., Tronche, F., Bonnefont, X., Tissier, P. L., Bunn, S. J., et al. (2013) · Journal of Neuroscience · doi:10.1523/jneurosci.4415-12.2013 · Cited by 104 · see citing works
“Phosphorylation of Ser 40 strongly enhances TH functionality, whereas phosphorylation at Ser 19 does not impact TH catalytic activity (Zigmond et al., 1989; Dunkley et al., 2004).”
Background
Tyrosine hydroxylase (TH), its cofactor tetrahydrobiopterin (BH4), other catecholamine-related enzymes, and their human genes in relation to the drug and gene therapies of Parkinson’s disease (PD): historical overview and future prospects
Nagatsu, T., & Nagatsu, I. (2016) · Journal of Neural Transmission · doi:10.1007/s00702-016-1596-4 · Cited by 107 · see citing works
“TH activity is regulated by activation due to phosphorylation mainly at serines 19, 31, and 40 in the N-terminal region of the enzyme (in hTH1; Dunkley et al. 2004; Fujisawa and Okuno 2005).”
Background
Protein Kinase Cδ Negatively Regulates Tyrosine Hydroxylase Activity and Dopamine Synthesis by Enhancing Protein Phosphatase-2A Activity in Dopaminergic Neurons
Zhang, D., Kanthasamy, A., Yang, Y., Anantharam, V., & Kanthasamy, A. G. (2007) · Journal of Neuroscience · doi:10.1523/jneurosci.4107-06.2007 · Cited by 103 · see citing works
“Phosphorylation of serine residues at 8, 19, 31, and 40 can activate TH, resulting in enhanced dopamine synthesis (Campbell et al., 1986; Haycock, 1990; Mitchell et al., 1990; Lindgren et al., 2001; McCulloch et al., 2001; Dunkley et al., 2004).”
Background
Hypoxia. 3. Hypoxia and neurotransmitter synthesis
Kumar, G. K. (2011) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00019.2011 · Cited by 103 · see citing works
“Phosphorylation of serine-19, serine-31, and serine-40 at the NH2-terminal regulatory domain of TH alters the Km and maximal velocity (Vmax) leading to more active form of TH with increased activity (19, 25).”
Background
Inhibition of aldehyde dehydrogenase-2 suppresses cocaine seeking by generating THP, a cocaine use–dependent inhibitor of dopamine synthesis
Yao, L., Fan, P., Arolfo, M. P., Jiang, Z., Olive, M. F., Zablocki, J. A., Sun, H.-L., Chu, N., Lee, J., Kim, H., et al. (2010) · Nature Medicine · doi:10.1038/nm.2200 · Cited by 99 · see citing works
The circadian clock and mood-related behavior
Hampp, G., & Albrecht, U. (2008) · Communicative & Integrative Biology · doi:10.4161/cib.1.1.6286 · Cited by 97 · see citing works
O-GlcNAcylation regulates dopamine neuron function, survival and degeneration in Parkinson disease
Lee, B. E., Kim, H. Y., Kim, H., Jeong, H., Kim, B., Lee, H.-E., Lee, J., Kim, H. B., Lee, S. E., Yang, Y. R., et al. (2020) · Brain · doi:10.1093/brain/awaa320 · Cited by 95 · see citing works
A neuropeptide hormone cascade controls the precise onset of post-eclosion cuticular tanning inDrosophila melanogaster
Davis, M. M., O’Keefe, S. L., Primrose, D. A., & Hodgetts, R. B. (2007) · Development · doi:10.1242/dev.009902 · Cited by 93 · see citing works
“In vertebrates, TH activity is regulated at a variety of levels, including transcriptional regulation, alternative splicing, RNA stability, DA feedback inhibition and protein kinase activation (Dunkley et al., 2004; Hufton et al., 1995; Kumer and Vrana, 1996; Zigmond et al., 1989).”
BackgroundInfluential
Functional Programming of the Autonomic Nervous System by Early Life Immune Exposure: Implications for Anxiety
Sominsky, L., Fuller, E. A., Bondarenko, E., Ong, L. K., Averell, L., Nalivaiko, E., Dunkley, P. R., Dickson, P. W., & Hodgson, D. M. (2013) · PLoS ONE · doi:10.1371/journal.pone.0057700 · Cited by 90 · see citing works
“TH is the first ratelimiting enzyme in catecholamine biosynthesis [36].”
BackgroundSelf-citation
Clioquinol rescues Parkinsonism and dementia phenotypes of the tau knockout mouse
Lei, P., Ayton, S., Appukuttan, A. T., Volitakis, I., Adlard, P. A., Finkelstein, D. I., & Bush, A. I. (2015) · Neurobiology of Disease · doi:10.1016/j.nbd.2015.03.015 · Cited by 89 · see citing works
“Lowering iron increases TH phosphorylation and enzyme activity (49, 50).”
Background
Tyrosine hydroxylase phosphorylation in vivo
Dunkley, P. R., & Dickson, P. W. (2019) · Journal of Neurochemistry · doi:10.1111/jnc.14675 · Cited by 85 · see citing works
Self-citation
Age‐related decline in striatal dopamine content and motor performance occurs in the absence of nigral cell loss in a genetic mouse model of Parkinson's disease
Colebrooke, R. E., Humby, T., Lynch, P. J., McGowan, D., Xia, J., & Emson, P. C. (2006) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2006.05143.x · Cited by 86 · see citing works
“Normalized data examining the content of TH, Ser40 TH, Ser31 TH and Ser19 TH from Image J were analysed using two-tailed Student’s t-tests.”
BackgroundInfluential
The catecholamine system in health and disease -Relation to tyrosine 3-monooxygenase and other catecholamine-synthesizing enzymes-
Nagatsu, T. (2006) · Proceedings of the Japan Academy Series B · doi:10.2183/pjab.82.388 · Cited by 83 · see citing works
Differential Regulation of the Human Tyrosine Hydroxylase Isoforms via Hierarchical Phosphorylation
Lehmann, I. T., Bobrovskaya, L., Gordon, S. L., Dunkley, P. R., & Dickson, P. W. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m512194200 · Cited by 81 · see citing works
Self-citation
Enhanced Catecholamine Synthesis in the Prefrontal Cortex after Traumatic Brain Injury: Implications for Prefrontal Dysfunction
Kobori, N., Clifton, G. L., & Dash, P. K. (2006) · Journal of Neurotrauma · doi:10.1089/neu.2006.23.1094 · Cited by 80 · see citing works
“These increases in Ser31 and Ser40 phosphorylation are accompanied by enhanced TH activity (Dunkley et al., 2004).”
Parkin cooperates with GDNF/RET signaling to prevent dopaminergic neuron degeneration
Meka, D. P., Müller-Rischart, A. K., Nidadavolu, P., Mohammadi, B., Motori, E., Ponna, S. K., Aboutalebi, H., Bassal, M. A., Annamneedi, A., Finckh, B., et al. (2015) · Journal of Clinical Investigation · doi:10.1172/jci79300 · Cited by 80 · see citing works
Advanced Research on Dopamine Signaling to Develop Drugs for the Treatment of Mental Disorders: Biochemical and Behavioral Profiles of Phosphodiesterase Inhibition in Dopaminergic Neurotransmission
Nishi, A., & Snyder, G. L. (2010) · Journal of Pharmacological Sciences · doi:10.1254/jphs.10r01fm · Cited by 79 · see citing works
Quantitative assessment of gait and neurochemical correlation in a classical murine model of Parkinson’s disease
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“Tyrosine hydroxylase (TH) is the key enzyme in DA synthesis, as it converts tyrosine into levodopa, and is often used as a biomarker for dopaminergic neurons [6,7].”
Background
HIV, Tat and dopamine transmission
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The herbicide glyphosate causes behavioral changes and alterations in dopaminergic markers in male Sprague-Dawley rat
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14-3-3ζ Contributes to Tyrosine Hydroxylase Activity in MN9D Cells
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Degradation of Tyrosine Hydroxylase by the Ubiquitin-Proteasome System in the Pathogenesis of Parkinson’s Disease and Dopa-Responsive Dystonia
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“α-Synuclein activates stress-related protein kinases to potentiate TH phosphorylation at serine 40, suggesting the possible mechanism of pSer40-TH elevation by α-synuclein aggregation [52,124,125].”
BackgroundInfluential
Sustained phosphorylation of tyrosine hydroxylase at serine 40: a novel mechanism for maintenance of catecholamine synthesis
Bobrovskaya, L., Gilligan, C., Bolster, E. K., Flaherty, J. J., Dickson, P. W., & Dunkley, P. R. (2006) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2006.04213.x · Cited by 74 · see citing works
“In bovine adrenal chromaffin cells (BACCs) nicotine (Nic), histamine (His), angiotensin II (Ang), muscarine and bradykinin all acutely increase TH phosphorylation at Ser40 (Haycock 1990, 1993, 1996; Dunkley et al. 2004).”
BackgroundMethodResultInfluentialSelf-citation
Naringin treatment induces neuroprotective effects in a mouse model of Parkinson's disease in vivo, but not enough to restore the lesioned dopaminergic system
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Dynamics of tyrosine hydroxylase mediated regulation of dopamine synthesis
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Transcription factors FOXA1 and FOXA2 maintain dopaminergic neuronal properties and control feeding behavior in adult mice
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“The activity of TH can be modulated by phosphorylation, and phospho-serine 40 TH (pSer40 TH) represents an active form of the enzyme (28).”
Background
Catheter-Based Renal Denervation Reduces Atrial Nerve Sprouting and Complexity of Atrial Fibrillation in Goats
Linz, D., van Hunnik, A., Hohl, M., Mahfoud, F., Wolf, M. A., Neuberger, H., Casadei, B., Reilly, S. N., Verheule, S., Böhm, M., et al. (2015) · Circulation Arrhythmia and Electrophysiology · doi:10.1161/circep.114.002453 · Cited by 71 · see citing works
“TH is the rate-limiting enzyme in norepinephrine biosynthesis and is regulated by phosphorylation.(25) The TH-p/Th ratio was not altered by RDN, indicating that the remaining TH-positive nerves were functional and had a normal activity level.”
BackgroundMethod
Characteristics of sensory neuronal groups in CGRP-cre-ER reporter mice: Comparison to Nav1.8-cre, TRPV1-cre and TRPV1-GFP mouse lines
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A new role for α‐synuclein in Parkinson's disease: Alteration of ER–mitochondrial communication
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“Tyrosine hydroxylase, a homotetramer,(90) has two forms: an “active” form, which is phosphorylated by a variety of kinases,(91) primarily at Ser40(92,93) (and potentiated by a prior phosphorylation at Ser19(91,94)), and an “inactive,” unphosphorylated form, either synthesized de novo or generated by dephosphorylation…”
Background
The aromatic amino acid hydroxylases: Structures, catalysis, and regulation of phenylalanine hydroxylase, tyrosine hydroxylase, and tryptophan hydroxylase
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Regulatory mechanism of tyrosine hydroxylase activity
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Activation and stabilization of human tryptophan hydroxylase 2 by phosphorylation and 14-3-3 binding
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Phosphorylation of the N-terminal portion of tyrosine hydroxylase triggers proteasomal digestion of the enzyme
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Increased microglial activation in the rat brain following neonatal exposure to a bacterial mimetic
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Effects of manganese on tyrosine hydroxylase (TH) activity and TH-phosphorylation in a dopaminergic neural cell line
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“Phosphorylation and dephosphorylation of TH represent important post-translational regulatory mechanisms of the enzymatic activity that in turn regulates the amount of catecholamine synthesized in a dopaminergic system (Goldstein and Lieberman, 1992; Dunkley et al., 2004; Fujisawa and Okuno, 2005).”
Background
Trojan Horse Delivery of 4,4′‐Dimethoxychalcone for Parkinsonian Neuroprotection
Zhang, W., Chen, H., Ding, L., Gong, J., Zhang, M., Guo, W., Xu, P., Li, S., & Zhang, Y. (2021) · Advanced Science · doi:10.1002/advs.202004555 · Cited by 65 · see citing works
Traumatic brain injury reduces striatal tyrosine hydroxylase activity and potassium-evoked dopamine release in rats
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“It should also be noted that other kinases such as protein kinase C and protein kinase G may also regulate pser40TH levels (Dunkley et al., 2004), although less extensively characterized than PKA’s effect is on pser40TH.”
Background
Angiotensin‐(1–7) through AT2receptors mediates tyrosine hydroxylase degradation via the ubiquitin–proteasome pathway
Verrilli, M. A. L., Pirola, C. J., Pascual, M. M., Dominici, F. P., Turyn, D., & Gironacci, M. M. (2009) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2009.05912.x · Cited by 65 · see citing works
Phosphodiesterase 4 inhibition enhances the dopamine D1 receptor/PKA/DARPP-32 signaling cascade in frontal cortex
Kuroiwa, M., Snyder, G. L., Shuto, T., Fukuda, A., Yanagawa, Y., Benavides, D. R., Nairn, A. C., Bibb, J. A., Greengard, P., & Nishi, A. (2011) · Psychopharmacology · doi:10.1007/s00213-011-2436-8 · Cited by 64 · see citing works
“Phosphorylation of TH, the rate-limiting enzyme in dopamine biosynthesis which is abundant in catecholaminergic nerve terminals, at Ser40 is known to play an important role in the synthesis of dopamine (Dunkley et al. 2004; Harada et al. 1996).”
Dichotomy of Tyrosine Hydroxylase and Dopamine Regulation between Somatodendritic and Terminal Field Areas of Nigrostriatal and Mesoaccumbens Pathways
Salvatore, M. F., & Pruett, B. S. (2012) · PLoS ONE · doi:10.1371/journal.pone.0029867 · Cited by 61 · see citing works
“DAT and TH function [4,11,23,25].”
Amphetamine Self-Administration Attenuates Dopamine D2 Autoreceptor Function
Calipari, E. S., Sun, H., Eldeeb, K., Luessen, D. J., Feng, X., Howlett, A. C., Jones, S. R., & Chen, R. (2014) · Neuropsychopharmacology · doi:10.1038/npp.2014.30 · Cited by 61 · see citing works
Role of N-terminus of tyrosine hydroxylase in the biosynthesis of catecholamines
Nakashima, A., Hayashi, N., Kaneko, Y. S., Mori, K., Sabban, E. L., Nagatsu, T., & Ota, A. (2009) · Journal of Neural Transmission · doi:10.1007/s00702-009-0227-8 · Cited by 62 · see citing works
Dopamine neuron-derived IGF-1 controls dopamine neuron firing, skill learning, and exploration
Pristerà, A., Blomeley, C. P., Lopes, E. F., Threlfell, S., Merlini, E., Burdakov, D., Cragg, S. J., Guillemot, F., & Ang, S. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1806820116 · Cited by 62 · see citing works
“TH is the rate-limiting enzyme in the synthesis of DA and its phosphorylation at Ser40 increases its activity both in vitro and in vivo (40).”
Background
Aging Reveals a Role for Nigral Tyrosine Hydroxylase ser31 Phosphorylation in Locomotor Activity Generation
Salvatore, M. F., Pruett, B. S., Spann, S. L., & Dempsey, C. (2009) · PLoS ONE · doi:10.1371/journal.pone.0008466 · Cited by 60 · see citing works
“Although phosphorylation of TH by ERK at ser31 or PKA at ser40 can increase DA biosynthesis in situ [25,26], which phosphorylation site affects DA bioavailability in intact neuropil is unknown.”
Background
Emotional stress and sympathetic activity: Contribution of dorsomedial hypothalamus to cardiac arrhythmias
Fontes, M. A. P., Xavier, C. H., Marins, F. R., Limborço‐Filho, M., Vaz, G. C., Müller-Ribeiro, F. C. D. F., & Nalivaiko, E. (2014) · Brain Research · doi:10.1016/j.brainres.2014.01.043 · Cited by 60 · see citing works
Anti-inflammatory effects of cell-based therapy with tyrosine hydroxylase-positive catecholaminergic cells in experimental arthritis
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Epigenetic, transcriptional and posttranscriptional regulation of the tyrosine hydroxylase gene
Lenartowski, R., & Goc, A. (2011) · International Journal of Developmental Neuroscience · doi:10.1016/j.ijdevneu.2011.07.006 · Cited by 58 · see citing works
RA Differentiation Enhances Dopaminergic Features, Changes Redox Parameters, and Increases Dopamine Transporter Dependency in 6-Hydroxydopamine-Induced Neurotoxicity in SH-SY5Y Cells
Lopes, F. M., da Motta, L. L., Bastiani, M. A. D., Pfaffenseller, B., de Aguiar, B. W., de Souza, L. F., Zanatta, G., de Vargas, D. M., Schönhofen, P., Londero, G. F., et al. (2017) · Neurotoxicity Research · doi:10.1007/s12640-016-9699-0 · Cited by 58 · see citing works
Intrauterine growth restriction increases the preference for palatable foods and affects sensitivity to food rewards in male and female adult rats
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Islet proteomics reveals genetic variation in dopamine production resulting in altered insulin secretion
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“ERK1/2-mediated phosphorylation at serine 31 stabilizes the enzyme and stimulates catalytic activity (29, 30).”
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Resveratrol delays 6-hydroxydopamine-induced apoptosis by activating the PI3K/Akt signaling pathway
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Enhanced tyrosine hydroxylase activity induces oxidative stress, causes accumulation of autotoxic catecholamine metabolites, and augments amphetamine effects in vivo
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“By releasing the enzyme from endpoint inhibition and returning it to its activate state, phosphorylation of TH plays a direct role in the rate of catecholamine synthesis and bioavailability (Daubner et al. 2011; Dunkley et al. 2004).”
Background
Neonatal immune challenge alters reproductive development in the female rat
Sominsky, L., Meehan, C. L., Walker, A. K., Bobrovskaya, L., McLaughlin, E. A., & Hodgson, D. M. (2012) · Hormones and Behavior · doi:10.1016/j.yhbeh.2012.02.005 · Cited by 55 · see citing works
“TH is a rate-limiting enzyme in catecholamine synthesis (Dunkley et al., 2004).”
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Targeted inhibition of RAGE in substantia nigra of rats blocks 6-OHDA–induced dopaminergic denervation
Gasparotto, J., Ribeiro, C. T., Bortolin, R. C., Somensi, N., Rabelo, T. K., Kunzler, A., Souza, N. C., Pasquali, M. A. D. B., Moreira, J. C. F., & Gelain, D. P. (2017) · Scientific Reports · doi:10.1038/s41598-017-09257-3 · Cited by 55 · see citing works
Morphological and functional alterations in the substantia nigra pars compacta of the Mecp2-null mouse
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Cyclin-Dependent Kinase 5 in the Ventral Tegmental Area Regulates Depression-Related Behaviors
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“predominant role in dopamine synthesis (Dunkley et al., 2004)”
BackgroundInfluential
3‐[(2,4‐dimethoxy)benzylidene]‐anabaseine dihydrochloride protects against 6‐hydroxydopamine‐induced parkinsonian neurodegeneration through α7 nicotinic acetylcholine receptor stimulation in rats
Suzuki, S., Kawamata, J., Matsushita, T., Matsumura, A., Hisahara, S., Takata, K., Kitamura, Y., Kem, W. R., & Shimohama, S. (2012) · Journal of Neuroscience Research · doi:10.1002/jnr.23160 · Cited by 53 · see citing works
“TH, a rate-limiting enzyme in catecholamine synthesis, is a marker for dopaminergic neurons in the CNS (Dunkley et al., 2004).”
Background
HIF prolyl hydroxylase inhibition increases cell viability and potentiates dopamine release in dopaminergic cells
Johansen, J. L., Sager, T. N., Lotharius, J., Witten, L. M., Mørk, A., Egebjerg, J., & Thirstrup, K. (2010) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2010.06917.x · Cited by 52 · see citing works
Assessing nicotine dependence using an oral nicotine free-choice paradigm in mice
Bağdaş, D., Diester, C. M., Riley, J., Carper, M., Alkhlaif, Y., Alomari, D., Alayoubi, H., Poklis, J. L., & Damaj, M. I. (2019) · Neuropharmacology · doi:10.1016/j.neuropharm.2019.107669 · Cited by 51 · see citing works
“Tyrosine hydroxylase is the rate-limiting enzyme of catecholamine synthesis (Daubner et al., 2011; Dunkley et al., 2004), and DA is the primary neurotransmitter that modulates nicotine reward (Grady et al.”
Background
Aging of the rat mesostriatal system: Differences between the nigrostriatal and the mesolimbic compartments
Cruz‐Muros, I., Afonso‐Oramas, D., Abreu, P. M., Barroso‐Chinea, P., Rodrı́guez, M., González, M. C., & González‐Hernández, T. (2006) · Experimental Neurology · doi:10.1016/j.expneurol.2006.10.004 · Cited by 52 · see citing works
Elevated Glucocorticoid Levels Are Responsible for Induction of Tyrosine Hydroxylase mRNA Expression, Phosphorylation, and Enzyme Activity in the Nucleus of the Solitary Tract during Morphine Withdrawal
Núñez, C., Földes, A., Pérez-Flores, D., García-Borrón, J. C., Laorden, M. L., Kovács, K., & Milanés, M. V. (2009) · Endocrinology · doi:10.1210/en.2008-1732 · Cited by 51 · see citing works
PACAP stimulates the sustained phosphorylation of tyrosine hydroxylase at serine 40
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Self-citation
The 14-3-3 Protein Affects the Conformation of the Regulatory Domain of Human Tyrosine Hydroxylase
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Differential regulation of human tyrosine hydroxylase isoforms 1 and 2 in situ: Isoform 2 is not phosphorylated at Ser35
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Phytochemicals Modulate Biosynthesis and Function of Serotonin, Dopamine, and Norepinephrine for Treatment of Monoamine Neurotransmission-Related Psychiatric Diseases
Naoi, M., Wu, Y., Maruyama, W., & Shamoto‐Nagai, M. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26072916 · Cited by 52 · see citing works
“TPH and TH activity are regulated by phosphorylation by protein kinases, and feedback inhibition by the monoamines and allosteric regulation [8].”
Vulnerability to glutamate toxicity of dopaminergic neurons is dependent on endogenous dopamine and MAPK activation
Izumi, Y., Yamamoto, N., Matsuo, T., Wakita, S., Takeuchi, H., Kume, T., Katsuki, H., Sawada, H., & Akaike, A. (2009) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2009.06178.x · Cited by 48 · see citing works
Metabolic Response to Oral Microcystin-LR Exposure in the Rat by NMR-Based Metabonomic Study
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Tyrosine hydroxylase as a sentinel for central and peripheral tissue responses in Parkinson’s progression: Evidence from clinical studies and neurotoxin models
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Self-citation
Direct Binding of GTP Cyclohydrolase and Tyrosine Hydroxylase
Bowling, K. M., Huang, Z., Xu, D., Ferdousy, F., Funderburk, C. D., Karnik, N., Neckameyer, W. S., & O’Donnell, J. M. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m802552200 · Cited by 46 · see citing works
Molecular determinants for PP2A substrate specificity: Charged residues mediate dephosphorylation of tyrosine hydroxylase by the PP2A/B' regulatory subunit
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“Multisite phosphorylation of the TH regulatory domain by several kinases [CaM kinase II → Ser19; extracellular signal-regulated kinase, ERK, and cyclin-dependent kinase 5 → Ser31; protein kinase A (PKA) → Ser40] can increase TH activity several-fold by relieving catecholamine end product inhibition (11,12).”
Background
Docosahexaenoic acid protects motor function and increases dopamine synthesis in a rat model of Parkinson's disease via mechanisms associated with increased protein kinase activity in the striatum
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“TH can be phosphorylated at Ser40 in situ directly by PKA in response to FSK or directly or indirectly by PKC in response to phorbol esters like PMA (Dunkley et al., 2004).”
BackgroundInfluential
Tyrosine hydroxylase activity is regulated by two distinct dopamine‐binding sites
Gordon, S. L., Quinsey, N. S., Dunkley, P. R., & Dickson, P. W. (2008) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2008.05509.x · Cited by 45 · see citing works
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Sympathetic control of reflex cutaneous vasoconstriction in human aging
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“TH activity is nevertheless predominantly dependent on the phosphorylation at Ser40; phosphorylation at Ser31 also enhances TH activity but to a much lesser extent than for Ser40, and phosphorylation at Ser19 or Ser8 has no effect on the enzyme activity [13].”
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New Insights Into the Pharmacological Potential of Plant Flavonoids in the Catecholamine System
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Three-way Interaction between 14-3-3 Proteins, the N-terminal Region of Tyrosine Hydroxylase, and Negatively Charged Membranes
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Differential Expression of the B′β Regulatory Subunit of Protein Phosphatase 2A Modulates Tyrosine Hydroxylase Phosphorylation and Catecholamine Synthesis
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Authors: Dunkley, P. R., Bobrovskaya, L., Graham, M. E., Von Nagy‐Felsobuki, E. I., & Dickson, P. W.
Affiliations: University of Newcastle Australia (AU)
Corresponding author: Dunkley, Peter R.
ORCID: Dunkley, Peter R.
Bobrovskaya, Larisa
Graham, Mark E.
Dickson, Phillip W.
Venue: Journal of Neurochemistry
Publisher: Wiley
Published: 2004-11-18
Volume: 91
Issue: 5
Pages: 1025-1043
ISSN: 0022-3042 (ISSN-L)
1471-4159
DOI: 10.1111/j.1471-4159.2004.02797.x
OpenAlex: W2114431124
Semantic Scholar: f10f568903c3e4d7cdc660f6816f0563cabf919f
Cited by: 455
References: 117
Citations by year: 2026: 6 · 2025: 12 · 2024: 13 · 2023: 16 · 2022: 8 · 2021: 23 · 2020: 19 · 2019: 26 · 2018: 20 · 2017: 23 · 2016: 19 · 2015: 29 · 2014: 24 · 2013: 32 · 2012: 28
FWCI: 1.16
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations: Journal of Neurochemistry (publishedVersion)
PubMed (publishedVersion)
Funders: Medical Research Council
National Health and Medical Research Council
Topics: Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Keywords: tyrosine hydroxylase, serine phosphorylation, catecholamine synthesis, protein kinases, protein phosphatase, enzyme activation, phosphorylation stoichiometry
MeSH terms: Animals, Models, Biological, Phosphoprotein Phosphatases, Phosphorylation, Protein Kinases, Serine, Tyrosine 3-Monooxygenase

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Tyrosine hydroxylase phosphorylation: Regulation and consequences

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