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Tyrosine hydroxylase phosphorylation: regulation and consequences
Open accessAbstract
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, 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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“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].”
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BackgroundThe Evolution of Dopamine Systems in Chordates
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“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).”
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“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).”
BackgroundHypoxia. 3. Hypoxia and neurotransmitter synthesis
Kumar, G. K. (2011) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00019.2011 · Cited by 105
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“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.”
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“These increases in Ser31 and Ser40 phosphorylation are accompanied by enhanced TH activity (Dunkley et al., 2004).”
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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].”
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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].”
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“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).”
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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).”
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“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.”
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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…”
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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).”
BackgroundTrojan 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 63
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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.”
BackgroundVerrilli, 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
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“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).”
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“DAT and TH function [4,11,23,25].”
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“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).”
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“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.”
BackgroundFontes, 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
Jenei‐Lanzl, Z., Capellino, S., Kees, F., Fleck, M., Lowin, T., & Straub, R. H. (2013) · Annals of the Rheumatic Diseases · doi:10.1136/annrheumdis-2013-203925 · Cited by 60
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
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 62
Molle, R. D., Laureano, D. P., Alves, M. B., Reis, T. M., Desai, M., Ross, M. G., & Silveira, P. P. (2015) · Brain Research · doi:10.1016/j.brainres.2015.05.019 · Cited by 58
Mitok, K. A., Freiberger, E. C., Schueler, K. L., Rabaglia, M. E., Stapleton, D. S., Kwiecien, N. W., Malec, P. A., Hebert, A. S., Broman, A. T., Kennedy, R. T., et al. (2018) · Journal of Biological Chemistry · doi:10.1074/jbc.ra117.001102 · Cited by 61
“ERK1/2-mediated phosphorylation at serine 31 stabilizes the enzyme and stimulates catalytic activity (29, 30).”
BackgroundResveratrol delays 6-hydroxydopamine-induced apoptosis by activating the PI3K/Akt signaling pathway
Huang, N., Zhang, Y., Chen, M., et al. (2019) · Experimental Gerontology · doi:10.1016/j.exger.2019.110653 · Cited by 57
Vecchio, L. M., Sullivan, P., Dunn, A. R., Bermejo, M. K., Fu, R., Masoud, S. T., Gregersen, E., Urs, N. M., Nazari, R., Jensen, P. H., et al. (2021) · Journal of Neurochemistry · doi:10.1111/jnc.15432 · Cited by 56
“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).”
BackgroundNeonatal 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
“TH is a rate-limiting enzyme in catecholamine synthesis (Dunkley et al., 2004).”
BackgroundSelf-citationGasparotto, 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
Panayotis, N., Pratte, M., Borges-Correia, A., Ghata, A., Villard, L., & Roux, J.-C. (2011) · Neurobiology of Disease · doi:10.1016/j.nbd.2010.10.006 · Cited by 54
Cyclin-Dependent Kinase 5 in the Ventral Tegmental Area Regulates Depression-Related Behaviors
Zhong, P., Liu, X., Zhang, Z., Hu, Y. C., Liu, S. J., Lezama-Ruiz, M., Joksimovic, M., & Liu, Q.-S. (2014) · Journal of Neuroscience · doi:10.1523/jneurosci.3673-13.2014 · Cited by 53
“predominant role in dopamine synthesis (Dunkley et al., 2004)”
BackgroundInfluentialSuzuki, 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
“TH, a rate-limiting enzyme in catecholamine synthesis, is a marker for dopaminergic neurons in the CNS (Dunkley et al., 2004).”
BackgroundJohansen, 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
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
“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.”
BackgroundCruz‐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
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
PACAP stimulates the sustained phosphorylation of tyrosine hydroxylase at serine 40
Bobrovskaya, L., Gelain, D. P., Gilligan, C., et al. (2007) · Cellular Signalling · doi:10.1016/j.cellsig.2006.12.006 · Cited by 51
Self-citationThe 14-3-3 Protein Affects the Conformation of the Regulatory Domain of Human Tyrosine Hydroxylase
Obšilová, V., Nedbalkova, E., Šilhán, J., Bouřa, E., Heřman, P., Večeř, J., Šulc, M., Teisinger, J., Dyda, F., & Obšil, T. (2008) · Biochemistry · doi:10.1021/bi7019468 · Cited by 51
Gordon, S. L., Bobrovskaya, L., Dunkley, P. R., & Dickson, P. W. (2009) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2009.10.001 · Cited by 49
Self-citationNaoi, M., Wu, Y., Maruyama, W., & Shamoto‐Nagai, M. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26072916 · Cited by 52
“TPH and TH activity are regulated by phosphorylation by protein kinases, and feedback inhibition by the monoamines and allosteric regulation [8].”
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
Metabolic Response to Oral Microcystin-LR Exposure in the Rat by NMR-Based Metabonomic Study
He, J., Chen, J., Wu, L., Li, G., & Xie, P. (2012) · Journal of Proteome Research · doi:10.1021/pr300685g · Cited by 47
Johnson, M., Salvatore, M. F., Maiolo, S., & Bobrovskaya, L. (2018) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2018.01.002 · Cited by 49
Self-citationDirect 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
Saraf, A., Oberg, E. A., & Strack, S. (2010) · Biochemistry · doi:10.1021/bi902160t · Cited by 45
“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).”
BackgroundChitre, N. M., Wood, B. J., Ray, A., Moniri, N. H., & Murnane, K. S. (2020) · Neuropharmacology · doi:10.1016/j.neuropharm.2020.107976 · Cited by 45
“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).”
BackgroundInfluentialTyrosine 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
Self-citationSympathetic control of reflex cutaneous vasoconstriction in human aging
Greaney, J. L., Alexander, L. M., & Kenney, W. L. (2015) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00527.2015 · Cited by 44
Bechmann, N., Poser, I., Seifert, V., Greunke, C., Ullrich, M., Qin, N., Walch, A. K., Peitzsch, M., Robledo, M., Pacák, K., et al. (2019) · Cancers · doi:10.3390/cancers11050594 · Cited by 44
“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].”
BackgroundNew Insights Into the Pharmacological Potential of Plant Flavonoids in the Catecholamine System
Yanagihara, N., Zhang, H., Toyohira, Y., Takahashi, K., Ueno, S., Tsutsui, M., & TAKAHASHI, K. (2014) · Journal of Pharmacological Sciences · doi:10.1254/jphs.13r17cp · Cited by 45
Singh, M., Murthy, V., & Ramassamy, C. (2013) · Neurochemistry International · doi:10.1016/j.neuint.2013.01.030 · Cited by 43
Halskau, Ø., Ying, M., Baumann, A., Kleppe, R., Rodríguez‐Larrea, D., Almås, B., Haavik, J., & Martı́nez, A. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.027706 · Cited by 43
Saraf, A., Virshup, D. M., & Strack, S. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m607407200 · Cited by 43
Metadata
- 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.
- Venue
- Journal of Neurochemistry
- Publisher
- Wiley
- Published
- 2004-11-18
- Volume
- 91
- Issue
- 5
- Pages
- 1025-1043
- ISSN
- 0022-3042 (ISSN-L)
- 1471-4159
- 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
- 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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