Site-specific phosphorylation of tyrosine hydroxylase after KCl depolarization and nerve growth factor treatment of PC12 cells.

Mitchell, Jeffrey P.; Hardie, D. Grahame; Vulliet, Philip R

doi:10.1016/s0021-9258(18)45713-4

Cited by 41 publications

(8 citation statements)

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“…This supported an earlier observation, before ser31 was identified, that the peptide fragment associated with TH activation had ser31 in the sequence (Tachikawa et al, 1987). Indeed, increased ser31 phosphorylation, alone from NGF treatment or in conjunction with depolarization-stimulated ser19 phosphorylation, enhances L-DOPA accumulation and is independent of any affect on ser40 phosphorylation (Mitchell et al, 1990;Harada et al, 1996;Salvatore et al, 2001).…”

Section: Site-specific Tyrosine Hydroxylase Phosphorylation In Vivo: Current Statussupporting

confidence: 88%

Mechanisms of Parkinson's Disease

Hewitt

Whitworth

2017

Current Topics in Developmental Biology

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The power of Drosophila genetics has attracted attention in tackling important biomedical challenges such as the understanding and prevention of neurodegenerative diseases. Parkinson's disease (PD) is the most common neurodegenerative movement disorder which results from the relentless degeneration of midbrain dopaminergic neurons. Over the past two decades tremendous advances have been made in identifying genes responsible for inherited forms of PD. The ease of genetic manipulation in Drosophila has spurred the development of numerous models of PD, including expression of human genes carrying pathogenic mutations or the targeted mutation of conserved orthologs. The genetic and cellular analysis of these models is beginning to reveal fundamental insights into the pathogenic mechanisms. Numerous pathways and processes are disrupted in these models but some common themes are emerging. These often implicate aberrant synaptic function, protein aggregation, autophagy, oxidative stress, and mitochondrial dysfunction. Moreover, an impressive list of small molecule compounds have been identified as effective in reversing pathogenic phenotypes, paving the way to explore these for therapeutic interventions.

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Section: Site-specific Tyrosine Hydroxylase Phosphorylation In Vivo: Current Statussupporting

confidence: 88%

Mechanisms of Parkinson's Disease

Hewitt

Whitworth

2017

Current Topics in Developmental Biology

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“…Phosphorylation occurs on residues which correspond to serines 19, 31, and 40 in the rat enzyme ( , ). In cells, increased calcium levels result in increased phosphorylation of Ser19, increased activity of the phosphoinositol/protein kinase C pathway results in increased phosphorylation of Ser31, and increased cAMP levels result in increased phosphorylation of Ser40 ( − ). Similar results have been obtained with pure proteins, in that calmodulin-dependent protein kinase phosphorylates Ser19, the kinases ERK1 and ERK2 phosphorylate Ser31, and cAMP-dependent protein kinase A phosphorylates Ser40 ( , ).…”

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confidence: 99%

Effects of Phosphorylation on Binding of Catecholamines to Tyrosine Hydroxylase: Specificity and Thermodynamics

Ramsey

Fitzpatrick

2000

Biochemistry

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As the catalyst for the rate-limiting step in the biosynthesis of the catecholamine neurotransmitters, the activity of tyrosine hydroxylase is tightly regulated. A principle means of posttranslational regulation is reversible phosphorylation of serine residues in an N-terminal regulatory domain. Phosphorylation of serine 40 has been shown to have a large effect on the rate constant for dissociation of dopamine and a much smaller effect on that for DOPA [Ramsey, A. J., and Fitzpatrick, P. F. (1998) Biochemistry 37, 8980-8986]. To determine the structural basis for the differences in affinity and to further test the validity of the previously proposed model for regulation, the effects of phosphorylation of serine 40 on the affinities for a series of catechols have been determined. The affinities of the unphosphorylated enzyme vary by 3 orders of magnitude due to differences in the rates of dissociation. The highest affinities are found with catecholamines which lack a carboxylate. The affinities of the phosphorylated enzyme show a much smaller range. In the case of binding of dihydroxyphenylalanine, the decrease in affinity upon phosphorylation is due primarily to a decrease in the enthalpy of the interaction. Based upon these results, a structural model for the effect of phosphorylation is proposed.

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“…15−17 For example, early studies have shown that site-specific phosphorylation of TH is observable under depolarization and nerve growth factor treatment conditions in PC12 cells. 18 Similarly, activation of soluble TH isolated from rat striatum by Ca 2+ , ATP, and Mg 2+ has also been reported. 19 μM concentrations of Ca 2+ in digitonin-permeabilized adrenal medullary cells 20 and electrical stimulation induced multiplesite phosphorylation of TH in perfused rat adrenal gland have also been reported.…”

Section: ■ Introductionmentioning

confidence: 81%

“…Protein kinases and phosphatases involved in the phosphorylation/dephosphorylation of regulatory domains Ser 19, 31, and 40, and the corresponding effects on the TH activity have been widely studied. ,, However, the nature of intracellular or extracellular signal(s) responsible for protein kinase stimulation leading to TH phosphorylation is not well defined. Elevation of intracellular Ca 2+ levels during membrane depolarization or electrical stimulation has been proposed as the major signal for TH activation. − For example, early studies have shown that site-specific phosphorylation of TH is observable under depolarization and nerve growth factor treatment conditions in PC12 cells . Similarly, activation of soluble TH isolated from rat striatum by Ca 2+ , ATP, and Mg 2+ has also been reported .…”

Section: Introductionmentioning

confidence: 99%

Extracellular H⁺ Ions are a Novel Signal for Tyrosine Hydroxylase Activation in Catecholaminergic Cells

Eldani

Truong

et al. 2023

ACS Chem. Neurosci.

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Tyrosine hydroxylase catalyzes the rate-limiting step in the catecholamine biosynthetic pathway. Short-term TH activity is proposed to be regulated by the phosphorylation/dephosphorylation of regulatory domains Ser 40, 31, and/or 19 in response to membrane depolarization coupled increase in intracellular Ca 2+ . Here, we present in situ evidence to support that extracellular H + ions ([H + ] o ) are an intracellular or extracellular Ca 2+ -independent novel signal for TH activation in catecholaminergic MN9D and PC12 cells. [H + ] o -mediated TH activation is a short-term process coupled with a Na +independent Cl − /HCO 3 − exchanger-mediated increase of intracellular hydrogen ions ([H + ] i ). While extracellular Ca 2+ is not required for [H + ] o -mediated TH activation, [H + ] o does not increase the cytosolic Ca 2+ levels in neuronal or non-neuronal cells in the presence or absence of extracellular Ca 2+ . Although [H + ] o -mediated TH activation is associated with a significant increase in Ser 40 phosphorylation, major protein kinases proposed to be responsible for this process appear to be not involved. However, we have not been able to identify the protein kinase(s) involved in [H + ] o -mediated phosphorylation of TH at present. Studies with a panphosphatase inhibitor, okadaic acid (OA), appear to indicate that the inhibition of phosphatase activities may not play a significant role in H + -mediated activation of TH. The relevance of these findings to the physiological TH activation mechanism and hypoxia, ischemia, and trauma-induced selective dopaminergic neural death is being discussed in this paper.

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Site-specific phosphorylation of tyrosine hydroxylase after KCl depolarization and nerve growth factor treatment of PC12 cells.

Cited by 41 publications

References 34 publications

Mechanisms of Parkinson's Disease

Mechanisms of Parkinson's Disease

Effects of Phosphorylation on Binding of Catecholamines to Tyrosine Hydroxylase: Specificity and Thermodynamics

Extracellular H⁺ Ions are a Novel Signal for Tyrosine Hydroxylase Activation in Catecholaminergic Cells

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Site-specific phosphorylation of tyrosine hydroxylase after KCl depolarization and nerve growth factor treatment of PC12 cells.

Cited by 41 publications

References 34 publications

Mechanisms of Parkinson's Disease

Mechanisms of Parkinson's Disease

Effects of Phosphorylation on Binding of Catecholamines to Tyrosine Hydroxylase: Specificity and Thermodynamics

Extracellular H+ Ions are a Novel Signal for Tyrosine Hydroxylase Activation in Catecholaminergic Cells

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Extracellular H⁺ Ions are a Novel Signal for Tyrosine Hydroxylase Activation in Catecholaminergic Cells