Tyrosine hydroxylase phosphorylation <i>in vivo</i>

Dunkley, Peter R.; Dickson, Phillip W.

doi:10.1111/jnc.14675

Cited by 67 publications

(63 citation statements)

References 176 publications

(509 reference statements)

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“…Modelling the structural response to S40 phosphorylation. The feedback inhibition of TH by DA is alleviated by PKA phosphorylation of TH at S40, both in vitro and in vivo 1,17,20 . We prepared S40 phosphorylated TH and, as expected, pS40-TH presented increased IC 50 for DA (25-fold higher than unphosphorylated TH) ( Fig.…”

Section: Structural Differences Between Apo-th and Th(da) When The Tmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…The activity and stability of TH are regulated through many mechanisms, notably feedback inhibition by CAs and phosphorylation at serine/threonine residues of the N-terminal tail 16,17 , viewed as key to maintain DA homeostasis. TH is phosphorylated on T8, S19, S31 and S40 by several protein kinases with different site specificities 1,17 . The different phosphorylation sites regulate TH through binding to 14-3-3 proteins (S19), cellular localization to the Golgi and synaptic vesicles (S31), and activity (S40) 1,17,18 .…”

Section: Introductionmentioning

confidence: 99%

“…TH is phosphorylated on T8, S19, S31 and S40 by several protein kinases with different site specificities 1,17 . The different phosphorylation sites regulate TH through binding to 14-3-3 proteins (S19), cellular localization to the Golgi and synaptic vesicles (S31), and activity (S40) 1,17,18 . Early preparations of TH from the adrenal medulla revealed copurified CAs in the active site, forming a strong bidentate catecholate-Fe(III) complex 19 .…”

Section: Introductionmentioning

confidence: 99%

“…TH inhibition by CAs is competitive with respect to BH4, and they are released from the active site either by incubation with BH4 or by phosphorylation at S40, which is performed by several kinases, including cAMP-dependent protein kinases (PKAs) 17,20,21 . Thus, the strength of feedback inhibition by DA can be modulated by S40-targeting signalling pathways, e.g.…”

Section: Introductionmentioning

confidence: 99%

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The Structure of Human Tyrosine Hydroxylase Reveals the Mechanism for Feedback Inhibition by Dopamine

Valpuesta¹,

Bueno-Carrasco²,

Cuéllar³

et al. 2020

Preprint

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Tyrosine hydroxylase (TH) is a highly regulated enzyme that catalyses the rate-limiting step in the biosynthesis of dopamine (DA) and other catecholamines. Mutations and dysfunction in this enzyme lead to DA deficiency and parkinsonisms of different severity. An understanding of TH deficiency at the level of structure and stability has been lacking to date, as only structures of truncated TH forms have been available. Here, we used cryoEM to determine the first high-resolution structure of full-length human tetrameric TH in the absence (3.4 Å) and presence (3.8 Å) of the end-product and feedback inhibitor DA bound to the active site. We show that upon DA binding, an α-helix (residues 39-59) included within the flexible N-terminal tail of the regulatory domain, is internalized in the active site. The observed structural changes reveal the molecular basis of the inhibitory and stabilizing DA effect, reversible by TH S40-phosphorylation, which are crucial regulatory mechanisms for catecholamine and TH homeostasis.

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Section: Structural Differences Between Apo-th and Th(da) When The Tmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

The Structure of Human Tyrosine Hydroxylase Reveals the Mechanism for Feedback Inhibition by Dopamine

Valpuesta¹,

Bueno-Carrasco²,

Cuéllar³

et al. 2020

Preprint

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Norepinephrine and Epinephrine: Introduction

Stanford

2020

Encyclopedia of Life Sciences

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The catecholamines, norepinephrine and epinephrine (formerly named noradrenaline and adrenaline) are released from the adrenal gland and neurons in the brain. Norepinephrine is also released from the majority of postganglionic, sympathetic neurons in the peripheral (autonomic) nervous system. Conversion of the amino acid, tyrosine, to l ‐3,4‐dihydroxyphenylalanine is the rate‐limiting step in the synthetic pathway for both these catecholamines. This process is regulated by several hormones and neurotransmitters, which act via intracellular messengers to help ensure that the rate of catecholamine synthesis matches the rate of their release. In the periphery, norepinephrine and epinephrine are essential for maintaining a stable internal body state (‘homoeostasis’). In the central nervous system, norepinephrine has an important role in the regulation of attention/vigilance/alarm and its synchronization with the autonomic nervous system, but little is known about the function of neuronal epinephrine. Key Concepts The distribution of norepinephrine and epinephrine in the periphery. The distribution of norepinephrine and epinephrine in and brain. Regulation of the biosynthesis of norepinephrine and epinephrine. The role of norepinephrine and epinephrine in the periphery. The role(s) of norepinephrine and epinephrine in the brain.

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Oxidative Stress and Apoptosis in Bisphenol AF–Induced Neurotoxicity in Zebrafish Embryos

Gyimah

Zhu

Zhang

et al. 2022

Enviro Toxic and Chemistry

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Bisphenol AF (BPAF) is a structural counterpart of bisphenol A that is utilized in the food and beverage industry.The present study investigated the potential mechanisms in BPAF-induced neurotoxicity in zebrafish embryos. The BPAF concentrations (0.03, 0.1, 0.3, and 1.0 µM) had no obvious effect on hatching, mortality, and body length of zebrafish larvae, while curved tail and pericardial edema were observed in the 1.0 μM group at 72 and 96 h postfertilization (hpf). Locomotor activity of the larvae (at 120 hpf) significantly decreased from dark to light but increased from light to dark transitions in BPAF groups (0.1, 0.3, and 1.0 μM). Acridine orange showed that BPAF significantly increased green fluorescence protein intensity (22.6%) in the 1.0 μM group. Consistently, the induced apoptosis significantly up-regulated caspase 3 at 0.3 μM (1.95-fold) and 1.0 μM (2.26-fold) and bax at 0.3 μM (1.60-fold) and 1.0 μM (1.78-fold), whereas bcl-2 expression was significantly decreased at 0.3 μM (0.72-fold) and 1.0 μM (0.53-fold). In addition, increased reactive oxygen species concentrations at 0.3 μM (27%) and 1.0 μM (61.4%) resulted in suppressed superoxide dismutase and catalase activities. Moreover, quantitative polymerase chain reaction results showed that BPAF (0.3 and 1.0 μM) significantly altered normal dopaminergic signaling where dat was up-regulated, while drd2a and th1 were down-regulated, in a concentration-dependent manner. Aberrations in dopamine-related genes were congruous with the dysregulations in neurodevelopment genes (sox11b, pax6a, syn2a, and rob2). Our findings suggest that BPAF-evoked oxidative stress and apoptosis could translate into phenotypical behavioral and neurodevelopmental abnormalities. These highlights could provide theoretical reference for risk assessment and act as an early indicator to BPAF exposure.

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Tyrosine hydroxylase phosphorylation in vivo

Cited by 67 publications

References 176 publications

The Structure of Human Tyrosine Hydroxylase Reveals the Mechanism for Feedback Inhibition by Dopamine

The Structure of Human Tyrosine Hydroxylase Reveals the Mechanism for Feedback Inhibition by Dopamine

Norepinephrine and Epinephrine: Introduction

Oxidative Stress and Apoptosis in Bisphenol AF–Induced Neurotoxicity in Zebrafish Embryos

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