Novel enhancement mechanism of tyrosine hydroxylase enzymatic activity by nitric oxide through S-nitrosylation

Abstract

Tyrosine hydroxylase (TH) is a rate-limiting step enzyme in the synthesis of catecholamines. Catecholamines function both as hormone and neurotransmitters in the peripheral and central nervous systems, therefore TH’s expression and enzymatic activity is tightly regulated by various mechanisms. Several post-translational modifications have been shown to regulate TH’s enzymatic activity such as phosphorylation, nitration and S-glutathionylation. While phosphorylation at N-terminal of TH can activate its enzymatic activity, nitration and S-glutathionylation can inactivate TH. In this study, we found that TH can also be S-nitrosylated by nitric oxide (NO). S-nitrosylation is a reversible modification of cysteine (cys) residue in protein and is known to be an emerging signaling mechanism mediated by NO. We found that TH can be S-nitrosylated at cys 279 and TH S-nitrosylation enhances its enzymatic activity both in vitro and in vivo. These results provide a novel mechanism of how NO can modulate TH’s enzymatic activity through S-nitrosylation.

ASL Metabolically Regulates Tyrosine Hydroxylase in the Nucleus Locus Coeruleus

“…GAPDH nitrosylation and expression of other CREB target genes (e.g., cFOS and VGF ) were reduced in SH-SY5Y shASL neurons as compared to shGFP controls (Figures 2C, S3D, and S3E). In addition, direct nitrosylation of TH, which has been established to enhance its enzymatic activity (Wang et al., 2017), was also significantly reduced in shASL neurons (Figures 2C and S3D). Supplementing SH-SY5Y shASL neurons with NOS-independent NO donor normalized nitrosylation of both GAPDH and TH and increased TH mRNA levels similar to that of shGFP control neurons (Figures 2D, 2E, and S3F).…”

Restoring pars intermedia dopamine concentrations and tyrosine hydroxylase expression levels with pergolide: evidence from horses with pituitary pars intermedia dysfunction

“…This finding highlights the independent synthetic pathways, turn over and genetic expression of DA receptors and TH in equid PI. Activation of DA D1 and D2 receptors in rodents has been shown to increase TH S-nitrosylation and its enzymatic activity [ 45 ]. It would be interesting in a further study to assess TH enzymatic activity and posttranslational modifications such as phosphorylation and nitrosylation in PI of young, old, and PPID-affected horses to determine if one of these modifications could potentially result in a difference in TH activity.…”

“…PPID causes depletion of DA and treatment with a DA agonist would allow the dopaminergic neurons to replenish DA storage in vesicles. In rodents, activation of DA D1 and D2 receptors has been shown to contribute to increasing TH enzymatic activity [ 45 ]. Thus, in the current study, DA concentrations and TH expression levels in PI tissue were compared between PPID-affected horses treated with pergolide over a period of 6 months, untreated PPID-affected horses, untreated aged horses without clinical signs of PPID, and untreated young horses.…”

Restoring pars intermedia dopamine concentrations and tyrosine hydroxylase expression levels with pergolide: evidence from horses with pituitary pars intermedia dysfunction

“…Activation of DA D1 and D2 receptors in rodents has been shown to increase TH S-nitrosylation and its enzymatic activity. 45 It would be interesting in a further study to assess TH enzymatic activity and posttranslational modi cations such as phosphorylation and nitrosylation in PI of young, old, and PPID-affected horses to determine one of these modi cations could potentially result in a difference in TH activity. This might explain the low concentration of DA, despite normal TH expression levels in aged horses.…”

“…In rodents, activation of DA D1 and D2 receptors has been shown to contribute to increasing TH enzymatic activity. 45 Thus, in the current study, DA concentrations and TH expression levels in PI tissue were compared between PPID-affected horses treated with pergolide over a period of 6 months, untreated PPID-affected horses, untreated aged horses without clinical signs of PPID, and untreated young horses. Our results suggest that equine PPID is a potential animal model for DA neurodegeneration which could give insights to PD and provides additional evidence of the therapeutic bene ts of dopaminergic receptor agonists.…”