Epigenetic, transcriptional and posttranscriptional regulation of the tyrosine hydroxylase gene

Lenartowski, Robert; Goc, Anna

doi:10.1016/j.ijdevneu.2011.07.006

Cited by 51 publications

(65 citation statements)

References 170 publications

(285 reference statements)

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“…Newly synthesized β-actin can polymerize more efficiently than "older" actin because of chaperone binding and protection from glutathionylation, a post-translational modification that decreases the rate of polymerization. Being the rate-limiting factor in the synthesis of catecholamines, TH expression and activity is highly regulated by both transcriptional and post-translational mechanisms (for review, see Lenartowski and Goc 2011). It would be interesting to compare the pattern of post-translational modification between newly synthesized and "older" TH.…”

Section: Discussionmentioning

confidence: 99%

The local expression and trafficking of tyrosine hydroxylase mRNA in the axons of sympathetic neurons

Gervasi

Scott

Aschrafi

et al. 2016

RNA

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Synthesis and regulation of catecholamine neurotransmitters in the central nervous system are implicated in the pathogenesis of a number of neuropsychiatric disorders. To identify factors that regulate the presynaptic synthesis of catecholamines, we tested the hypothesis that the rate-limiting enzyme of the catecholamine biosynthetic pathway, tyrosine hydroxylase (TH), is locally synthesized in axons and presynaptic nerve terminals of noradrenergic neurons. To isolate pure axonal mRNA and protein, rat superior cervical ganglion sympathetic neurons were cultured in compartmentalized Campenot chambers. qRT-PCR and RNA in situ hybridization analyses showed that TH mRNA is present in distal axons. Colocalization experiments with nerve terminal marker proteins suggested that both TH mRNA and protein localize in regions of the axon that resemble nerve terminals (i.e., synaptic boutons). Analysis of polysome-bound RNA showed that TH mRNA is present in polysomes isolated from distal axons. Metabolic labeling of axonally synthesized proteins labeled with the methionine analog, L-azidohomoalanine, showed that TH is locally synthesized in axons. Moreover, the local transfection and translation of exogenous TH mRNA into distal axons facilitated axonal dopamine synthesis. Finally, using chimeric td-Tomato-tagged constructs, we identified a sequence element within the TH 3 ′ UTR that is required for the axonal localization of the reporter mRNA. Taken together, our results provide the first direct evidence that TH mRNA is trafficked to the axon and that the mRNA is locally translated. These findings raise the interesting possibility that the biosynthesis of the catecholamine neurotransmitters is locally regulated in the axon and/or presynaptic nerve terminal.

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Section: Discussionmentioning

confidence: 99%

The local expression and trafficking of tyrosine hydroxylase mRNA in the axons of sympathetic neurons

Gervasi

Scott

Aschrafi

et al. 2016

RNA

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“…This activation is mediated by indirect reflex excitation of the splanchnic nerve, which evokes large increases in catecholamine secretion (resulting in up to 70% of epinephrine content depletion) (47) accompanied by activation of TH enzyme and compensatory catecholamine biosynthesis in the adrenal medulla to maintain cellular catecholamine levels constant (41). As an index of catecholamine biosynthesis, we quantified changes in adrenal TH mRNA (25). After the hypoglycemic clamp, TH mRNA levels increased in all treatment groups compared with nonmanipulated controls.…”

Section: Transsynaptic Modulationmentioning

confidence: 99%

Partial blockade of nicotinic acetylcholine receptors improves the counterregulatory response to hypoglycemia in recurrently hypoglycemic rats

LaGamma

Kirtok

Chan

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

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LaGamma EF, Kirtok N, Chan O, Nankova BB. Partial blockade of nicotinic acetylcholine receptors improves the counterregulatory response to hypoglycemia in recurrently hypoglycemic rats. Am J Physiol Endocrinol Metab 307: E580 -E588, 2014. First published August 12, 2014; doi:10.1152/ajpendo.00237.2014.-Recurrent exposure to hypoglycemia can impair the normal counterregulatory hormonal responses that guard against hypoglycemia, leading to hypoglycemia unawareness. This pathological condition known as hypoglycemia-associated autonomic failure (HAAF) is the main adverse consequence that prevents individuals with type 1 diabetes mellitus from attaining the long-term health benefits of tight glycemic control. The underlying molecular mechanisms responsible for the progressive loss of the epinephrine response to subsequent bouts of hypoglycemia, a hallmark sign of HAAF, are largely unknown. Normally, hypoglycemia triggers both the release and biosynthesis of epinephrine through activation of nicotinic acetylcholine receptors (nAChR) on the adrenal glands. We hypothesize that excessive cholinergic stimulation may contribute to impaired counterregulation. Here, we tested whether administration of the nAChR partial agonist cytisine to reduce postganglionic synaptic activity can preserve the counterregulatory hormone responses in an animal model of HAAF. Compared with nicotine, cytisine has limited efficacy to activate nAChRs and stimulate epinephrine release and synthesis. We evaluated adrenal catecholamine production and secretion in nondiabetic rats subjected to two daily episodes of hypoglycemia for 3 days, followed by a hyperinsulinemic hypoglycemic clamp on day 4. Recurrent hypoglycemia decreased epinephrine responses, and this was associated with suppressed TH mRNA induction (a measure of adrenal catecholamine synthetic capacity). Treatment with cytisine improved glucagon responses as well as epinephrine release and production in recurrently hypoglycemic animals. These data suggest that pharmacological manipulation of ganglionic nAChRs may be promising as a translational adjunctive therapy to avoid HAAF in type 1 diabetes mellitus.hypoglycemia-associated autonomic failure; tyrosine hydroxylase; epinephrine release; cytisine; partial nicotinic acetylcholine receptor agonists AN ATTENUATED SYMPATHOADRENAL RESPONSE following recurrent exposure to hypoglycemia results in a pathological inability to recover from low blood glucose levels, contributes to patient unawareness of hypoglycemia, and is associated with increased mortality in type 1 and possibly type 2 diabetic patients, a condition known as hypoglycemia-associated autonomic failure (HAAF) (1, 11). HAAF is recognized as a major public health problem for patients with diabetes. It can also be induced in healthy subjects, in infants and in animal models suggesting it may involve a maladaptive response to repeated stress (9,12,14,20).Despite the well-established role of hypoglycemia per se in the development of HAAF, the mechanism(s) underlying the key feature of t...

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“…The explanation of the mechanism of TH gene regulation is one of the key issues in the field of neurology. Only a few laboratories have studied epigenetic mechanisms of the TH gene expression during the last decade [13,30]. We demonstrated that H3 acetylation showed a significant increase 24 h after chronic morphine treatment in the LC.…”

Section: Quantification Of Morphine-induced Histone Modifications At mentioning

confidence: 87%

“…These experiments make it evident that histone H3 acetylation may be involved in the molecular basis of neural and behavioral responses to addictive drugs [18,29]. In addition to histone modifications, other epigenetic systems including DNA methylation and microRNAs have also shown to affect the activity of the TH gene in a variety of animal models [30]. Thus, it is well established that TH gene methylation causes a decrease in TH expression, for example, in mesocortical projection of dopaminergic neurons after a mild isolation stress in a mouse model of depression [31].…”

Section: Introductionmentioning

confidence: 98%

Expression Levels of the Tyrosine Hydroxylase Gene and Histone Modifications Around its Promoter in the Locus Coeruleus and Ventral Tegmental Area of Rats during Forced Abstinence from Morphine

Mashayekhi¹,

Rasti²,

Khoshdel³

et al. 2018

Eur Addict Res

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Background: Epigenetic mechanisms such as histone modifications may be involved in the structural and behavioral changes associated with addiction. We studied whether morphine-induced changes in mRNA levels of the catecholamine biosynthesis enzyme, tyrosine hydroxylase (TH), are associated with histone modifications around the promoter of this gene in the locus coeruleus (LC) and ventral tegmental area (VTA) of rats. Methods: Dependence was induced in rats by intraperitoneal injections of morphine for 11 days. The animals were killed 2 h (chronic morphine), 24 h and 7 days (spontaneous withdrawal) after the last injection of morphine. Results: Analysis of our real-time quantitative reverse transcription PCR results by 1-way ANOVA showed significant upregulation (5.13 ± 0.39 folds) of LC levels of the TH transcript 24 h after the last injection of morphine to rats, when compared with 2 h and 7 days time points. Chronic morphine and morphine abstinence failed to cause any significant changes in the levels of TH mRNA in the VTA after cessation of morphine. Consistently, chromatin immunoprecipitation real-time quantitative PCR assays revealed that 24 h after the last injection of morphine, levels of H3 acetylation were significantly increased (4.12 ± 0.38 folds) at the promoter of the TH gene in the LC but not in the VTA. Our data also showed that histone H3 trimethylation failed to change around the TH gene promoter either in the VTA or in the LC after morphine abstinence. Conclusions: Results of the present study, for the first time, demonstrate the involvement of histone H3 acetylation in the regulation of TH gene expression in the LC of rats during forced abstinence from morphine.

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Epigenetic, transcriptional and posttranscriptional regulation of the tyrosine hydroxylase gene

Cited by 51 publications

References 170 publications

The local expression and trafficking of tyrosine hydroxylase mRNA in the axons of sympathetic neurons

The local expression and trafficking of tyrosine hydroxylase mRNA in the axons of sympathetic neurons

Partial blockade of nicotinic acetylcholine receptors improves the counterregulatory response to hypoglycemia in recurrently hypoglycemic rats

Expression Levels of the Tyrosine Hydroxylase Gene and Histone Modifications Around its Promoter in the Locus Coeruleus and Ventral Tegmental Area of Rats during Forced Abstinence from Morphine

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