Post-transcriptional Regulation of Tyrosine Hydroxylase Expression in Adrenal Medulla and Brain

Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, New York 14642, USA.
Annals of the New York Academy of Sciences (Impact Factor: 4.31). 01/2009; 1148(1):238-48. DOI: 10.1196/annals.1410.054
Source: PubMed

ABSTRACT It is well established that long-term stress leads to induction of tyrosine hydroxylase (TH) mRNA and TH protein in adrenal medulla and brain. This induction is usually associated with stimulation of the TH gene transcription rate. However, a number of studies have reported major discrepancies between the stress-induced changes in TH gene transcription, TH mRNA, and TH protein. These discrepancies suggest that post-transcriptional mechanisms also play an important role in regulating TH expression in response to stress and other stimuli. In this report, we summarize some of our findings and literature reports that demonstrate these discrepancies in adrenal medulla, locus ceruleus, and midbrain dopamine neurons. We then describe our recent work investigating the molecular mechanisms that mediate this post-transcriptional regulation in adrenal medulla and midbrain. Our results suggest that trans-acting factors binding to the polypyrimidine-rich region of the 3' untranslated region of TH mRNA play a role in these post-transcriptional mechanisms. A hypothetical cellular model describing this post-transcriptional regulation is proposed.

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    • "These studies also showed that posttranscriptional regulations have a crucial role in the synthesis of TH in the SN/VTA (Chen et al., 2008; Tank et al., 2008). Posttranscriptional modulation occurs after the production of mRNA is completed, and includes the stabilization of the mRNA, the attachment to polyribosomes, and the regulation of the efficacy of translation into protein (Tank et al., 2008; Lenartowski and Goc, 2011). For all these reasons, we believe that is necessary to study TH protein levels in the SN/VTA in schizophrenia, to assess the possibility of pathologies that could be located in posttranscriptional steps in the synthesis of TH, rather than at the transcription level. "
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    ABSTRACT: Introduction: Despite the importance of dopamine neurotransmission in schizophrenia, very few studies have addressed anomalies in the mesencephalic dopaminergic neurons of the substantia nigra/ventral tegmental area (SN/VTA). Tyrosine hydroxylase (TH) is the rate-limiting enzyme for the production of dopamine, and a possible contributor to the anomalies in the dopaminergic neurotransmission observed in schizophrenia. Objectives: In this study, we had three objectives: (1) Compare TH expression (mRNA and protein) in the SN/VTA of schizophrenia and control postmortem samples. (2) Assess the effect of antipsychotic medications on the expression of TH in the SN/VTA. (3) Examine possible regional differences in TH expression anomalies within the SN/VTA. Methods: To achieve these objectives three independent studies were conducted: (1) A pilot study to compare TH mRNA and TH protein levels in the SN/VTA of postmortem samples from schizophrenia and controls. (2) A chronic treatment study was performed in rodents to assess the effect of antipsychotic medications in TH protein levels in the SN/VTA. (3) A second postmortem study was performed to assess TH and phosphorylated TH protein levels in two types of samples: schizophrenia and control samples containing the entire rostro-caudal extent of the SN/VTA, and schizophrenia and control samples containing only mid-caudal regions of the SN/VTA. Results and Conclusion: Our studies showed impairment in the dopaminergic system in schizophrenia that could be mainly (or exclusively) located in the rostral region of the SN/VTA. Our studies also showed that TH protein levels were significantly abnormal in schizophrenia, while mRNA expression levels were not affected, indicating that TH pathology in this region may occur posttranscriptionally. Lastly, our antipsychotic animal treatment study showed that TH protein levels were not significantly affected by antipsychotic treatment, indicating that these anomalies are an intrinsic pathology rather than a treatment effect.
    Frontiers in Psychiatry 04/2012; 3:31. DOI:10.3389/fpsyt.2012.00031
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    • "The tissue specificity of transcriptional activation may depend on the balance of repressor and activator trans-acting factors, sometimes interacting with the same cis element, as in the case of CREB and ICER binding to the cAMP responsive element (CRE) in the TH promoter (Tinti et al., 1996). A stressor of a given type activates different response mechanisms in various TH + cells (reviewed in Tank et al., 2008). Neurons are characterized by their diversified sensitivity to the stimulus depending on the tissue type, as demonstrated in the adrenal medulla and locus coeruleus. "
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    ABSTRACT: The activity of tyrosine hydroxylase (TH, EC gene and protein determines the catecholamine level, which, in turn, is crucial for the organism homeostasis. The TH gene expression is regulated by near all possible regulatory mechanisms on epigenetic, transcriptional and posttranscriptional levels. Ongoing molecular characteristic of the TH gene reveals some of the cis and trans elements necessary for its proper expression but most of them especially these responsible for tissue specific expression remain still obscure. This review will focus on some aspects of TH regulation including spatial chromatin organization of the TH locus and TH gene, regulatory elements mediating basal, induced and cell-specific activity, transcriptional elongation, alternative TH RNA processing, and the regulation of TH RNA stability in the cell.
    International journal of developmental neuroscience: the official journal of the International Society for Developmental Neuroscience 07/2011; 29(8):873-83. DOI:10.1016/j.ijdevneu.2011.07.006 · 2.92 Impact Factor
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    • "However, no studies have systematically investigated the time course of phosphorylation of these sites in vivo in response to different stressors. Many studies have investigated TH mRNA and/or TH protein changes in response to stressors (Watanabe et al., 1995; Rusnák et al., 2001; Tank et al., 2008), but these measures are only detectable many hours after exposure to the stressor. In the LC, TH mRNA levels were significantly increased 6 h after a 15-min period of footshock stress (Chang et al., 2000), while TH protein levels were significantly increased 24 h after a 2-h period of immobilization stress (Hebert et al., 2005). "
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    ABSTRACT: Tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine biosynthesis, is regulated acutely by protein phosphorylation. No studies have systematically investigated the time course of TH phosphorylation in vivo in response to different stressors. We therefore determined the extent of TH phosphorylation at Ser19, Ser31, and Ser40 over a 40-min period in response to footshock or immobilization stress in the rat locus coeruleus and adrenal medulla. There were significant changes in TH phosphorylation in both tissues and the responses to the two stressors differed markedly. With each of the phosphorylation sites immobilization stress caused a much smaller, or less sustained, response than footshock stress. With immobilization stress there was a transient increase in Ser31 phosphorylation in the locus coeruleus and in the adrenal medulla, but there were no effects on Ser19 or Ser40 phosphorylation. With footshock stress there was a substantial decrease in Ser19 phosphorylation over time, a substantial increase in Ser31 phosphorylation over time, but there were no effects on Ser40 phosphorylation. Measuring TH phosphorylation at Ser19, Ser31, and Ser40 over time can therefore be used as a sensitive index to differentiate the effects of different stressors on catecholaminergic cells.
    Neuroscience 07/2011; 192:20-7. DOI:10.1016/j.neuroscience.2011.06.087 · 3.33 Impact Factor
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