Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.1.99.3 (PRE)
 1,923 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Steroid hormones, especially glucocorticoids, exert physiologic effects on dopaminergic neurotransmission and have been implicated in several dopamine-mediated neuropsychiatric conditions. D(2) dopamine receptor gene expression is regulated by the zinc finger-type nuclear protein GDNF-inducible transcription factor (GIF). In this study, we sought to investigate if steroids could regulate transcription of the GIF gene itself. Transient co-transfection of the D(2) expressing neuroblastoma cell line NB41A3 with GIF promoter-luciferase constructs along with expression vectors for steroid hormone receptors showed that activation of glucocorticoid receptors but not estrogen receptors up-regulates transcription from the GIF promoter 5.0-fold. Progesterone receptors, which share the same consensus DNA recognition sequence as glucocorticoid receptors, also activated the GIF promoter. Serial 5'-deletion mutants of the GIF gene upstream region localized the glucocorticoid-responsive segment between nucleotides -128 and -66 relative to the transcription start site. This region contains a putative glucocorticoid-responsive element/progesterone-responsive element (GRE/PRE). Additionally, this fragment of the GIF gene 5'-upstream region activated the heterologous herpes simplex virus thymidine kinase (TK) promoter, which is known to be glucocorticoid and progesterone responsive. Furthermore, glucocorticoid receptor activation up-regulated endogenous GIF gene mRNA expression in NB41A3 cells. These observations demonstrate a molecular basis for glucocorticoid and progesterone-induced up-regulation of GIF gene transcription and provide a mechanism for the modulation of dopamine-mediated behaviors by these hormones.
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PMID:Activation of the GDNF-inducible transcription factor (GIF) gene promoter by glucocorticoid and progesterone. 1942 58

The sigma-1 receptor, an endoplasmic reticulum-associated molecular chaperone, is attracting great interest as a potential target for neuroprotective treatments. We provide the first evidence that pharmacological modulation of this protein produces functional neurorestoration in experimental parkinsonism. Mice with intrastriatal 6-hydroxydopamine lesions were treated daily with the selective sigma-1 receptor agonist, PRE-084, for 5 weeks. At the dose of 0.3 mg/kg/day, PRE-084 produced a gradual and significant improvement of spontaneous forelimb use. The behavioural recovery was paralleled by an increased density of dopaminergic fibres in the most denervated striatal regions, by a modest recovery of dopamine levels, and by an upregulation of neurotrophic factors (BDNF and GDNF) and their downstream effector pathways (extracellular signal regulated kinases 1/2 and Akt). No treatment-induced behavioural-histological restoration occurred in sigma-1 receptor knockout mice subjected to 6-hydroxydopamine lesions and treated with PRE-084. Immunoreactivity for the sigma-1 receptor protein was evident in both astrocytes and neurons in the substantia nigra and the striatum, and its intracellular distribution was modulated by PRE-084 (the treatment resulted in a wider intracellular distribution of the protein). Our results suggest that sigma-1 receptor regulates endogenous defence and plasticity mechanisms in experimental parkinsonism. Boosting the activity of this protein may have disease-modifying effects in Parkinson's disease.
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PMID:Pharmacological stimulation of sigma-1 receptors has neurorestorative effects in experimental parkinsonism. 2475 75