0000000000745881
AUTHOR
Nadhim Bayatti
Corticotropin-Releasing Hormone-Mediated Induction of Intracellular Signaling Pathways and Brain-Derived Neurotrophic Factor Expression Is Inhibited by the Activation of the Endocannabinoid System
CRH receptor (CRHR) 1 and the cannabinoid receptor 1 (CB1) are both G protein-coupled receptors. Activation of CRHR1 leadstoincreasesincAMPproductionandphosphorylationof the transcription factor cAMP response element-binding protein (CREB). In contrast, CB1 is negatively coupled to the cAMP signaling cascade. In this study, we analyzed a putative interaction between these two systems focusing on the regulation of the expression of brain-derived neurotrophic factor (BDNF), a CREB-regulated gene. In situ hybridization revealed coexpression of CRHR1 and CB1 receptors in the granular layer of the cerebellum. Therefore, we analyzed the effects of CRH and the CB1 agonist WIN-55,212-2 on BDNF expr…
Membrane protein oxidation determines neuronal degeneration
Oxidative stress is an early hallmark in neurodegenerative disorders such as Alzheimer's and Parkinson's diseases. However, the critical biochemical effector mechanisms of oxidative neurotoxicity have remained surprisingly elusive. In screening various peroxides and potential substrates of oxidation for their effect on neuronal survival, we observed that intramembrane compounds were significantly more active than aqueous or amphiphilic compounds. To better understand this result, we synthesized a series of competitive and site-specific membrane protein oxidation inhibitors termed aminoacyllipids, whose structures were designed on the basis of amino acids frequently found at the protein-lipi…
Caveolin and GLT-1 gene expression is reciprocally regulated in primary astrocytes: Association of GLT-1 with non-caveolar lipid rafts
Caveolae represent membrane microdomains acting as integrators of cellular signaling and functional processes. Caveolins are involved in the biogenesis of caveolae and regulate the activity of caveolae-associated proteins. Although caveolin proteins are found in the CNS, the regulation of caveolins in neural cells is poorly described. In the present study, we investigated different modes and mechanisms of caveolin gene regulation in primary rat astrocytes. We demonstrated that activation of cAMP-dependent signaling pathways led to a marked reduction in protein levels of caveolin-1/-2 in cortical astrocytes. Application of transforming growth factor-alpha (TGF-alpha) also resulted in a decre…
Differential Promotion of Glutamate Transporter Expression and Function by Glucocorticoids in Astrocytes from Various Brain Regions
Steroids that activate glucocorticoid receptors (GRs) and mineralocorticoid receptors have important regulatory effects on neural development, plasticity, and the body's stress response. Here, we investigated the role of corticosteroids in regulating the expression of the glial glutamate transporters glial glutamate transporter-1 (GLT-1) and glutamate-aspartate transporter (GLAST) in rat primary astrocytes. The synthetic glucocorticoid dexamethasone provoked a marked increase of GLT-1 transcription and protein levels in cortical astrocytes, whereas GLAST expression remained unaffected. Up-regulation of GLT-1 expression was accompanied by an enhanced glutamate uptake, which could be blocked …
The neuroprotective actions of corticotropin releasing hormone
Corticotropin-releasing hormone (CRH) modulates the activity of the hypothalamic-pituitary-adrenal (HPA) axis, and has a key role in mediating neuroendocrine effects that occur in response to stressful stimuli. Disruption of the CRH system however has been shown to be closely associated with the progression of Alzheimer's disease (AD), and these observations prompted an investigation into the potential neuroprotective effects of the hormone. In addition to its regulatory affects on the molecular processes that underlie AD i.e., amyloid precursor protein (APP) processing and potentially tau phosphorylation, evidence is provided that the neuroprotective effects of CRH are mediated by a number…
Functional interaction of estrogen receptor α and caveolin isoforms in neuronal SK-N-MC cells
Estrogen receptors (ERs) are expressed in neuronal cells and exhibit a wide variety of activities in the central nervous system. The actions of ERs are regulated in a hormone-dependent manner as well as by a number of co-activators and -repressors. A recently identified co-activator of ERalpha is caveolin-1 which has been shown to mediate the ligand-independent activation of this steroid receptor. In the present study we have demonstrated that neuronal SK-N-MC cells lacking functional ERalpha show high levels of caveolin-1/-2 specific transcripts and proteins. Ectopic expression of ERalpha in SK-N-MC cells leads to the transcriptional suppression of caveolin-1 and -2 genes. This silencing e…