Adrenoceptors in brain: cellular gene expression and effects on astrocytic metabolism and (Ca(2+))i. Neurochem Int

Department of Clinical Pharmacology, College of Basic Medical Sciences, China Medical University, Shenyang, PR China.
Neurochemistry International (Impact Factor: 3.09). 04/2010; 57(4):411-20. DOI: 10.1016/j.neuint.2010.03.019
Source: PubMed


Recent in vivo studies have established astrocytes as a major target for locus coeruleus activation (Bekar et al., 2008), renewing interest in cell culture studies on noradrenergic effects on astrocytes in primary cultures and calling for additional information about the expression of adrenoceptor subtypes on different types of brain cells. In the present communication, mRNA expression of alpha(1)-, alpha(2)- and beta-adrenergic receptors and their subtypes was determined in freshly isolated, cell marker-defined populations of astrocytes, NG2-positive cells, microglia, endothelial cells, and Thy1-positive neurons (mainly glutamatergic projection neurons) in murine cerebral cortex. Immediately after dissection of frontal, parietal and occipital cortex of 10-12-week-old transgenic mice, which combined each cell-type marker with a specific fluorescent signal, the tissue was digested, triturated and centrifuged, yielding a solution of dissociated cells of all types, which were separated by fluorescence-activated cell sorting (FACS). mRNA expression in each cell fraction was determined by microarray analysis. alpha(1A)-Receptors were unequivocally expressed in astrocytes and NG2-positive cells, but absent in other cell types, and alpha(1B)-receptors were not expressed in any cell population. Among alpha(2)-receptors only alpha(2A)-receptors were expressed, unequivocally in astrocytes and NG-positive cells, tentatively in microglia and questionably in Thy1-positive neurons and endothelial cells. beta(1)-Receptors were unequivocally expressed in astrocytes, tentatively in microglia, and questionably in neurons and endothelial cells, whereas beta(2)-adrenergic receptors showed tentative expression in neurons and astrocytes and unequivocal expression in other cell types. This distribution was supported by immunochemical data and its relevance established by previous studies in well-differentiated primary cultures of mouse astrocytes, showing that stimulation of alpha(2)-adrenoceptors increases glycogen formation and oxidative metabolism, the latter by a mechanism depending on intramitochondrial Ca(2+), whereas alpha(1)-adrenoceptor stimulation enhances glutamate uptake, and beta-adrenoceptor activation causes glycogenolysis and increased Na(+), K(+)-ATPase activity. The Ca(2+)- and cAMP-mediated association between energy-consuming and energy-yielding processes is emphasized.

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Available from: Steven A Goldman, Oct 06, 2015
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    • "However, Gibbs and Summers showed that NE released by brainstem noradrenergic neurons, besides its neurotransmitter role, is also involved in maintaining the Fig. 9Correlation plots illustrating the relationship of norepinephrine (NE) concentration and interleukine-6 mRNA (IL-6 mRNA) in cornu ammonis (CA) of wild-type controls (a, white circle), transgenic controls (b, black circle), wild-type rats exposed to a single 2-h immobilization stress (c, white circle), and transgenic rats exposed to a single 2-h immobilization stress (d, black circle) brain's tissue milieu[4]. Furthermore, centrally released NE modulates synaptic plasticity, neurogenesis, energy metabolism, activity of astrocytes and microglia, cortical perfusion, and the permeability of the blood-brain barrier4567. Moreover, it also exerts several potent anti-inflammatory and anti-oxidative effects on the brain tissue[26]. "
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    ABSTRACT: Brain norepinephrine (NE) plays an important role in the modulation of stress response and neuroinflammation. Recent studies indicate that in Alzheimer’s disease (AD), the tau neuropathology begins in the locus coeruleus (LC) which is the main source of brain NE. Therefore, we investigated the changes in brain NE system and also the immune status under basal and stress conditions in transgenic rats over-expressing the human truncated tau protein. Brainstem catecholaminergic cell groups (LC, A1, and A2) and forebrain subcortical (nucleus basalis of Meynert), hippocampal (cornu ammonis, dentate gyrus), and neocortical areas (frontal and temporal association cortices) were analyzed for NE and interleukin 6 (IL-6) mRNA levels in unstressed rats and also in rats exposed to single or repeated immobilization. Moreover, gene expression of NE-biosynthetic enzyme, tyrosine hydroxylase (TH), and several pro- and anti-inflammatory mediators were determined in the LC. It was found that tauopathy reduced basal NE levels in forebrain areas, while the gene expression of IL-6 was increased in all selected areas at the same time. The differences between wild-type and transgenic rats in brain NE and IL-6 mRNA levels were observed in stressed animals as well. Tauopathy increased also the gene expression of TH in the LC. In addition, the LC exhibited exaggerated expression of pro- and anti-inflammatory mediators (IL-6, TNFα, inducible nitric oxide synthases 2 (iNOS2), and interleukin 10 (IL-10)) in transgenic rats suggesting that tauopathy affects also the immune background in LC. Positive correlation between NE and IL-6 mRNA levels in cornu ammonis in stressed transgenic animals indicated the reduction of anti-inflammatory effect of NE. Our data thus showed that tauopathy alters the functions of LC further leading to the reduction of NE levels and exaggeration of neuroinflammation in forebrain. These findings support the assumption that tau-related dysfunction of LC activates the vicious circle perpetuating neurodegeneration leading to the development of AD.
    Preview · Article · Dec 2016 · Journal of Neuroinflammation
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    • "- established to be limited by glucose availability , and the procognitive effects of exogenous glucose administration have been suggested to be via glia rather than neurons ( McNay and Gold , 2002 ) . NE acts via G - protein coupled receptors ; α - and β - type 1 and 2 adrenergic receptors ( ARs ) . Astrocytes primarily express β1 , α1 , and α2 ( Hertz et al . , 1984 , 2010 ; Deecher et al . , 1993 ) . Like GCs , NE regulate astrocytic calcium signaling ( Gibbs and Bowser , 2010 ) : administration of the α1 agonist phenylephrine increases intracellular Ca 2+ , and similarly stimulation of the LC increases intracellular astrocytic Ca 2+ via an α1 - dependent mechanism ( O ' Donnell et al . , 2012 ) . Becaus"
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    ABSTRACT: Both acute and chronic stress profoundly affect hippocampally-dependent learning and memory: moderate stress generally enhances, while chronic or extreme stress can impair, neural and cognitive processes. Within the brain, stress elevates both norepinephrine and glucocorticoids, and both affect several genomic and signaling cascades responsible for modulating memory strength. Memories formed at times of stress can be extremely strong, yet stress can also impair memory to the point of amnesia. Often overlooked in consideration of the impact of stress on cognitive processes, and specifically memory, is the important contribution of glia as a target for stress-induced changes. Astrocytes, microglia, and oligodendrocytes all have unique contributions to learning and memory. Furthermore, these three types of glia express receptors for both norepinephrine and glucocorticoids and are hence immediate targets of stress hormone actions. It is becoming increasingly clear that inflammatory cytokines and immunomodulatory molecules released by glia during stress may promote many of the behavioral effects of acute and chronic stress. In this review, the role of traditional genomic and rapid hormonal mechanisms working in concert with glia to affect stress-induced learning and memory will be emphasized.
    Preview · Article · Jan 2016 · Frontiers in Integrative Neuroscience
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    • "Adrenergic pathways have never been investigated in human microglia, therefore available evidence so far regards murine models. In murine microglia, by means of microarray and immunohistochemistry, β 2 -AR and possibly β 1 -AR and α 2A -AR have been identified (Hertz et al., 2010). β-AR activation increases the production of IL-1 β, TNF-α, and IL-6 through cAMP and cAMP-dependent protein kinase (Tomozawa et al., 1995) as well as ERK1/2 and P38 MAPK (Wang et al., 2010). "
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    ABSTRACT: The sympathetic nervous system has a major role in the brain-immune cross-talk, but few information exist on the sympathoadrenergic regulation of innate immune system. The aim of this review is to summarize available knowledge regarding the sympathetic modulation of the innate immune response, providing a rational background for the possible repurposing of adrenergic drugs as immunomodulating agents. The cells of immune system express adrenoceptors (AR), which represent the target for noradrenaline and adrenaline. In human neutrophils, adrenaline and noradrenaline inhibit migration, CD11b/CD18 expression, and oxidative metabolism, possibly through β-AR, although the role of α1- and α2-AR requires further investigation. Natural Killer express β-AR, which are usually inhibitory. Monocytes express β-AR and their activation is usually antiinflammatory. On murine Dentritic cells (DC), β-AR mediate sympathetic influence on DC-T cells interactions. In human DC β2-AR may affect Th1/2 differentiation of CD4+ T cells. In microglia and in astrocytes, β2-AR dysregulation may contribute to neuroinflammation in autoimmune and neurodegenerative disease. In conclusion, extensive evidence supports a critical role for adrenergic mechanisms in the regulation of innate immunity, in peripheral tissues as well as in the CNS. Sympathoadrenergic pathways in the innate immune system may represent novel antiinflammatory and immunomodulating targets with significant therapeutic potential.
    Full-text · Article · Aug 2015 · Frontiers in Pharmacology
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