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Regulation of the nicotinic receptor alpha7 subunit by chronic stress and corticosteroids.

ABSTRACT: The alpha7 subunit of the nicotinic acetylcholine receptor (NAchRalpha7) is one of the principal brain receptors for nicotine and is thought to be a mediator of nicotine's pro-cognitive effects. While nicotine is known to interact with the stress axis, little is known about the effect of stress or corticosteroids on the expression in the hippocampus, a brain region important to both cognition and stress reactivity. We examined the effects of chronic (21 day) restraint stress (CRS) and adrenalectomy with hormone replacement with the selective mineralocorticoid receptor (MR) agonist aldosterone, the selective glucocorticoid receptor (GR) agonist RU28,362 or corticosterone for 7 days, on the hippocampal expression of NAchRalpha7 mRNA and protein, as measured by (125)I alpha-Bungarotoxin autoradiography. We found that CRS increased the levels of NAchRalpha7 mRNA in the CA1, CA3 and dentate gyrus while levels of the protein were lowered by the same treatment. Corticosteroid replacement showed a GR specific increase in NAchRalpha7 mRNA, consistent with a corticosteroid mediated effect of CRS. While the mechanism behind these observations is as yet unclear, they may be neuroprotective against the damaging effects of CRS or an example of adaptation to the allostatic load produced by CRS.

SUBMITTER: Hunter RG

PROVIDER: S-EPMC2856334 | biostudies-literature | 2010 Apr

REPOSITORIES: biostudies-literature

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Regulation of the nicotinic receptor alpha7 subunit by chronic stress and corticosteroids.

Hunter Richard G RG Bloss Erik B EB McCarthy Katharine J KJ McEwen Bruce S BS

Brain research 20100211

The alpha7 subunit of the nicotinic acetylcholine receptor (NAchRalpha7) is one of the principal brain receptors for nicotine and is thought to be a mediator of nicotine's pro-cognitive effects. While nicotine is known to interact with the stress axis, little is known about the effect of stress or corticosteroids on the expression in the hippocampus, a brain region important to both cognition and stress reactivity. We examined the effects of chronic (21 day) restraint stress (CRS) and adrenalect ...[more]

PMID: 20153739

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Project description:ObjectiveThe central nervous system can regulate peripheral inflammation, but the efferent neuronal routes and the mediators remain poorly defined. One candidate is the cholinergic pathway, which releases acetylcholine (ACh). This neurotransmitter can bind to the alpha7 cholinergic receptor (alpha7R) expressed by nonneuronal cells and reduce inflammation. To test this possibility, we evaluated the expression of alpha7R and its potential role as a target in rheumatoid arthritis (RA).MethodsThe expression of alpha7R in human synovium and fibroblast-like synoviocytes (FLS) was determined using immunohistochemical, Western blot, and quantitative polymerase chain reaction (PCR) analyses. The effects of ACh in vitro were determined in interleukin-1 (IL-1)-stimulated FLS using immunoassays for protein, quantitative PCR for messenger RNA (mRNA), luciferase reporter constructs for IL-6 and NF-kappaB promoter activity, and electrophoretic mobility shift assays. Expression of alpha7R was knocked down with small interfering RNA (siRNA) or was inhibited with the selective alpha7R antagonist methyllycaconitine (MLA).ResultsProtein and mRNA for alpha7R were demonstrated in RA and osteoarthritis synovium and cultured synoviocytes. Expression in synovium was mainly in the intimal lining. ACh significantly reduced the production of IL-6, CXCL8, CCL2, CCL3, CCL5, and granulocyte colony-stimulating factor by IL-1-stimulated FLS. This effect was blocked by the alpha7R antagonist MLA or by using alpha7R siRNA to knock down receptor expression. The selective alpha7R agonist PNU-282,987 decreased the production of IL-6 by IL-1-stimulated FLS. ACh did not reduce IL-6 transcription, but it decreased IL-6 mRNA half-life and reduced IL-6 mRNA steady-state levels.ConclusionThe alpha7 receptor is expressed in the synovium and by synoviocytes. Receptor ligation inhibits cytokine expression in FLS through a posttranscriptional mechanism. Therefore, alpha7R is a potential therapeutic target for inflammatory diseases.

Project description:The notion of functional interactions between the alpha7 nicotinic acetylcholine (alpha7 nACh) and the cannabinoid systems is emerging from recent in vitro and in vivo studies. Both the alpha7 nACh receptor and the cannabinoid receptor 1 (CB1) are highly expressed in the hippocampus. To begin addressing possible anatomical interactions between the alpha7 nACh and the cannabinoid systems in the rat hippocampus, we investigated the distribution of neurons expressing alpha7 nACh mRNA in relation to those containing CB1 mRNA. By in situ hybridization we found that the alpha7 nACh mRNA is diffusely expressed in principal neurons and is highly expressed in a subset of interneurons. We observed that the pattern of distribution of hippocampal interneurons co-expressing transcripts encoding alpha7 nACh and glutamate decarboxylase (GAD; synthesizing enzyme of GABA) closely resembles the one displayed by interneurons expressing CB1 mRNA. By double in situ hybridization we established that the majority of hippocampal interneurons expressing alpha7 nACh mRNA have high levels of CB1 mRNA. As CB1 interneurons contain cholecystokinin (CCK), we investigated the degree of cellular co-expression of alpha7 nACh mRNA and CCK, and found that the cellular co-existence of alpha7 nACh and CCK varies within the different layers of the hippocampus. In summary, we established that most of the hippocampal alpha7 nACh expressing interneurons are endowed with CB1 mRNA. We found that these alpha7 nACh/CB1 interneurons are the major subpopulation of hippocampal interneurons expressing CB1 mRNA. The alpha7 nACh expressing interneurons represent half of the detected population of CCK containing neurons in the hippocampus. Since it is well established that the vast majority of hippocampal interneurons expressing CB1 mRNA have 5-HT type 3 (5-HT3) receptors, we conclude that these hippocampal alpha7 nACh/5HT3/CB1/CCK interneurons correspond to those previously postulated to relay inputs from diverse cortical and subcortical regions about emotional, motivational, and physiological states.

Project description:We and others have shown that one of the mechanisms of growth regulation of small cell lung cancer cell lines and cultured pulmonary neuroendocrine cells is by the binding of agonists to the alpha7 neuronal nicotinic acetylcholine receptor. In addition, we have shown that the nicotine-derived carcinogenic nitrosamine, 4(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), is a high affinity agonist for the alpha7 nicotinic acetylcholine receptor. In the present study, our goal was to determine the extent of alpha7 mRNA and protein expression in the human lung.Experiments were done using reverse transcription polymerase chain reaction (RT-PCR), a nuclease protection assay and western blotting using membrane proteins.We detected mRNA for the neuronal nicotinic acetylcholine receptor alpha7 receptor in seven small cell lung cancer (SCLC) cell lines, in two pulmonary adenocarcinoma cell lines, in cultured normal human small airway epithelial cells (SAEC), one carcinoid cell line, three squamous cell lines and tissue samples from nine patients with various types of lung cancer. A nuclease protection assay showed prominent levels of alpha7 in the NCI-H82 SCLC cell line while alpha7 was not detected in SAEC, suggesting that alpha7 mRNA levels may be higher in SCLC compared to normal cells. Using a specific antibody to the alpha7 nicotinic receptor, protein expression of alpha7 was determined. All SCLC cell lines except NCI-H187 expressed protein for the alpha7 receptor. In the non-SCLC cells and normal cells that express the alpha7 nAChR mRNA, only in SAEC, A549 and NCI-H226 was expression of the alpha7 nicotinic receptor protein shown. When NCI-H69 SCLC cell line was exposed to 100 pm NNK, protein expression of the alpha7 receptor was increased at 60 and 150 min.Expression of mRNA for the neuronal nicotinic acetylcholine receptor alpha7 seems to be ubiquitously expressed in all human lung cancer cell lines tested (except for NCI-H441) as well as normal lung cells. The alpha7 nicotinic receptor protein is expressed in fewer cell lines, and the tobacco carcinogen NNK increases alpha7 nicotinic receptor protein levels.

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Regulation of the nicotinic receptor alpha7 subunit by chronic stress and corticosteroids.

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Regulation of the nicotinic receptor alpha7 subunit by chronic stress and corticosteroids.

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