Tag: Receptor

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Multiple Polymorphisms Affect Expression and Function of the Neuropeptide S Receptor (NPSR1).

Multiple Polymorphisms Affect Expression and Function of the Neuropeptide S Receptor (NPSR1).

PLoS One. 2011;6(12):e29523

Authors: Anedda F, Zucchelli M, Schepis D, Hellquist A, Corrado L, D’Alfonso S, Achour A, McInerney G, Bertorello A, Lördal M, Befrits R, Björk J, Bresso F, Törkvist L, Halfvarson J, Kere J, D’Amato M

Abstract
BACKGROUND: neuropeptide S (NPS) and its receptor NPSR1 act along the hypothalamic-pituitary-adrenal axis to modulate anxiety, fear responses, nociception and inflammation. The importance of the NPS-NPSR1 signaling pathway is highlighted by the observation that, in humans, NPSR1 polymorphism associates with asthma, inflammatory bowel disease, rheumatoid arthritis, panic disorders, and intermediate phenotypes of functional gastrointestinal disorders. Because of the genetic complexity at the NPSR1 locus, however, true causative variations remain to be identified, together with their specific effects on receptor expression or function. To gain insight into the mechanisms leading to NPSR1 disease-predisposing effects, we performed a thorough functional characterization of all NPSR1 promoter and coding SNPs commonly occurring in Caucasians (minor allele frequency >0.02).
PRINCIPAL FINDINGS: we identified one promoter SNP (rs2530547 [-103]) that significantly affects luciferase expression in gene reporter assays and NPSR1 mRNA levels in human leukocytes. We also detected quantitative differences in NPS-induced genome-wide transcriptional profiles and CRE-dependent luciferase activities associated with three NPSR1 non-synonymous SNPs (rs324981 [Ile107Asn], rs34705969 [Cys197Phe], rs727162 [Arg241Ser]), with a coding variant exhibiting a loss-of-function phenotype (197Phe). Potential mechanistic explanations were sought with molecular modelling and bioinformatics, and a pilot study of 2230 IBD cases and controls provided initial support to the hypothesis that different cis-combinations of these functional SNPs variably affect disease risk.
SIGNIFICANCE: these findings represent a first step to decipher NPSR1 locus complexity and its impact on several human conditions NPS antagonists have been recently described, and our results are of potential pharmacogenetic relevance.

PMID: 22216302 [PubMed – in process]

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The G protein-coupled receptor OGR1 mediates diverse signaling and contraction of airway smooth muscle in response to small reductions in extracellular pH.

The G protein-coupled receptor OGR1 mediates diverse signaling and contraction of airway smooth muscle in response to small reductions in extracellular pH.

Br J Pharmacol. 2011 Dec 6;

Authors: Saxena H, Deshpande DA, Tiegs BC, Yan H, Battafarano RJ, Burrows WM, Damera G, Panettieri RA, Dubose TD, An SS, Penn RB

Abstract
Background and Purpose.? Previous studies have linked a reduction of pH in the airway, caused by either environmental factors, microaspiration of gastric acid, or inflammation, with airway smooth muscle (ASM) contraction and increased airway resistance. Neural mechanisms have been shown capable of mediating airway contraction in response to reductions in airway pH to values of < pH 6.5; whether reduced extracellular pH (pHo) has direct effects on ASM is unknown. Experimental Approach.? Intracellular signaling events stimulated by ?pHo in cultured human ASM cells were examined by immunoblotting, phosphoinositide hydrolysis and calcium mobilization assays. ASM cell contractile state was examined using Magnetic Twisting Cytometry. Expression of putative proton-sensing G protein-coupled receptors (GPCRs) in ASM was assessed by real-time PCR. The role of OGR1 in acid-induced ASM signaling and contraction was assessed in cultures subjected to siRNA-mediated OGR1 knockdown. Key Results.? ASM cells responded to incremental reductions in pHo (from pH 8.0-6.8) by activating multiple signaling pathways, involving p42/p44, Akt, PKA, and calcium mobilization. Coincidently, ASM cells contracted in response to decreased pHo with similar “dose” dependence. Real-time PCR suggested OGR1 was the only proton-sensing GPCR expressed in ASM cells. Both acid-induced signaling (excepting Akt activation) and contraction were significantly attenuated by knockdown of OGR1. Conclusions and Implications.? These studies reveal OGR1 to be a physiologically-relevant GPCR in ASM cells, capable of pleiotropic signaling and mediation of contraction in response to small reductions in extracellular pH. Accordingly, ASM OGR1 may contribute to asthma pathology and represent a therapeutic target in obstructive lung diseases.

PMID: 22145625 [PubMed – as supplied by publisher]

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Beta-adrenergic receptor polymorphisms associated with length of ICU stay in pediatric status asthmaticus.

Beta-adrenergic receptor polymorphisms associated with length of ICU stay in pediatric status asthmaticus.

Pediatr Pulmonol. 2011 Sep 8;

Authors: Carroll CL, Sala KA, Zucker AR, Schramm CM

Abstract
BACKGROUND: During severe exacerbations, asthmatic children vary significantly in their response to high-dose continuous ?(2) -adrenergic receptor (ADR?(2) ) agonist therapy. Genetic polymorphisms have been identified within the ADR?(2) that may be functionally relevant, but few studies have been performed in this population. Our hypothesis was that genotypic differences are associated with magnitude of response to ADR?(2) agonist treatment during severe asthma exacerbations in children. METHODS: Children aged 2-18 years admitted to the ICU (intensive care unit) with a severe asthma exacerbation between 2006 and 2008 were eligible. Genotyping of the ADR?(2) was performed. RESULTS: Eighty-nine children consented and were enrolled. Despite similar clinical asthma scores on admission, children with the Gly(16) Gly genotype at amino acid position 16 had significantly shorter ICU length of stay (LOS) and hospital LOS, compared to children with Arg(16) Arg and Arg(16) Gly genotypes. Children with either the Gln(27) Glu or Glu(27) Glu genotype at amino acid position 27 also had significantly shorter ICU LOS and hospital LOS compared to children with the Gln(27) Gln genotype. The Arg(16) Gly-Gln(27) Gln haplotype was associated with the longest ICU LOS, but this was not statistically different from other haplotypes. CONCLUSIONS: In this cohort of children with severe asthma exacerbations, ADR?(2) polymorphisms were associated with responses to therapy. Knowledge of the genetic profile of children with asthma may allow for targeted therapy during acute exacerbations. Pediatr Pulmonol. © 2011 Wiley-Liss, Inc.

PMID: 21905268 [PubMed – as supplied by publisher]

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Studies Link Asthma with Variations in IL6 Receptor Gene and Chromosome 11q13.5 – Genetic Engineering News

Studies Link Asthma with Variations in IL6 Receptor Gene and Chromosome 11q13.5
Genetic Engineering News
Genome-wide association studies focused on asthma risk genes have identified a variation in the interleukin-6 receptor (IL6R), and alterations at another site on chromosome 11q13.5 near the leucine-rich repeat containing 32 gene (LRRC32, also known as …

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Molecular expression and functional role of canonical transient receptor potential channels in airway smooth muscle cells.

Molecular expression and functional role of canonical transient receptor potential channels in airway smooth muscle cells.

Adv Exp Med Biol. 2011;704:731-47

Authors: Wang YX, Zheng YM

Multiple canonical or classic transient receptor potential (TRPC) molecules are expressed in animal and human airway smooth muscle cells (SMCs). TRPC3, but not TRPC1, is a major molecular component of native non-selective cation channels (NSCCs) to contribute to the resting [Ca(2+)](i) and muscarinic increase in [Ca(2+)](i) in freshly isolated airway SMCs. TRPC3-encoded NSCCs are significantly increased in expression and activity in airway SMCs from ovalbumin-sensitized/challenged “asthmatic” mice, whereas TRPC1-encoded channel activity, but not its expression, is largely augmented. The upregulated TRPC3- and TRPC1-encoded NSCC activity both mediate “asthmatic” membrane depolarization in airway SMCs. Supportively, tumor necrosis factor-? (TNF?), an important asthma mediator, increases TRPC3 expression, and TRPC3 gene silencing inhibits TNF?-mediated augmentation of acetylcholine-evoked increase in [Ca(2+)](i) in passaged airway SMCs. In contrast, TRPC6 gene silencing has no effect on 1-oleoyl-2-acetyl-sn-glycerol (OAG)-evoked increase in [Ca(2+)](i) in primary isolated cells. These findings provide compelling information indicating that TRPC3-encoded NSCCs are important for physiological and pathological cellular responses in airway SMCs. However, continual studies are necessary to further determine whether, which, and how TRPC-encoded channels are involved in cellular responses in normal and diseased (e.g., asthmatic) airway SMCs.

PMID: 21290324 [PubMed – in process]

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Flagellin Induces the Expression of Thymic Stromal Lymphopoietin in Human Keratinocytes via Toll-Like Receptor 5.

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Flagellin Induces the Expression of Thymic Stromal Lymphopoietin in Human Keratinocytes via Toll-Like Receptor 5.

Int Arch Allergy Immunol. 2010 Nov 25;155(1):31-37

Authors: Le TA, Takai T, Vu AT, Kinoshita H, Chen X, Ikeda S, Ogawa H, Okumura K

Background: Thymic stromal lymphopoietin (TSLP), highly expressed by keratinocytes in skin lesions of atopic dermatitis patients and bronchial epithelial cells in asthma, plays a key role in allergic diseases. Information on triggers for the release of TSLP in keratinocytes is still limited. Keratinocytes express Toll-like receptor (TLR) 5, the ligand for which is flagellin, the major structural protein of the flagella of Gram-negative bacteria. IL-4, IL-13 and TNF-? (Th2/TNF) are associated with allergic diseases. TGF-?, one of the ligands for the epidermal growth factor receptor, is overexpressed in keratinocytes in atopic dermatitis. We investigated the induction of TSLP expression in keratinocytes stimulated with flagellin and its modulation by the Th2/TNF cytokines and TGF-?. Methods: Primary human keratinocytes were stimulated with flagellin with or without cytokines. The TSLP released was measured by ELISA. Gene expression was analyzed by quantitative real-time PCR. Results: Stimulation of keratinocytes with flagellin induced the release of TSLP protein and upregulation of the gene expression of TSLP and other pro-inflammatory molecules. The flagellin-induced release of TSLP was enhanced by the Th2/TNF cytokines or TGF-?. Small interfering RNA-mediated knockdown of TLR5 expression suppressed the flagellin-induced TSLP gene expression. Conclusions: Flagellin induces TSLP expression in keratinocytes via TLR5 and the expression can be upregulated by a cytokine milieu with Th2/TNF or TGF-?, suggesting that exposure of barrier-defective skin to Gram-negative bacteria or environmental flagellin contributes to the initiation and/or amplification of Th2-type skin inflammation including atopic dermatitis through the induction of TSLP expression in keratinocytes.

PMID: 21109746 [PubMed – as supplied by publisher]

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