Suchtforschungsverbund Muenchen: Neurobiologisch-pharmakologische Grundlagenforschung zur Suchtentstehung und Drogenabhaengigkeit. Die Rolle von Dopamin- und Opioidrezeptoren in der Alkoholsucht: Untersuchungen an rezeptor-defizienten Maeusen und Analyse von Rezeptorpolymorphismen bei Alkoholikern Schlussbericht

SIGLEAvailable from TIB Hannover: DtF QN1(90,4) / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekBundesministerium fuer Bildung, Wissenschaft, Forschung und Technologie, Bonn (Germany)DEGerman

Wirkung von Ethanol auf die Genexpression von Opioidpeptiden und Opiatrezeptoren in vitro Schlussbericht

Endogeneous opioids play a major role in the development of alcohol dependence. In the present study the effect of ethanol on the gene expression of the opioid precursor proenkephalin and of the delta-opioid receptor in cultured cells was investigated. Ethanol caused an increase in the levels of proenkephalin mRNA in bovine adrenal medullary chromaffin cells, whereas norharman, a putative product of the ethanol metabolism inhibited the nicotine-induced expression of proenkephalin. In neuroblastoma x glioma cells (NG108-15) incubation with ethanol resulted in a 3-fold elevation of delta-opioid receptor mRNA levels. This increase was primarily due to the effect of ethanol on mRNA stability. In contrast, the transcription of the delta-opioid receptor gene was practically not affected by ethanol. These results provide evidence that ethanol and/or its putative metabolite nor-harman exert distinct effect on the gene expression of opioid peptides and receptors. (orig.)SIGLEAvailable from TIB Hannover: DtF QN1(68,24) / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekBundesministerium fuer Bildung, Wissenschaft, Forschung und Technologie, Bonn (Germany)DEGerman

Differential beta-arrestin trafficking and endosomal sorting of somatostatin receptor subtypes.

The physiological responses of somatostatin are mediated by five different G protein-coupled receptors. Although agonist-induced endocytosis of the various somatostatin receptor subtypes (sst1–sst5) has been studied in detail, little is known about their postendocytic trafficking. Here we show that somatostatin receptors profoundly differ in patterns of -arrestin mobilization and endosomal sorting. The -arrestin-dependent trafficking of the sst2A somatostatin receptor resembled that of a class B receptor in that upon receptor activation, -arrestin and the receptor formed stable complexes and internalized together into the same endocytic vesicles. This pattern was dependent on GRK2 (G protein-coupled receptor kinase 2)-mediated phosphorylation of a cluster of phosphate acceptor sites within the cytoplasmic tail of the sst2A receptor. Unlike other class B receptors, however, the sst2A receptor was rapidly resensitized and recycled to the plasma membrane. The -arrestin mobilization of the sst3 and the sst5 somatostatin receptors resembled that of a class A receptor in that upon receptor activation, -arrestin and the receptor formed relatively unstable complexes that dissociated at or near the plasma membrane. Consequently, -arrestin was excluded from sst3-containing vesicles. Unlike other class A receptors, a large proportion of sst3 receptors was subject to ubiquitin-dependent lysosomal degradation and did not rapidly recycle to the plasma membrane. The sst4 somatostatin receptor is unique in that it did not exhibit agonist-dependent receptor phosphorylation and -arrestin recruitment. Together, these findings may provide important clues about the regulation of receptor responsiveness during long-term administration of somatostatin analog

Suchtforschungsverbund Muenchen: Neurobiologisch-pharmakologische Grundlagenforschung zur Suchtentstehung und Drogenabhaengigkeit. Teilprojekt 1: Akute und chronische Wirkungen von Alkohol auf Neurone des Zentralnervensystems. Teilprojekt 2: Alkohol 'Reward' und Sucht. Zentrale NO/cGMP-Rezeptoren bei Aethanolabusus. Die Rolle von Dopoamin- und #mu#-Opioidrezeptoren in der Alkoholsucht: Untersuchungen an rezeptor-defizienten Maeusen und Analyse von Rezeptorpolymorphismen bei Alkoholikern Abschlussbericht

SIGLEAvailable from TIB Hannover: DtF QN1(89,44) / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekBundesministerium fuer Bildung, Wissenschaft, Forschung und Technologie, Bonn (Germany)DEGerman

Identification of a Disease-Associated Network of Intestinal Immune Cells in Treatment-Naive Inflammatory Bowel Disease

Chronic intestinal inflammation underlies inflammatory bowel disease (IBD). Previous studies indicated alterations in the cellular immune system; however, it has been challenging to interrogate the role of all immune cell subsets simultaneously. Therefore, we aimed to identify immune cell types associated with inflammation in IBD using high-dimensional mass cytometry. We analyzed 188 intestinal biopsies and paired blood samples of newly-diagnosed, treatment-naive patients (n=42) and controls (n=26) in two independent cohorts. We applied mass cytometry (36-antibody panel) to resolve single cells and analyzed the data with unbiased Hierarchical-SNE. In addition, imaging-mass cytometry (IMC) was performed to reveal the spatial distribution of the immune subsets in the tissue. We identified 44 distinct immune subsets. Correlation network analysis identified a network of inflammation-associated subsets, including HLA-DR(+)CD38(+) EM CD4(+) T cells, T regulatory-like cells, PD1(+) EM CD8(+) T cells, neutrophils, CD27(+) TCR gamma delta cells and NK cells. All disease-associated subsets were validated in a second cohort. This network was abundant in a subset of patients, independent of IBD subtype, severity or intestinal location. Putative disease-associated CD4(+) T cells were detectable in blood. Finally, imaging-mass cytometry revealed the spatial colocalization of neutrophils, memory CD4(+) T cells and myeloid cells in the inflamed intestine. Our study indicates that a cellular network of both innate and adaptive immune cells colocalizes in inflamed biopsies from a subset of patients. These results contribute to dissecting disease heterogeneity and may guide the development of targeted therapeutics in IBD