Down-Regulation of GABAA Receptor via Promiscuity with the Vasoactive Peptide Urotensin II Receptor. Potential Involvement in Astrocyte Plasticity

GABAA receptor (GABAAR) expression level is inversely correlated with the proliferation rate of astrocytes after stroke or during malignancy of astrocytoma, leading to the hypothesis that GABAAR expression/activation may work as a cell proliferation repressor. A number of vasoactive peptides exhibit the potential to modulate astrocyte proliferation, and the question whether these mechanisms may imply alteration in GABAAR-mediated functions and/or plasma membrane densities is open. The peptide urotensin II (UII) activates a G protein-coupled receptor named UT, and mediates potent vasoconstriction or vasodilation in mammalian vasculature. We have previously demonstrated that UII activates a PLC/PIPs/Ca2+ transduction pathway, via both Gq and Gi/o proteins and stimulates astrocyte proliferation in culture. It was also shown that UT/Gq/IP3 coupling is regulated by the GABAAR in rat cultured astrocytes. Here we report that UT and GABAAR are co-expressed in cerebellar glial cells from rat brain slices, in human native astrocytes and in glioma cell line, and that UII inhibited the GABAergic activity in rat cultured astrocytes. In CHO cell line co-expressing human UT and combinations of GABAAR subunits, UII markedly depressed the GABA current (β3γ2>α2β3γ2>α2β1γ2). This effect, characterized by a fast short-term inhibition followed by drastic and irreversible run-down, is not relayed by G proteins. The run-down partially involves Ca2+ and phosphorylation processes, requires dynamin, and results from GABAAR internalization. Thus, activation of the vasoactive G protein-coupled receptor UT triggers functional inhibition and endocytosis of GABAAR in CHO and human astrocytes, via its receptor C-terminus. This UII-induced disappearance of the repressor activity of GABAAR, may play a key role in the initiation of astrocyte proliferation

Beyond Autonomy: Coersion and Morality in Clinical Relationships

International audienc

Appeal No. 0678: Perto Drilling Corp., Inc. v. Division of Mineral Resources Management

Chief\u27s Order 99-15

Experiencing transitions in life of mothers of young children

V magistrskem delu smo raziskovali doživljanje življenjskih prehodov mater majhnih otrok. Teoretični del je bil namenjen pregledu literature s področja blagostanja, življenjskih prehodov in materinstva. Za raziskovanje doživljanja življenjskih prehodov je bil uporabljen psihološko fenomenološki pristop. V skladu s tem smo pridobili vpogled v doživljanje šestih udeleženk, hkrati pa vnaprej nismo predvidevali rezultatov ali postavljali hipotez. Cilj psihološko fenomenološke metode je bil oblikovati splošni opis bistvenih značilnosti doživljanja oziroma osnovne strukture, ki določa raziskovano doživljanje. Na podlagi intervjujev smo oblikovali splošno strukturo doživljanja življenjskih prehodov pri materah majhnih otrok. Ugotovili smo, da je za polovico udeleženk materinstvo najpomembnejši prehod v življenju, za ostale tri pa je na drugem mestu. Bistvene spremembe prehoda v materinstvo je mogoče razdeliti na dva dela: povzamejo občutenje, ki se dotika drugih in okolice ter občutenje, ki jih ima ženska do same sebe. Prav tako materinstvo pomembno zaznamuje doživljanje na področju telesnega, relacijskega, čustvenega in duhovnega blagostanja. Vpogled v doživljanje življenjskih prehodov pri materah majhnih otrok, ki ga daje ta raziskava, je lahko uporabna in v pomoč ljudem, ki profesionalno delujejo na področju psihologije, psihoterapije ali na katerem drugem profesionalnem področju, ki vključuje delo z ljudmi, še posebej z ženskami. Kot tako, bo lahko omogočilo pripravo strokovnih smernic programov za ženske, priprave na starševstvo ali podporne skupine za ženske. Verjamemo pa, da bo delo v pomoč tudi tistim, ki si želijo pridobiti vedenje in znanje o tej tematiki, saj lahko služi kot pomoč pri razumevanju doživljanja žensk, ko se te soočajo z življenjskimi prehodi, predvsem s prehodom v materinstvo.This Masters thesis researches how mothers with young children dealt with and experienced their life transition to the role of being a mother. The theoretical part of the thesis focuses on the literature review from the fields of welfare, life transitions and motherhood. A psychological-phenomenological approach has been used to research the life transitions. Based on this an insight into the transition experience of six women has been received, whereas there were no predictions on the outcome or setting hypothesis. The goal of the psychological-phenomenological method is to form a general description of key characteristics or the basic structure, which describe the researched transition. Based on performed interviews a general structure of experiencing the life transitions with mothers with young children has been made. The results show that for half of women experiencing motherhood is the most important transition in life, whereas the other three placed it to the second position in importance of life transitions. Key changes in the transition to the motherhood can be divided to feelings referring to the surrounding and others and secondly, feelings which a woman experiences with regard to herself. Motherhood also significantly affects woman’s relations to physical, relational, emotional and spiritual well-being. Insight to experiencing the life transitions with mothers with young children which this research offers, is useful and of help to anyone who is professionally involved in the fields of psychology, psychotherapy or any other related field which involves working with people, especially women. As such the thesis can enable preparation of professional guidelines and programs for women, parenthood preparations or support groups for women. We believe, that thesis will also assist to those, that would like to develop knowledge on this topic as it can serve as outreach at understanding of experiencing of women, when these are deal with different life transitions, particulary transition to the motherhood

The Conservation Status of the Southern Cavefish Typhlichthys subterraneus in Arkansas,

National audienc

Étude du rôle et du mécanisme d'action de deux peptides vasoactifs, l'urotensine II et l'urotensin II-related peptide sur la fonction astrocytaire

Mes travaux de thèse ont porté sur l étude du rôle et du mécanisme d action du système urotensinergique sur le contrôle de la fonction astrocytaire. Ce projet a été développé au sein du laboratoire EA4310/U413 sous la direction du Dr Pierrick Gandolfo. Les résultats montrent que les astrocytes en culture expriment des sites de liaison spécifiques et fonctionnels pour l urotensine II (UII) et son paralogue urotensin II-related peptide (URP). L'interaction des peptides avec le récepteur métabotropique UT stimule une phospholipase C et entraîne une élévation de la concentration cytosolique de calcium en recrutant les pools intra- et extracellulaires via les canaux de type T. En dépit de leurs analogies structurales, plusieurs singularités distinguent l UII et l'URP. En particulier, seule l'UII interagit avec un site de très haute affinité couplé à une protéine G sensible à la toxine pertussique. De plus, l'UII possède des propriétés mitogènes sur les astrocytes tandis que l URP est inactif. Par ailleurs, à partir d une série d analogues développés au laboratoire, nous avons montré que l'[Orn5]URP se comporte comme un puissant antagoniste dans notre modèle. La présence d ARNm codant les peptides et le récepteur a systématiquement été détectée dans des extraits de lignées tumorales cérébrales et de glioblastomes humains, et seuls les niveaux d expression de l'UII et de l'UT sont positivement corrélés. L'ensemble de ces données indique que le système urotensinergique est impliqué dans le contrôle de la fonction astrocytaire en conditions physiologiques et physiopathologiques. En particulier, l'UII pourrait jouer un rôle majeur dans le contrôle de la tumorigenèse cérébrale.During my Ph.D work, I studied the role and the mechanism of the urotensinergic system on the control of astroglial function. This project has been developed in the laboratory EA4310/U413 under the management of Dr Pierrick Gandolfo. The results showed that cultured astrocytes express specific and functional binding sites for urotensin II (UII) and its paralog urotensin II-related peptide (URP). The interaction of both peptides with their metabotropic receptor UT leads to an activation of a phospholipase C and provoke an increase of cytosolic calcium concentration via intra- and extra-cellular pools mediated by T-type calcium channel opening. Despite of their structural analogies, several discrepancies exist between UII and URP. In particular, UII is the sole peptide able to interact with a very high affinity binding site, which is coupled with a pertussis toxin-sensitive G protein. Moreover, UII exhibits mitogenic properties on astrocytes, whereas URP is inactive. By testing a series of analogs developed in the laboratory, we showed that [Orn5]URP behaves as a potent non competitive/insurmountable antagonist in our model. The presence of mRNA encoding the peptides and their receptor was systematically detected in all human brain tumoral cell lines and glioblastoma extracts, and only UII and UT expression levels are correlated. Taken together, these data indicate that the urotensinergic system is involved in the control of astroglial function in physiological and pathophysiological conditions. In particular, UII may play a major role in the control of glial tumorigenesis.ROUEN-BU Sciences (764512102) / SudocSudocFranceF

Etude des effets des peptides vasoactifs urotensinergiques sur des cellules astrocytaires natives et d'inhibiteurs de kinases dépendantes des cyclines sur des tumeurs astrogliales

ROUEN-BU Sciences (764512102) / SudocSudocFranceF

The Autophagy Machinery: A New Player in Chemotactic Cell Migration

International audienceAutophagy is a highly conserved self-degradative process that plays a key role in diverse cellular processes such as stress response or differentiation. A growing body of work highlights the direct involvement of autophagy in cell migration and cancer metastasis. Specifically, autophagy has been shown to be involved in modulating cell adhesion dynamics as well as epithelial-to-mesenchymal transition. After providing a general overview of the mechanisms controlling autophagosome biogenesis and cell migration, we discuss how chemotactic G protein-coupled receptors, through the repression of autophagy, may orchestrate membrane trafficking and compartmentation of specific proteins at the cell front in order to support the critical steps of directional migration