Dissertations / Theses on the topic 'GPCR'
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Blankenship, Elise. "Conserved solvent networks in GPCR activation." Case Western Reserve University School of Graduate Studies / OhioLINK, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=case1458221506.
Full textPoudel, Sagar. "GPCR-Directed Libraries for High Throughput Screening." Thesis, University of Skövde, School of Humanities and Informatics, 2006. http://urn.kb.se/resolve?urn=urn:nbn:se:his:diva-29.
Full textGuanine nucleotide binding protein (G-protein) coupled receptors (GPCRs), the largest receptor family, is enormously important for the pharmaceutical industry as they are the target of 50-60% of all existing medicines. Discovery of many new GPCR receptors by the “human genome project”, open up new opportunities for developing novel therapeutics. High throughput screening (HTS) of chemical libraries is a well established method for finding new lead compounds in drug discovery. Despite some success this approach has suffered from the near absence of more focused and specific targeted libraries. To improve the hit rates and to maximally exploit the full potential of current corporate screening collections, in this thesis work, identification and analysis of the critical drug-binding positions within the GPCRs were done, based on their overall sequence, their transmembrane regions and their drug binding fingerprints. A proper classification based on drug binding fingerprints on the basis for a successful pharmacophore modelling and virtual screening were done, which facilities in the development of more specific and focused targeted libraries for HTS.
Majin, Wodu. "Mathematical modelling of GPCR-mediated calcium signalling." Thesis, University of Nottingham, 2012. http://eprints.nottingham.ac.uk/12451/.
Full textTang, Lisa Sarah. "GPCR expressions in Saccharomyces cerevisiae : engineering transductions." Thesis, University of Leeds, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.423190.
Full textMishra, Satyakam. "Frequent Subgraph Mining Analysis of GPCR Activation." Case Western Reserve University School of Graduate Studies / OhioLINK, 2021. http://rave.ohiolink.edu/etdc/view?acc_num=case1613575702373053.
Full textKiess, Alexandra. "Funktionelle Relevanz intrazellulärer Splicevarianten des Brain-specific Angiogenesis Inhibitor 2 (BAI2)." Doctoral thesis, Universitätsbibliothek Leipzig, 2014. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-156171.
Full textSladek, Barbara. "Structural studies of integral membrane GPCR accessory proteins." Thesis, University of Oxford, 2013. http://ora.ox.ac.uk/objects/uuid:09bf7ada-8e58-49f4-a979-bcd0cec95e8b.
Full textRichardson, Kathryn. "Mechanisms of GPCR signal regulation in fission yeast." Thesis, University of Warwick, 2014. http://wrap.warwick.ac.uk/63554/.
Full textGoddard, Alan David. "Functional analysis of GPCR signalling cascades in Schizosaccharomyces pombe." Thesis, University of Warwick, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.437696.
Full textKoyama, Hiroyuki. "Comprehensive Profiling of GPCR Expression in Ghrelin-producing Cells." Kyoto University, 2016. http://hdl.handle.net/2433/215953.
Full textEngemaier, Eva. "Die strukturelle und funktionelle Evolution des G-Protein-gekoppelten Rezeptors GPR34." Doctoral thesis, Universitätsbibliothek Leipzig, 2012. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-86270.
Full textThamm, Markus. "Charakterisierung der Serotonin-Rezeptoren der Honigbiene Apis mellifera : von den Genen zum Verhalten." Phd thesis, Universität Potsdam, 2009. http://opus.kobv.de/ubp/volltexte/2010/4073/.
Full textThe serotonergic system plays an important role in the control and modulation of many physiological and behavioral processes in both vertebrates and invertebrates. In the honeybee Apis mellifera, serotonin (5-hydroxytryptamine, 5-HT) has been implicated in the control and regulation of division of labor as well as learning and memory. A key role in understanding the serotonergic system plays the molecular and functional characterization of 5-HT receptor subtypes. In most cases, serotonin receptors represent G protein-coupled receptors (GPCRs). This work describes the characterization of honeybee serotonin receptors. This comprises the identification of their molecular structure, intracellular second messenger pathways, pharmacological properties, expression profiles and functions. By screening the honeybee genome, we found three candidate genes encoding for putative serotonin receptors. The cDNAs of these genes were cloned and the deduced amino acid sequences were analysed. The sequence information was used to isolate the cDNAs encoding for these three receptors. Comparison of the deduced amino acid sequences with sequences of other known receptors suggests that one receptor belongs to the 5-HT1 (Am5-HT1) and the other two receptors to the 5-HT2 receptor class (Am5-HT2α and Am5-HT2β). Major characteristics common to all GPCRs (e.g. the heptahelical architecture) were confirmed by structural analyses of the deduced amino acid sequences. Furthermore, truncated receptor transcripts representing alternative splice variants of both 5-HT2 receptors could be detected. HEK293 cells were stably transfected with the cDNAs of Am5-HT1 or Am5-HT2_ and functionally and pharmacologically analysed. The activation of Am5-HT1 by 5-HT results in the dose dependent attenuation of adenylyl cyclase activity. 5-methoxytryptamine (5-MT) and 5-carboxamidotryptamine are able to imitate the 5-HT effect. In contrast, methiothepin is able to block the entire 5-HT effect, whereas prazosine and WAY100635 block the 5-HT effect only partially. The Am5-HT2α receptor stimulates the synthesis of the second messenger inositol trisphosphate which in turn mediates an increase in the intracellular Ca2+. The substances 5-MT and 8-OH-DPAT were identified as agonists of the Am5-HT2α receptor. In contrast, clozapine, methiothepine, mianserine, and cyproheptadine show strong antagonistic actions. A truncated alternative splice variant of the Am5-HT2α-receptor was also analysed but didn’t show any functional coupling by itself. An antiserum was raised against the third cytoplasmic loop (CPL3) of the Am5-HT1 receptor. This antiserum detects a protein with a molecular mass of 50 kDa in western blot analyses. The expression of the Am5-HT1 receptor was studied in detail using immunohistochemistry. Strong Am5-HT1-like immunofluorescence was observed in the ocellar nerve, in the three optic ganglia and in the α- and β-lobes, the pedunculi, the lip and the basal ring of the mushroom bodies. Furthermore, co-labeling with an antibody against 5-HT showed that this receptor is expressed in close vicinity to serotonergic neurons. Finally, behavioral experiments suggest a possible role of the Am5-HT1 receptor in phototactic behavior. Feeding of 5-HT to worker honeybees results in a decrease of phototactic behavior. This 5-HT action could be mimiced by feeding of the Am5-HT1 agonist 5-CT. In contrast, the Am5-HT1 antagonist prazosine prevents the 5-HT-induced decrease in phototaxis.
Zhang, Boyang. "Functional and Structural Insights into the First and Second Intracellular Domains for D1-Class Dopaminergic Receptors." Thesis, Université d'Ottawa / University of Ottawa, 2017. http://hdl.handle.net/10393/35932.
Full textGuerrero, Hernández Martina. "Targeting tumor microenvironment crosstalk through GPCR receptors and PI3K pathway." Doctoral thesis, Universitat de Barcelona, 2019. http://hdl.handle.net/10803/667975.
Full textEl estudio del microambiente tumoral está ganando importancia en las últimas décadas debido a su contribución en la formación y desarrollo del cáncer, además de contribuir en la resistencia de las células tumorales a diferentes terapias. Este microambiente interactúa con las células tumorales y activa diferentes vías. El linfoma folicular (FL), es el linfoma no Hodgkin indolente más común y con mayor dependencia del microambiente tumoral, además es considerado incurable. PI3K desempeña un papel importante en la comunicación con el microambiente, y es importante en múltiples funciones celulares, además de contribuir en la angiogénesis, reclutamiento de células inflamatorias y promover el crecimiento tumoral. Idelalisib es un inhibidor de PI3K (específicamente de la isoforma δ), que se aprobó en 2014 por la FDA. Paralelamente la desregulación de BCL2 es primordial en la patogénesis de FL, como consecuencia de la t (14; 18), presente en un 85% de los pacientes, y por lo tanto es un objetivo atractivo para novedosos enfoques terapéuticos. Venetoclax (ABT-199, AbbVie) es un pequeño inhibidor de BCL2, que mostró unos resultados del primer ensayo clínico no satisfactorios (respuesta global del 38%). De este primer estudio concluimos que Idelalisib interfiere en la comunicación de FL y su microambiente inmune, además potencia la actividad de venetoclax atacando a las células tumorales, lo que representa una terapia de combinación prometedora que puede mejorar el resultado del tratamiento de FL.
Gardner, Jacob Andrew. "GPCR Signaling in the Genesis and Progression of Pancreatic Cancer." Diss., Temple University Libraries, 2009. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/35453.
Full textPh.D.
Ductal adenocarcinomas of the pancreas are the 4th most common cause of cancer death. The 1 and 5 year survival rates for all stages combined are currently 26% and 5% respectively. Median survival is less than 6 months. Despite remarkable progress in the fields of genetics, cancer biology, and advances in surgical techniques as well as chemotherapeutics, our ability to recognize and treat patients with pancreatic cancer remains poor. GPCR signaling modules have been increasingly implicated in the genesis and progression of pancreatic cancers. Aberrant agonist production, receptor expression and dysfunctional signaling resulting from genomic instability in a background of a heterotopic tumor-stromal microenvironment, contribute to the initiation, progression, and eventual metastasis of the disease. Numerous GPCR agonists, including lysophosphatidic acid (LPA), along with their cognate receptors have been implicated in this oncogenic process. LPA, one of the simplest bioactive lipids, has been shown to be a potent stimulant of metastatic behavior in in vitro models. It also acts as a mitogen by inducing proliferation and cell survival pathways in various normal and transformed cell lines. In patients with pancreatic cancer both the receptors and ligand have been found to be overexpressed. It has been noted that pancreatic cancer cell lines expressing higher levels of the LPA receptors present with greater motility. This has led to the hypothesis that LPA contributes to the progression of pancreatic cancer through the promotion of a metastatic phenotype. However, the underlying mechanisms have not been well described. LPA receptors have been shown to couple to the Gi, Gq, or G12 family of heterotrimeric G proteins. Consequently, signals transduced through these receptors have been shown to stimulate Gαi, Gαq, and Gα12/13 dependent pathways. While earlier studies have linked Gαi to LPA induced migration, there is recent evidence to suggest that Gα13 may provide a major signaling mechanism for LPA receptors stimulating migration in diverse cell types including cancer cell lines. Given the ominous nature of pancreatic cancers it is of critical importance to understand the mechanisms that promote more malignant phenotypes and to assess the role of Gα13 in this process. The goal of this thesis therefore is to define the role of Gα13 in LPA-mediated migration of pancreatic cancer cells. To assess the oncogenic potential of LPA and the role of Gα13 in stimulating the migration of pancreatic cancer cells, a panel of pancreatic cancer cell lines was assembled and characterized with regard to their expression of the LPA receptors as well as the Gα subunits of the heterotrimeric G proteins. These cell lines were further studied through a series of proliferation, wound healing, and transwell migration assays to assess the role of LPA in the induction of proliferation and migration in pancreatic cancer cells. The results demonstrated that LPA functions as a mitogen in certain pancreatic cancer cell lines, but is a potent stimulant of cell motility and invasive migration. Interestingly, these studies indicated that this response proceeds through routes that may not involve Gαi, as a potent migratory response was observed in MDAPanc28 cells which lack expression of the Gαi subunit. This was verified through the transwell assays conducted in the presence of PTX demonstrating that migration occurs independently of PTX sensitive mechanism and thus independently of Gαi.. Using a dominant negative mutant strategy, the studies presented in this thesis establishes the role of Gα13 in mediating LPA-LPAR stimulated migration of pancreatic cancer cells. Using pancreatic cancer cell lines that stably express the competitively inhibitory dominant negative mutant of Gα13, the ability of these mutants to inhibit a LPA mediated migratory response was monitored by wound-healing as well as transwell migration assays The results of these studies indicated a substantial attenuation of the migratory response and demonstrated for the first time the critical role of Gα13in LPA induced migration in a pancreatic cancer cell line.
Temple University--Theses
Senarath, Kanishka D. "Interrogation of GPCR-G Protein Signaling using Novel Optogenetic Tools." University of Toledo / OhioLINK, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=toledo155681039815937.
Full textJha, Ankita. "Quantitative control of GPCR organization and signaling by endocytosis in epithelial morphogenesis." Thesis, Aix-Marseille, 2017. http://www.theses.fr/2017AIXM0393/document.
Full textDuring Drosophila gastrulation, apical activation of the actomyosin networks drives apical constriction in the invaginating mesoderm and cell-cell intercalation in the extending ectoderm. Here, we show that cell-surface G-protein coupled receptor, Smog activates G-proteins, Rho1 and Rho-kinase that is required for apical constriction and cell-cell intercalation. Quantitative control over GPCR activity and thereby Rho1 activation underlies differences in deformation of the mesoderm and ectoderm cells but the mechanisms remain elusive. We show that GPCR-Smog activity is concentrated on two different apical plasma membrane compartments i.e. the surface and the plasma membrane invaginations. Using FCS, we probe the surface of the plasma membrane (PM) and show that Smog homo-clusters in response to its activating ligand Fog. Endocytosis of Smog is facilitated by the kinase Gprk2 and the adaptor protein β-Arrestin-2 that clears active Smog from the surface of PM. When Fog concentration is high or endocytosis is low, Smog arranges in homo-clusters and accumulates in plasma membrane invaginations (PMI), that are hubs for Rho1 activation. Lastly, we find high Smog homo-cluster concentrations and numerous apical PMIs in the mesoderm compared to the ectoderm. We identify that dynamic partitioning of active Smog on the surface of the PM or PMI directly impact on Rho1 signaling. PMIs accumulate high Rho1-GTP suggesting they form signaling centers. Fog concentration and Smog endocytosis form coupled regulatory processes that regulate quantitative differential Rho1/MyoII activation in the Drosophila mesoderm and ectoderm
Cutolo, Pasquale. "Etude de l'interaction structurelle et fonctionnelle entre la chimiokine CXCL12 et ses récepteurs : CXCR4 et ACKR3/CXCR7." Thesis, Université Paris-Saclay (ComUE), 2016. http://www.theses.fr/2016SACLS550/document.
Full textThe axis formed by the chemokine CXCL12 and its receptor CXCR4 is conserved in vertebrates where it plays an important role in embryogenesis and adult life, regulates many processes of immune responses through its functions in cell migration, survival and proliferation.In addition, this axis is involved in pathological processes such as cancers (growth and metastasis) and immune deficiencies and malfunctions (eg deregulated expression, mutations or polymorphisms) and is also hijacked by certain pathogens (eg HIV, human papilloma virus).A large working group is dedicated to this pair as a therapeutic target, but only a compound (ie Plerixafor) achieved approval for clinical use by the potential of this area as a drug target unexplored.Although this axis is the subject of great interest, questions remain about the structural determinants involved in CXCL12 / CXCR4 interaction.However, the recently resolved diffraction structure of CXCR4 gave some clue about these questions, and beyond possible stoichiometry between CXCL12 and CXCR4.Several lines of evidence support the concept that forms CXCR4 homo- and hetero-oligomers (which can contribute to the diversity of the receptor functions), as shown in the diffraction structure, the gain function of a mutant CXCR4 receptor responsible for the syndrome WHIM and allosteric modulation of CXCR4 functions by CXCR7 (ACKR3), the second receptor of the chemokine CXCL12. The ability to form oligomers opens many issues of CXCL12 and its interaction with CXCR4 and CXCR7 / ACKR3.The stoichiometry of this interaction still remains an open question, as the receptor is capable to form oligomers with the same receptor or other receptors, particularly CXCR7 / ACKR3. This receptor, known as scavenger, has not solved structure and the mechanism of interaction with CXCL12 is unknown.To study the interactions CXCL12 / CXCR4 / CXCR7, we applied several molecular modeling techniques such as peptide-peptide docking and molecular dynamics simulations.Objectives of this project were: the resolution of the different stoichiometric forms for the interaction of CXCR4 and CXCL12 (molecular modeling, docking and dynamic); modeling the CXCR7 / ACKR3 receptor structure and its interaction with CXCL12 (homology modeling), with the characterization of domains and residues key in the activation of downstream signaling pathways of the receptor (CXCR7 / ACKR3 mutants); the study and characterization of new innovative tools for the detection of oligomerization of these receptors in endogenous conditions. (Nanobodies, HTRF)The results of the first objective were published in January 2016: PMID 26813575.Modeling of CXCR7 / ACKR3 allowed us to generate several mutants of the receptor to test our hypothesis about the activation pathways.Nanobodies were fully characterized for CXCR4 to be used in a second study to identify oligomeric forms of the receptor in tissues and cells
Adamson, Roslin Jane. "Probing GPCR-Gα interactions : a functional study by EM and SPR." Thesis, University of Oxford, 2014. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.669745.
Full textMason, Vicki Louise. "Effects of different assay configurations on pharmacological profiling of GPCR targets." Thesis, University of Reading, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.494820.
Full textSantos, Geisa Aparecida dos. "Análise comparativa de perfis de sinalização do receptor AT1 ativado por agonistas seletivos para a via de -arrestinas." Universidade de São Paulo, 2013. http://www.teses.usp.br/teses/disponiveis/17/17131/tde-31102013-150124/.
Full textG protein coupled receptors (GPCRs), also known as 7TM receptors, are known to regulate virtually all physiological processes in mammals and approximately 40% of all current clinical drugs act by modulating such receptors. The signaling mediated by them is classically by coupling to G protein, which is activated by exchanging bound GDP for GTP, dissociation of G and G subunits, then leading to production of second messengers such as cAMP, Ca2+, and DAG. After the signal transduction, GPCR are phosphorylated by GPCR kinases (GRKs), followed by recruitment of cytoplasmic -arrestins, which initiate the endosome formation with consequent internalization and desensitization of the receptor. However, is has been demonstrated that the endosome assembling the ligand-receptor--arrestin complex can interact with cytoplasmic signaling proteins, therefore activating signaling pathways independently of G protein coupling. Recently, for different receptors, it has been described ligands capable of selectively activating one of these signaling pathways, G protein or -arrestin, called biased agonists. The AT1 receptor is a particularly interesting GPCR for the study of biased agonism, either due to its wide tissue expression as well as also due the existence of known and established biased ligands, such as SII and TRV120027. The aim of our study was to comparatively analyze the AT1 receptor signaling pathways profiles after activation by SII or TRV120027, using kinases arrays, and expression modulation of genes related to GPCRs signaling. AngII is the natural and full agonist of this receptor (activates both G protein and -arrestin signaling pathways) was used for comparison. Our data show that the signaling profile mediated by AT1 receptor can be distinct not only when comparing the profiles from AngII and the biased agonists, but also when comparing the profiles from the two biased ligands SII and TRv120027; revealing that the complex ligand-receptor can influence the downstream signaling pathways in a fine-tune way, further to the activation of -arrestin or G-protein. This data show that there are perspectives for the future development of ligands with even higher degree of selectivity.
Jaén, Cristina. "Differential coupling of RGS3s and RGS4 to GPCR-GIRK channel signaling complexes." [Tampa, Fla] : University of South Florida, 2006. http://purl.fcla.edu/usf/dc/et/SFE0001533.
Full textAltosaar, Katrin. "Dimer-dependent allosteric modulation within GPCR signalling complexes can influence signalling diversity." Thesis, McGill University, 2013. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=114353.
Full textLes récepteurs couplés aux protéines G (RCPG) constituent le plus grand groupe de récepteurs de la surface cellulaire, qui traduisent les signaux environnementaux en réponses cellulaires via leurs protéines G associées. Contrairement à notre compréhension initiale, la majorité des RCPG ne fonctionnent pas en tant que monomères, mais possiblement en tant que dimères ou même oligomères. Les approches actuelles de conception de médicament estiment que lors de la liaison d'un médicament aux deux récepteurs d'un dimère quelconque, ces derniers fonctionnent potentiellement indépendamment l'un de l'autre. Cependant, cette notion a été reconsidérée par une étude récente montrant que la liaison d'un ligand aux deux récepteurs peut les altérer par voie de communication allostérique. Alors qu'un premier récepteur peut être requis pour initialiser la signalisation, un second peut contrôler ou modifier ces signaux, n'ayant pas nécessairement une signalisation directe comme résultante. Dans l'étude suivante, basée sur la notion de modulation allostérique au sein d'homodimère et d'hétérodimère, les changements de signalisation en aval ainsi qu'au niveau du complexe récepteur/protéine G/effecteur (RGE) ont été étudiés et comparés en réponse à différentes combinaisons de ligands pour chaque protomère. En utilisant une combinaison d'essais de signalisation de calcium, d'adénosine monophosphate cyclique (cAMP) et de protéine kinase activée par des agents mitogènes (MAPK), une interaction fonctionnelle entre le récepteur dopaminergique D2 et le récepteur de l'ocytocine (D2R/OTR) a été démontrée dans les cellules HEK 293. Des expériences d'immunoprécipitation, de transfert d'énergie de résonance par bioluminescence (BRET) et de microscopie confocale ont révélé la présence d'hétérodimère entre le D2R et l'OTR in vitro, ce qui pourrait expliquer la nature des interactions fonctionnelles allostériques. En utilisant la technique de BRET, la dynamique fonctionnelle du complexe RGE dans les cellules HEK 293 a été examinée chez deux autres hétérodimères, soit celui composé du récepteur adrénergique β2 et du récepteur cannabinoïde CB1 (β2AR/CB1R) et l'hétérodimère β2AR/OTR, afin de déterminer comment ils traduisent les évènements de signalisation. Ces études démontrent donc qu'une interaction fonctionnelle peut survenir sur le plan de la conformation du complexe de signalisation. Par conséquent, la signalisation d'un RCPG peut être modulée par son récepteur partenaire au niveau des effecteurs ou au niveau du complexe de signalisation lui-même. Pour cette raison, il serait impératif de réanalyser in vivo les propriétés allostériques d'hétérodimères putatifs, ce qui pourrait expliquer certains effets secondaires d'une multitude de médicaments et ce qui pourrait impliquer des changements majeurs dans la façon de concevoir de nouveaux médicaments.
Hall, Caroline Jane. "The effect of GPCR crosstalk on intracellular Ca2+ responses and downstream signalling." Thesis, University of Leicester, 2011. http://hdl.handle.net/2381/9528.
Full textJaén, Cristina. "Differential coupling of RGS3s and RGS4 to GPCR-GIRK channel signaling complexes." Scholar Commons, 2006. http://scholarcommons.usf.edu/etd/2571.
Full textRanganathan, Anirudh. "The impact of GPCR structures on understanding receptor function and ligand binding." Doctoral thesis, Stockholms universitet, Institutionen för biokemi och biofysik, 2016. http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-129879.
Full textAt the time of the doctoral defense, the following paper was unpublished and had a status as follows: Paper 3: Manuscript.
Bahena, Silvia. "Computational Methods for the structural and dynamical understanding of GPCR-RAMP interactions." Thesis, Uppsala universitet, Institutionen för biologisk grundutbildning, 2020. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-416790.
Full textScarlin, Hugh. "Studies on the synthesis of novel PP2A inhibitors and a GPCR detergent." Thesis, University of Glasgow, 2016. http://theses.gla.ac.uk/7370/.
Full textElenko, Eric. "Localization and fate of GAIP following G[alpha]i̳ linked GPCR stimulation /." Diss., Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 2001. http://wwwlib.umi.com/cr/ucsd/fullcit?p3026385.
Full textHeuninck, Joyce. "Analysis of CXCR4 and ACKR3 oligomerisation." Thesis, Montpellier, 2019. http://www.theses.fr/2019MONTT018.
Full textDuring my PhD, I focused on two chemokine receptors, CXCR4 and ACKR3. They have several important physiological functions, such as chemotaxis of immune cells. However, on the other hand, when their function is disturbed, they are involved in different immunological pathologies and cancer. Both receptors recognise the same chemokine, CXCL12 and many studies have reported a crosstalk between CXCR4 and ACKR3. However, the mechanisms behind this crosstalk are still poorly understood. This crosstalk can occur because both receptors are competing for CXCL12, at the level of signalling pathways or due to the formation of complexes between CXCR4 and ACKR3 receptors, called oligomers. The oligomers might have specific pharmacological properties different from the receptor monomers. Oligomeric complexes have been described since the nineties. Most of the studies on these oligomers were performed on heterologous expression systems, but still a lot of debate exists about their existence and their role in native tissues. One of the reasons behind this controversy is that studying oligomers in a native context is complicated, especially because we often lack the molecular tools for these studies.The first objective of my PhD was to generate efficient tools to study the existence of CXCR4 and ACKR3 oligomers in native systems. In collaboration with laboratories from Amsterdam and Ghent, we have developed fluorescent nanobodies, small antibodies produced by llamas. These specific tools allow the detection of receptors endogenously expressed at the cell surface. In order to fluorescently label these nanobodies, we have used an original strategy that can specifically attach the fluorophore to the C-terminus of the nanobody. Interestingly, the fluorescent nanobodies retain high affinity and specificity for their target. With these nanobodies, I have demonstrated the existence of CXCR4 oligomers in cell lines that endogenously express CXCR4. We are currently investigating the existence of ACKR3 oligomers.The second objective of my PhD consists of defining the functional roles of these oligomers. I have shown that CXCR4/ACKR3 hetero-oligomers have specific binding characteristics. It seems that CXCL12 is binding only to ACKR3 within this hetero-oligomer and that ACKR3 impairs the CXCL12 binding to CXCR4 within the hetero-oligomer. This is interesting, since we also have demonstrated that CXCL12 is binding much faster on CXCR4 than on ACKR3.In addition, I have studied the consequences of this negative cooperativity within the CXCR4/ACKR3 hetero-oligomer on different signalling pathways. We have compared conditions where the receptor was expressed alone or when receptors were co-expressed. No major modifications have been found on their signalling properties. However, when investigating the internalisation of CXCR4 and ACKR3, it seems that CXCR4/ACKR3 hetero-oligomers remain blocked on the cellular surface.This opens interesting perspectives, since it is the first time CXCR4 oligomers have been detected at an endogenous level. Moreover, the observation of a different internalisation pattern of the hetero-oligomer is a first step to further investigate the specific roles of these oligomers in the crosstalk between the receptors
Brewer, Cynthia. "Use of PC12 cells to characterize PAFR-GPCR-mediated activity in neural precursors." Thesis, University of Ottawa (Canada), 2001. http://hdl.handle.net/10393/9170.
Full textJackson, Verity. "Mechanistic studies of the adhesion-GPCR latrophilin and its interactions in neural guidance." Thesis, University of Oxford, 2017. http://ora.ox.ac.uk/objects/uuid:ecc6187a-3e20-4753-ada6-dc009ad7f6e2.
Full textBucco, Olgatina, and olgatina@gmail com. "Preparing, measuring and capturing G-protein coupled receptor (GPCR) signalling complexes for future development of cell-free assay technologies." Flinders University. medicine, 2006. http://catalogue.flinders.edu.au./local/adt/public/adt-SFU20060703.114912.
Full textPeyrassol, Xavier. "Développement et caractérisation d’anticorps de camélidés dirigés contre des récepteurs couplés aux protéines G et leur utilisation dans des approches structurales." Doctoral thesis, Universite Libre de Bruxelles, 2018. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/270870.
Full textDoctorat en Sciences biomédicales et pharmaceutiques (Médecine)
info:eu-repo/semantics/nonPublished
do, Nascimento Júnior Francisco. "Classificação de Proteínas usando Máquinas de Aprendizagem e Descoberta de Padrões." Universidade Federal de Pernambuco, 2008. https://repositorio.ufpe.br/handle/123456789/1596.
Full textMáquinas de aprendizagem têm sido aplicadas em diferentes problemas em Bioinformática. Similarmente, algoritmos de descoberta de padrões também têm sido usados para descobrir motifs em seqüências de proteínas, contribuindo na definição de assinaturas (tais como impressões digitais) que caracterizam classes funcionais de proteínas. Como por exemplo, a classe de receptores acoplados a proteína-G (GPCR) que representam uma das maiores famílias no Genoma Humano. Esta família é um dos grandes alvos de pesquisa para a descoberta e desenvolvimento de novas drogas, conseqüentemente, de grande interesse para a indústria farmacêutica. O modelo proposto nesta dissertação combina máquinas de aprendizagem, como SVM (Support Vector Machine) e MLP (Multilayer Perceptron), e métodos de descoberta de padrões no desenvolvimento de um procedimento para predizer a relação entre uma seqüência primária de proteínas e sua classe funcional. Como caso de estudo, este trabalho apresenta experimentos com a superfamília GPCR, usando padrões em forma de expressões regulares desta família extraídos pelo SPEXS (Sequence Pattern EXhaustive Search), um algoritmo para descoberta de padrões
Garcia, De Las Bayonas Alain. "Spatio-temporal and quantitative control of Rho1 activity by GPCR signaling during tissue morphogenesis." Thesis, Aix-Marseille, 2018. http://www.theses.fr/2018AIXM0548/document.
Full textCell apical constriction in the mesoderm and cell intercalation in the ectoderm are controlled by contractile actomyosin networks in the developing Drosophila embryo. The extent of both actomyosin activation and polarization determines the nature of these cell deformations. We find that the GPCR Smog and the downstream G proteins (Gα,Gβγ) activate Rho1 signaling and thereby myosin-II in both tissues. In the ectoderm, Gα12/13 activates Rho1 at the apical membrane (also called medial-apical compartment) while Gβ13F-Gγ1 subunits promote Rho1 activity at the apical membrane and at cell junctions. How such a polarized activation of Rho1 is achieved remains unclear. Here, we show that two RhoGEFs, RhoGEF2 and a previously uncharacterized RhoGEF Wireless/p114RhoGEF, control Rho1 activity downstream of G proteins in the ectoderm. RhoGEF2 activates medial-apical Rho1 under control of Gα12/13 and Wireless/p114RhoGEF is required to mediate Gβ13F-Gγ1-dependent activation of Rho1 at junctions. RhoGEF2 is present both at junctions and at the apical membrane. In contrast, Wireless/p114RhoGEF only localizes at junctions together with Gβ13F-Gγ1 which recruit the GEF. Finally, we show that Wireless/p114RhoGEF is absent from junctions in the mesoderm. Collectively, GPCRs shape Rho1 activity through distinct biochemical modules in the ectoderm. Heterotrimeric G proteins transduce the signal by recruiting and activating two complementary RhoGEFs apically and at junctions. Variation in type of GPCRs, G proteins or RhoGEFs underlie the tissue-specific control of Rho1 signaling during morphogenesis
Liebscher, Ines. "Die Physiologische Relevanz des G-Protein-gekoppelten Rezeptors GPR34." Doctoral thesis, Universitätsbibliothek Leipzig, 2011. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-64305.
Full textAkkuzu, Selin. "The Functional Assessment Of Fluorecently Tagged Adenosine A2a And Dopamine D2 Receptors And Qualitative Analysis Of Dimerization Of Adenosine A2a And Dopamine D2 Receptor By Using Fret." Master's thesis, METU, 2013. http://etd.lib.metu.edu.tr/upload/12615474/index.pdf.
Full textSheng, Yinglun. "G protein signaling and G protein coupled receptor (GPCR) pathway in Xenopus oocyte maturation." Thesis, University of Ottawa (Canada), 2005. http://hdl.handle.net/10393/29262.
Full textEllaithy, Amr. "Metabotropic Glutamate Receptor 2 Activation: Computational Predictions and Experimental Validation." VCU Scholars Compass, 2018. https://scholarscompass.vcu.edu/etd/5319.
Full textMOLTENI, LAURA. "PHARMACOLOGICAL CHARACTERIZATION OF THE INTRACELLULAR SIGNALLING PATHWAY ACTIVATED BY TLQP-21." Doctoral thesis, Università degli Studi di Milano-Bicocca, 2017. http://hdl.handle.net/10281/158161.
Full textObesity is a global epidemic for which the current weight loss therapies are relatively ineffective. Many central and peripheral factors are involved in the mechanisms controlling eating behaviour, and the integration of these signals within the hypothalamus results in the generation of specific responses aimed at regulating energy balance. TLQP-21 is a novel neuropeptide that has been implicated in the regulation of energy homeostasis, nociception, gastric function and several other physiologic functions. Although recent studies identified different receptors as the targets for TLQP-21, its molecular mechanisms of action at the cellular level remain largely unknown. Thus, since TLQP-21 is emerging as a novel target for obesity-associated disorders, diabetes, neuropathic pain, and other human pathologies, the purpose of this study was to better investigate the intracellular signalling pathway activated by the peptide-receptor interaction. Here, using intracellular calcium mobilization assay and western blot analysis, we have pharmacologically characterized the intracellular signalling pathway activated by TLQP-21 in ovary, macrophage and microglial cells. TLQP-21 dose-dependently stimulated a rapid and transient intracellular Ca2+ increase in CHO, RAW264.7 and N9 cells, and repeated exposure to the peptide resulted in a reduced response, indicating a possible desensitization mechanism of TLQP-21 receptor. In particular, TLQP-21 stimulation induced an increase of cytoplasmic Ca2+ levels that was sustained by Ca2+ release from the ER, since treatment of the cells with thaspigargin reduced the TLQP-21-mediated increase of intracellular Ca2+. The release of Ca2+ from the ER store is regulated by the activation of PLCs and the subsequent production of IP3 that binds to its receptors on the surface of the ER. In our cellular systems, TLQP-21 activity was reduced by the treatment with the PLC inhibitor U73122 and the IP3R antagonist 2-APB, confirming a PLC-dependent mechanism of action for the peptide. Furthermore, TLQP-21 induced a rapid dephosphorylation of PLCγ1 in CHO cells, suggesting that Ca2+ response to TLQP-21 is mediated by the binding of the peptide to a Gq-coupled receptor that in turn activates PLCβ. Ca2+ release from the ER activated Ca2+ entry from the extracellular environment, as demonstrated by the treatment of the cells with SKF-96365 and YM-58483, two specific inhibitors of the SOCE pathway. In CHO cells, TLQP-21 induced also an increase of PKC phosphorylation and, afterwards, of ERK1/2 phosphorylation. Moreover, the increase of cytosolic Ca2+ concentration following TLQP-21 administration, stimulated the activation of Akt/PKB. Our results suggest that the receptor stimulated by TLQP-21 belongs to the family of the Gq-coupled receptors, that activates membrane-lipid derived second messengers which thereby induce Ca2+ mobilization from the ER followed by a slower store-operated Ca2+ entry from outside the cell. In conclusion, our research provides additional evidences about the molecular mechanisms of action of TLQP-21, and could be useful to open new approaches to improve the treatment of several human disorders, including obesity and diabetes.
Holmes, Steven P. "The characterization, functional expression, and localization of the first arthropod myokinin receptor from the southern cattle tick, Boophilus microplus (Acari: ixodidae)." Diss., Texas A&M University, 2003. http://hdl.handle.net/1969.1/60.
Full textSohn, Johann. "IDENTIFICATION AND CHARACTERIZATION OF CONTACT SITES BETWEEN HUMAN FOLLICLE STIMULATING HORMONE AND THE FOLLICLE STIMULATING HORMONE RECEPTOR." UKnowledge, 2005. http://uknowledge.uky.edu/gradschool_diss/270.
Full textMcCaffrey, Rebecca. "IDENTIFICATION AND CHARACTERIZATION OF CONTACT SITES BETWEEN HUMAN CHORIONIC GONADOTROPIN AND THE AMINO TERMINAL REGION OF THE LUTEINIZING HORMONE/CHORIOGONADOTROPIN RECEPTOR." UKnowledge, 2002. http://uknowledge.uky.edu/gradschool_theses/204.
Full textPreißler, Julia. "Die gliale Relevanz des G-Protein-gekoppelten Rezeptors 34." Doctoral thesis, Universitätsbibliothek Leipzig, 2015. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-167010.
Full textBittencourt, Fabiola M. "Examination of the Function of the Murine Cytomegalovirus Encoded G Protein-Coupled Receptor M33 in vivo." University of Cincinnati / OhioLINK, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1397234044.
Full textJin, Hongjun. "Structural and functional investigation of human chemokines and applications of human chemokines in blocking HIV-1 entry." [College Station, Tex. : Texas A&M University, 2007. http://hdl.handle.net/1969.1/ETD-TAMU-2430.
Full textAlice, Brown. "Allosteric Coupling in the Dimeric Calcium Sensing Receptor." Thesis, The University of Sydney, 2017. http://hdl.handle.net/2123/17738.
Full textKunisue, Sumihiro. "Roles of the Orphan Receptor Gpr176-mediated G-protein Signaling in the Central Circadian Clock." Kyoto University, 2019. http://hdl.handle.net/2433/242672.
Full textGhimire, Ganga D., ガンガ D. ギミレ, Kenichiro Imai, 賢一郎 今井, Fumitsugu Akazawa, 史嗣 赤沢, Toshiyuki Tsuji, et al. "Physicochemical properties of amino acid sequences of G-proteins for understanding GPCR-G-protein coupling." Chem-Bio Informatics Society, 2006. http://hdl.handle.net/2237/9277.
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