Dissertations / Theses: 'Receptors'

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Zhang, Shengwen. "The opioid receptor-like receptor ORL1 signaling and interaction with opioid receptors /." Cincinnati, Ohio : University of Cincinnati, 2002. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=ucin1029419843.

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Meira, Guilherme Louzada Silva. "Analíse da expressão do receptor olfativo M93 em sistemas heterólogos." Universidade de São Paulo, 2004. http://www.teses.usp.br/teses/disponiveis/46/46131/tde-31082016-115408/.

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O sistema olfatório de mamífero pode discriminar milhares de odores presentes no meio ambiente. Aproximadamente 1000 diferentes receptores olfatórios (ORs) são expressos no epitélio olfatório (OE) do nariz, Os ORs detectam os odores e transmitem os sinais resultantes para o bulbo olfatório (OB) no cérebro. Os ORs pertencem a super família dos receptores acoplados a proteína G (GPCR) e apresentam sete domínios transmembrânicos putativos. Por razões desconhecidas, os ORs são retidos no retículo endoplasmático quando expressos em linhagens de células de mamíferos heterólogas. Provavelmente, proteínas acessórias sejam requeridas para o endereçamento dos Ors para a superficie celular. No presente estudo, utilizamos o OR M93 para estudar os mecanismos de expressão de um ORo A dissertação teve como objetivos específicos: (l) construção de um vetor para expressão do OR M93 em fusão com GFP em levedura e análise de sua localização celular; (2) identificar proteínas expressas no epitélio olfatório de camundongo que interajam com os ORs. A análise por microscopia de fluorescência revelou que a expressão do OR M93 fusionado a GFP demonstrou um padrão de fluorescência que sugere a retenção do OR M93 no retículo endoplasmático. Nós utilizamos o sistema de duplo híbrido em levedura para varrer uma biblioteca de cDNA de epitélio olfatório de camundongo com uma isca correspondente à região N-terminal do OR M93. Quatro proteínas candidatas foram identificadas: HLA-B associado ao transcrito 3 (BAT-3/ Scythe), superfamília transmembrana 4 (membro CD82), superfamília transmembrana 4 (membro OAP-I) e sindecan (membro SDC2) (\"GenBank accession numbers\": BC026647, D14883, BC0430n e BC047144). A análise da hibridação in situ destas proteínas, revelou que a proteína OAP-1 é a melhor candidata a interação com OR M93. Dessa maneira, nós indicamos a proteína OAP-1 como possível proteína candidata a auxiliar o OR a ser expresso de maneira funcional em sistemas heterólogos. The mammalian olfactory system can discrim inate thousands of odorants present in the environrnent. Approximately 1000 different olfactory receptors (ORs) are expressed in the olfactory epithelium (OE) of the nose. The ORs detect odorants and transmit the resulting signals to the olfactory bulb (OB) of the brain. ORs belong to the G-protein-coupled receptor (GPCR) super family and have seven putative transmembrane domains. For unknown reasons, the ORs are retained in the endoplasmatic reticulum when expressed in heterologous mammalian cell lines. Probably accessory proteins are required for the sorting of the ORs to the cell surface. In the present work, we used the OR M93 to study the mechanisms of OR expression. Our goals were to (1) construct an expression vector for OR M93 in fusion with GFP in yeast and (2) to identify proteins expressed in the mouse OE that interact with ORs. The analysis by fluorescence microscopy suggested that OR M93 in fusion with GFP was retained in the endoplasmic reticulum (ER) of yeast. We used the yeast two-hybrid system to screen a mouse OE cDNA library with a bait corresponding to the N-terminal region ofthe üR M93. Four potential candidates were identified: HLA-B associated transcript 3 (BAT-3/Scythe), transmembrane 4 superfamily (CD82 member), transmembrane 4 superfamily (TSPN-3 member) and syndecan (SDC2). In situ hybridization analysis suggests that OAP-l protein represents the best candidate for interaction with OR M93. We suggest the OAP-l protein could be an accessory protein required for the sorting of the ORs to the cell surface in heterologous cell lines.

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Carvalhosa, Artur Aburad de. ""Pesquisa dos receptores de estrógeno (RE) e do receptor da progesterona (RP) in vivo e verificação da influência destes hormônios in vitro em duas linhagens de adenomas pelomórficos"." Universidade de São Paulo, 2001. http://www.teses.usp.br/teses/disponiveis/23/23141/tde-02042004-115521/.

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RESUMO A similaridade entre o tecido da mama e o da glândula salivar está bem estabelecida. A porção das estruturas acinares e ductais destes órgãos são basicamente semelhantes. Estes aspectos, associados ao fato de que uma coexistência de carcinomas da mama e de glândula salivar, têm sido relatados em uma incidência maior do que a esperada. Guiaram estudos tentando determinar a importância dos receptores de estrógeno e progesterona em adenomas pleomórficos (AP). A neoplasia é mais freqüente nas glândulas salivares e exibe uma predileção para o sexo feminino. Recentemente a presença do receptor de estrógeno (RE) e do receptor de progesterona (RP) tem sido investigada no AP, entre outras neoplasias de glândula salivar, questionando-se a possibilidade da existência da dependência hormonal. A expressão dos receptores hormonais nos carcinomas de mama é importante para determinar o prognóstico e a probabilidade de responder à manipulação hormonal. Neoplasias que apresentam positividade para ambos os receptores, estrógeno e progesterona, exibem maior probabilidade de resposta à terapia anti-estrogênica do que as neoplasias que são negativas para estes receptores. Baseando-se na literatura científica pertinente, o presente trabalho se propõe a investigar a presença da proteína RE e da proteína RP em APs humanos, relacionando-os com a proliferação de linhagens celulares sob a influência destes hormônios. A técnica utilizada foi a imuno-histoquímica para a pesquisa dos RE e RP em 10 APs emblocados em parafina pertencentes ao arquivo do Serviço de Patologia Cirúrgica da FOUSP, e de duas linhagens de APs estabelecidas no mesmo serviço: uma derivada de um paciente do sexo masculino e a outra de um paciente do sexo feminino. No meio de cultivo onde subculturas destas células proliferavam foram diluídos 17-b-estradiol e progesterona. Através de contagens destas células em períodos pré-determinados (24 horas, 48 horas e 72 horas), pretendeu-se verificar a influência dos respectivos hormônios na multiplicação celular. Como controle positivo utilizou-se uma linhagem denominada T-47D, que foi largamente estudada na literatura. A T-47D é derivada de um carcinoma metastático de mama, reconhecidamente hormônio dependente. E como controle negativo, utilizou-se de uma linhagem de carcinoma epidermóide, denominada HN30. Encontrou-se positividade para o RE em 7 de 10 APs estudados (4 em homens e 3 em mulheres) e positividade para o RP em 8 Aps estudados (4 em mulheres e 4 em homens). Pela análise estatística, constatou-se que existe uma diferença significativa no índice proliferativo entre o controle e as células submetidas à ação do 17-b-estradiol e da progesterona. Para a linhagem derivada do paciente do sexo masculino houve diferença entre o controle e as células expostas ao 17-b-estradiol e a progesterona somente nas últimas 72 horas. Para a linhagem derivada do sexo feminino constatou-se uma diferença significativa entre o controle e as células sob a influência da progesterona, a partir de 48 horas de proliferação celular. A diferença significativa entre o controle e as células sob a ação do 17-b-estradiol ocorreu somente a partir das 72 horas, sugerindo que o AP poderia ser uma neoplasia influenciada pela ação hormonal. SUMARY It is well established the similarity between mammary and salivary glands especially between the acinic and ductile structures. These aspects, associated to the fact of coexistence of breast carcinomas and of salivary gland tumors been described, leaded studies in attempt to determine the importance of the ERs and Pr in pleomorphic adenomas (PA), the most frequent salivary gland tumor and with predilection for the females. Lately, the presence of ERs and of the PRs has been investigated in PA and other salivary gland tumors pointing out their hormonal dependency. The expression of hormone receptors in breast carcinomas is crucial to determine a presence for both receptors. These tumors exhibit better response to anti-estrogenic therapy than the negative ones. Basing on the pertinent scientific literature, the present study proposes to investigate the presence of the RE and of the RP in humans PA and connecting them with cellular proliferation in vitro, under the influence of these hormones. Immunohistochemistry technique was used for the detection of RE and RP in paraffin embedded 10 PAs from the files of the Department of Oral Pathology, School of Dentistry, University of São Paulo, and two PA cell lines one from a male patient and other female. The culture midia was supplied with, 17-b-estradiol and progesterone. A growth curve was performed (24 hours, 48 hours and 72 hours) to verify the influence of the respective hormones in the cellular proliferation. As a positive control T-47-D cells derived from a hormone dependent metastatic breast carcinoma were used, and as negative control HN30 cells, derived from a tongue squamous cell carcinoma. 7 of 10 PAs were positive (4 in men and 3 in women) for RP and 8 of 8 PAs (4 in women and 4 in men) for RE. The statistical analysis verified a significant difference in the proliferative index between the control cells and the ones submitted to the action of the 17-b-estradiol and of the progesterone: for male derived lineage a difference was only observed in the last 72 hours. In the other hand, for the female derived lineage a significant difference was verified starting from 48 hours, suggesting that PA can be influenced by hormonal action.

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Tchetchelnitski, V. "Regulation of neurotrophin receptors by receptor-type protein tyrosine phosphatases." Thesis, University College London (University of London), 2011. http://discovery.ucl.ac.uk/1310477/.

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Reversible protein phosphorylation plays a key role in cell signalling during neural development and thus controls cell proliferation, survival, differentiation and function. Kinases and their counter-partners the phosphatases tightly regulate protein phosphorylation. In the developing nervous system the neurotrophin receptor family of protein tyrosine kinases (TrkA, B and C) are major players in this signalling network during normal neuron development and also in several diseases such as neuropathies, degenerative disorders and cancers. Recently, receptor-type protein tyrosine phosphatases (RPTPs) were suggested to be possible regulators of Trks. Thus understanding the relationships between RPTPs and Trks may help to develop new therapeutics to control aberrant neurotrophin signalling in disease. In this study I investigated the relationship between RPTPs and Trks in murine embryonic sensory neurons from dorsal root ganglia (DRGs), a primary cell model. The expression and coexpression of RPTPs and Trks was extensively studied during critical stages of DRG maturation using qPCR arrays at Merck-Serono, Geneva, and fluorescent in-situ hybridization and immunohistochemical techniques. This revealed a relatively high expression of several candidate RPTPs, which were expressed in particular TrkA+, TrkB+ and/or TrkC+ subpopulations of sensory neurons, indicating a potential relationship in their signalling functions. To further analyze a potential direct interaction between candidate RPTPs with Trk proteins, a bimolecular-fluorescent complementation assay (BiFc) was tested. However, this particular assay, when used with type I transmembrane proteins, suffered from high, unspecific protein interactions. In the main experimental approach, a lentiviral-mediated shRNAi-induced knockdown system in primary cell cultures was set-up and the effects of the knockdowns of Ptprf, Ptprs and Ptpro on endogenous Trk gene expression and Trk phosphorylation and activation were analysed. These results suggest a potential role of the encoded proteins LAR and RPTPσ in Trk function and of RPTP-BK in the differentiation and specification of Trk+ neurons.

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Lee, ChangWoo. "CIS- AND TRANS-ACTIVATION OF HORMONE RECEPTORS: THE LH RECEPTOR." Lexington, Ky. : [University of Kentucky Libraries], 2003. http://lib.uky.edu/ETD/ukybiol2003d00082/changwoo.pdf.

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Thesis (Ph. D.)--University of Kentucky, 2003. Title from document title page. Document formatted into pages; contains xix, 74p. : ill. Includes abstract. Includes bibliographical references (p. 62-72).

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VERGASSOLA, MATTEO. "Presynaptic release regulating metabotropic receptors: dimerization and receptor cross talk." Doctoral thesis, Università degli studi di Genova, 2020. http://hdl.handle.net/11567/993002.

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The Class C subfamily of the G protein coupled receptor (GPCR) family is one of the most important in the central nervous system (CNS), and includes the glutamatergic and GABAergic metabotropic receptors (mGlu and GABAB). The mGlu receptors are fundamental in modulating the efficiency of chemical neurotransmission in the CNS and, as a consequence, they are also involved in several neurological and neurodegenerative disorders. Recently, dimerization of these receptors has become an important topic of investigation and it has been proposed to be crucial to physio-pathological processes in the CNS, as well as to the impact of therapeutics in patients. In this thesis, I will discuss the basic properties of Class C GPCRs focusing on the first and second group of mGlu receptors (Group I and II) and their possible dimerization and/or cross talk with other receptors. I will focus on recent findings concerning these processes that have been mainly obtained by using purified isolated nerve endings (here referred to as synaptosomes), a subcellular preparation of choice for studying presynaptic release regulating receptors. Starting from the pharmacological characterization of Group I and II mGlu receptors, I will then discuss different examples of cross-talk linking these receptors to other ones (i.e. the GABAB and the 5HT2A receptors). I will also show results obtained using electrophysiology to study the role of these receptor subtypes in the modulation of synaptic transmission in hippocampal slices. The resulting picture is undoubtedly complex and highlights how the cross-talk and dimerization of these receptors represent a new frontier in neuropharmacological studies.

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Björnström, Linda. "Molecular mechanisms of alternative estrogen receptor signaling /." Stockholm, 2003. http://diss.kib.ki.se/2003/91-7349-509-3/.

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Castro, Diogo Sampaio e. "Functional studies on the orphan receptor Nurr1 and related retinoid receptors /." Stockholm, 2001. http://diss.kib.ki.se/2001/91-628-4608-6/.

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Murphy, Shannon L. "Heteroditopic receptors." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1996. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp04/MQ30920.pdf.

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Rosser, Mark Joseph. "Synthetic receptors." Thesis, Durham University, 1993. http://etheses.dur.ac.uk/5761/.

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Novel, rigid cyclophanes have been designed and synthesised as receptors for the biologically important neurotransmitter, acetyl choline. The receptor cavities were less symmetrical than those of similar cyclophanes which had been previously prepared, as they incorporated two quite different functional groups on opposite sides of the cavity. NMR experiments indicated that a cyclophane which incorporated a benzoate residue bound acetyl choline, with an exchange between the free and bound species which was slow on the NMR time scale. A second cyclophane, which incorporated both a benzoate and a pyridinium residue, also bound acetyl choline, but the exchange between the free and bound species was fast on the NMR time scale. NMR experiments also indicated that a third cyclophane, which incorporated only uncharged pyridyl and benzyl residues, did not bind acetyl choline. However, acetyl choline was efficiently transported across a PVC membrane by this neutral cyclophane with very little interference from ammonium and group I and group II metal cations. Urea and thiourea residues were incorporated into crown-type macrocyclic frameworks. The crystal structures of two macrocycles incorporating thiourea residues (18N(_4)O(_2).2CS and 24N(_4)O(_4).2CS) were determined, as was the crystal structure of the 18N(_4)O(_2).2CS/silver(I) complex. Preliminary experiments indicate that the bisthioureas 18N(_4)O(_2).2CS and 24N(_4)O(_4).2CS form quite stable complexes with the 'soft' metal cations silver (I), zinc (II), cadmium (II) and mercury (H), and that the analogous bisureas 18N(_4)O(_2).2CO and 24N(_4)O(_4).2CO form stable complexes with sodium and potassium, for which they are selective.

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Joseph, Christine G. "Design, synthesis, and characterization of peptides and peptidomimetics for mouse melanocortin receptors." [Gainesville, Fla.] : University of Florida, 2004. http://purl.fcla.edu/fcla/etd/UFE0008368.

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Thesis (Ph. D.)--University of Florida, 2004. Typescript. Title from title page of source document. Document formatted into pages; contains 202 pages. Includes Vita. Includes bibliographical references.

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Chakraborty, Raja. "Structure function studies on prostanoid receptors: Thromboxane A2 receptor (TP) and Prostacyclin receptor (IP)." Elsevier Ltd, 2011. http://hdl.handle.net/1993/23744.

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Cell membrane receptors help to mediate communication between the cell and its environment. The largest group of these membrane receptors belong to the family of G protein-coupled receptors (GPCRs). GPCRs contain seven transmembrane (TM) helices and signal predominantly through heterotrimeric G proteins in response to diverse extracellular stimuli. Previously, three levels of amino acid conservation were proposed to understand the structure and function of a GPCR. This includes “signature” amino acids, “group –conserved” amino acids and amino acids conserved only within a specific subfamily. The group-conserved residues in class A GPCR family involve amino acid conservation of up to 99% when considered as a group of small and weakly polar residues (Ala, Gly, Ser, Cys and Thr). These group-conserved residues have been proposed as key determinants in helix-helix interactions. Therefore, I selected these residues for structure-function analysis in the amine and the prostanoid receptor sub-families of class A GPCRs. Molecular and biochemical assays clearly demonstrate the importance of group-conserved residues in β2-adrenergic receptor and thromboxane A2 receptor (TP) structure and function. These studies led to the identification of a non-synonymous single nucleotide polymorphic variant (nsSNP) A160T in TP to be a constitutively active mutant (CAM). Further, the TP-CAM was used as a pharmacological tool that enabled classification of well-known TP-blockers, into neutral antagonists and inverse agonists. The role of TP-A160T in prostanoid receptors, TP- Prostacyclin receptor (IP) heterodimerization and signaling was investigated. Activation of a GPCR ultimately leads to structural changes in its intracellular loops (ICLs), which in turn activates G-protein. TP activates its cognate G protein (Gαq), while IP mediates signaling, through Gαs. Using TP-IP chimeric receptors, molecular modelling, and site directed mutagenesis studies I determined the specific ICL regions required for G protein coupling in TP and IP. Significant challenges exist in expressing and purifying GPCR-CAMs in amounts required to pursue biophysical studies. Using tetracycline inducible HEK293S system, A160T was expressed at high-levels and CD spectropolarimetry studies were successfully pursued on the purified A160T. The CD spectra showed that the loss of thermal stability of the A160T mutant is due to the subtle changes in the secondary structure of the A160T protein. These studies involving molecular, biochemical and pharmacological approaches provide novel insights into the structure and function of prostanoid receptors TP and IP.

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Oliveira-Giacomelli, Ágatha. "Papel dos receptores purinérgicos em modelo animal de doença de Parkinson." Universidade de São Paulo, 2018. http://www.teses.usp.br/teses/disponiveis/46/46131/tde-26112018-074709/.

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A Doença de Parkinson é uma doença altamente incapacitante e de grande prevalência. Pouco se sabe sobre sua etiologia e os tratamentos atuais consistem na diminuição dos sintomas, uma vez que ainda não foi encontrada uma maneira de reverter o déficit de neurônios dopaminérgicos observados nos pacientes acometidos. Sabe-se que os receptores purinérgicos são encontrados por todo o sistema nervoso central, não só no indivíduo adulto como também em diferentes estágios do desenvolvimento embrionário e estão envolvidos com proliferação e diferenciação celular. Este trabalho estudou a participação dos receptores purinérgicos em modelo animal de doença de Parkinson por lesão dos neurônios dopaminérgicos da via nigroestriatal com 6-OH dopamina (6-OHDA). Realizamos a análise do perfil de expressão gênica dos diferentes receptores após a lesão e subsequente modulação. Observamos expressão gênica alterada dos receptores P2X7 e P2Y6 até 5 semanas após a lesão. O uso do antagonista do receptor P2X7 Brilliant Blue G (BBG) induziu a regeneração da via nigroestriatal e o uso do antagonista do receptor P2Y6 MRS2578 preveniu a morte dos neurônios. Como esses efeitos foram acompanhados pela inativação de células microgliais, supõe-se que o controle do microambiente neuroinflamatório causado pela injeção de 6-OHDA seja a principal causa do efeito antiparkinsoniano observado pelo tratamento com BBG e MRS2578. Além disso, o transplante celular com células precursoras neuraisnão foi capaz de reverter o comportamento hemiparkinsoniano dos animais lesionados. Apesar do uso concomitante com BBG reduzir o comportamento, parece que esse efeito deve-se ao BBG per se, uma vez que o tratamento somente com o antagonista de P2X7 foi mais eficaz. De maneira geral, a modulação da atividade dos receptores purinérgicos se mostrou uma ferramenta promissora na pesquisa de cura e compreensão das bases moleculares da Doença de Parkinson Parkinson\'s disease is a highly disabling and prevalent disease. Little is known about its etiology and the current treatments consist in the reduction of the symptoms, since there is no known method to reverse the dopaminergic neurons deficit observed in patients. Purinergic receptors are found throughout the central nervous system, not only in the adult individual but also at different stages of embryonic development, and are involved in proliferation and differentiation. This work investigated the role of purinergic receptors in the animal model of Parkinson\'s disease induced by 6-OH dopamine (6-OHDA) injection and consequent death of dopaminergic neurons of the nigrostriatal pathway. Patterns of purinergic receptors gene expression after the lesion and subsequent modulation were analyzed. We observed altered gene expression of P2X7 and P2Y6 receptors within 5 weeks of injury. The use of the P2X7 receptor antagonist Brilliant Blue G (BBG) induced the regeneration of the nigrostriatal pathway and treatment with P2Y6 receptor antagonist MRS2578 prevented the death of the neurons. Since these effects were accompanied by the inactivation of microglial cells, it is assumed that the control of neuroinflammatory milieu caused by the 6-OHDA injection is the main cause of the antiparkinsonian effect observed by the treatment with BBG and MRS2578. In addition, transplantation with neural precursor cells was not able to reverse the hemiparkinsonian behavior of injured animals. Although concomitant use with BBG improved cell engraftment, it appears that this effect is due to BBG per se, since treatment with only this P2X7receptor antagonist was more effective. In general, modulation of purinergic receptor activity showed to be a promising tool in the research of cure and understanding of the molecular bases of Parkinson\'s Disease.

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Sallander, Eva Jessica. "The mechanism of G protein coupled receptor activation: the serotonin receptors." Doctoral thesis, Universitat Pompeu Fabra, 2011. http://hdl.handle.net/10803/77901.

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Una de las principales cuestiones en farmacología molecular de los GPCR es entender los mecanismos estructurales de las siete hélices transmembrana (TM) que se producen para estabilizar ya sea Rg o los diferentes estados R*. Para entender el mecanismo que cambia el equilibrio del conjunto a un estado activo R* se construyeron tres de los receptores de la serotonina (5-HT4, 5-HT6, y 5 HT7) sobre la base de su información más reciente de cristalografía de rayos X. Dando lugar a dos modelos de cada receptor: una inactiva y otra activa. Los modelos, mejorados y evaluados con la ayuda de datos farmacológicos y químicos se utilizaron principalmente para comprender la interacción entre un ligando y su receptor y su mecanismo de acción. Estos hallazgos estructurales pueden a su vez resultar útiles para el diseño de nuevos fármacos más eficaces y selectivos. One of the main questions in G protein coupled receptors (GPCRs) molecular pharmacology is to understand the structural arrangements of the seven transmembrane (TM) helices that occur to stabilize either the ground state (Rg) or different active states (R*) of the receptors. In order to understand the mechanism that shift the equilibrium of the ensemble to an active R* state models of the inactive and the active state of three serotonin receptors (5-HT4, 5-HT6, and 5-HT7) were built based on the latest information from X-ray crystallography. The resulting models were mainly used to understand the interaction between a ligand and its receptor and the mechanism of action. With the help of pharmacological and chemical data these models and complexes were improved and evaluated. These findings may prove valuable for structural based drug discovery efforts and facilitate the design of more effective and selective pharmaceuticals.

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Malouitre, Sylvanie DeÌsireÌe Marie. "Glucocorticoid receptor function, interactions with oestrogen receptors and a steroid inhibitor." Thesis, Queen Mary, University of London, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.413737.

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Pringle, Ashley Ker. "Modulation of cerebellar GABAâ†A receptors by benzodiazephine receptor inverse agonists." Thesis, University of Southampton, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.295917.

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Björnberg, Flemming. "Processing of TNF-receptors to soluble receptor forms in myeloid cells." Lund : Dept. of Hematology, Lund University, 1998. http://catalog.hathitrust.org/api/volumes/oclc/39176479.html.

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Scammells, Peter J., and n/a. "Pyrazolo(3,4-d)Pyrimidines and adenosine receptors: a structure/activity study." Griffith University. Division of Science and Technology, 1990. http://www4.gu.edu.au:8080/adt-root/public/adt-QGU20050826.141630.

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Pyrazolopyrimidines are a general class of compounds which exhibit Aj adenosine receptor affmity. A number of pyrazolo(3,4-d)pyrimidine analogues of isoguanosine and i-methylisoguanosine has been synthesised. All compounds were tested forAi adenosine receptor affinity using a (311) R-PIA competitive binding assay. The N-i and N-5 positions were substituted with a number of different ailcyl and aryi groups. 3-Chiorophenyl substitution of the N-i position and butyl substitution of the N-5 position greatly enhanced the overall adenosine receptor affinity. Substitution by a methyl group at the N-7 position fixed the C-4 position in the imino tautomeric form. This resulted in a marked reduction in activity. The substitution of the N-2 position with a phenyl group produced an analogue with a similar structure to i,3-dipropyl-8-(2-amino-4-chlorophenyl)xanthine (PACPX). A 2-phenyl substituent was favourable for interaction with the adenosine receptor. A number of pyrazolo(3,4-d)pyrirnidine analogues of 4,6-bis-a-carbamoylethylthio-i-phenylthiopyrazolo(3,4-d)pyrinhidine (DJB-KK) has also been synthesised and tested for Aj adenosine receptor affinity. 4,6-Bis-alkylthio-1-phenylpyrazolo(3,4-d)pyrimidines with a-carbamoylethyl and u-carbamoylpropyi groups were compared. The additional methyiene of the a-carbamoylpropyl group produced increased adenosine receptor affinity. 6-a-Carbamoylethylthio-4-mercapto-1-phenylpyrazolo(3,4-d)pyrimidine and 4-cc-carbamoylethylthio- i-phenylpyrazolo(3,4-dlpyrimidine were compared. Substitution of the C-6 position maintained activity, while substitution of the C-4 reduced activity.

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Scammells, Peter. "Pyrazolo(3,4-d)Pyrimidines and adenosine receptors: a structure/activity study." Thesis, Griffith University, 1990. http://hdl.handle.net/10072/365214.

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Pyrazolopyrimidines are a general class of compounds which exhibit Aj adenosine receptor affmity. A number of pyrazolo(3,4-d)pyrimidine analogues of isoguanosine and i-methylisoguanosine has been synthesised. All compounds were tested forAi adenosine receptor affinity using a (311) R-PIA competitive binding assay. The N-i and N-5 positions were substituted with a number of different ailcyl and aryi groups. 3-Chiorophenyl substitution of the N-i position and butyl substitution of the N-5 position greatly enhanced the overall adenosine receptor affinity. Substitution by a methyl group at the N-7 position fixed the C-4 position in the imino tautomeric form. This resulted in a marked reduction in activity. The substitution of the N-2 position with a phenyl group produced an analogue with a similar structure to i,3-dipropyl-8-(2-amino-4-chlorophenyl)xanthine (PACPX). A 2-phenyl substituent was favourable for interaction with the adenosine receptor. A number of pyrazolo(3,4-d)pyrirnidine analogues of 4,6-bis-a-carbamoylethylthio-i-phenylthiopyrazolo(3,4-d)pyrinhidine (DJB-KK) has also been synthesised and tested for Aj adenosine receptor affinity. 4,6-Bis-alkylthio-1-phenylpyrazolo(3,4-d)pyrimidines with a-carbamoylethyl and u-carbamoylpropyi groups were compared. The additional methyiene of the a-carbamoylpropyl group produced increased adenosine receptor affinity. 6-a-Carbamoylethylthio-4-mercapto-1-phenylpyrazolo(3,4-d)pyrimidine and 4-cc-carbamoylethylthio- i-phenylpyrazolo(3,4-dlpyrimidine were compared. Substitution of the C-6 position maintained activity, while substitution of the C-4 reduced activity. Thesis (PhD Doctorate) Doctor of Philosophy (PhD) Division of Science and Technology Full Text

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Beltrán, Sáez Elisa. "Information transmission through a nonlinear molecular signaling system: ErbB as a case study." Doctoral thesis, Universitat Autònoma de Barcelona, 2019. http://hdl.handle.net/10803/667354.

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La capacitat dels éssers vius d’obtenir i processar informació és clau per adaptar-se i sobreviure en l’ambient que els envolta. Les cèl·lules, des de procariotes unicel·lulars fins a organismes multicel·lulars (eucariotes), capten informació de l’entorn mitjançant diversos mecanismes, entre ells a través de receptors de membrana, que fan de canal per a la informació entre l’exterior i l’interior de la cèl·lula. Per tant, aquestos receptors representen un canal de transmissió d’informació a través del qual la informació ambiental pot afectar el comportament cel·lular per adaptar-se a l’ambient. En aquesta tesi, hem estudiat la transmissió d’informació a través del sistema de receptors ErbB, una família de receptors involucrats en diferents comportaments cel·lulars, com per exemple la proliferació o la migració. Gràcies a l’estudi de malalties complexes -centrem-nos en el càncer- des d’una perspectiva molecular, s’han pogut identificar els receptors de la família ErbB com a factors que causen l’enfermetat: quan els receptors ErbB es troben sobreexpressats (produïts en excés), les cèl·lules deixen d’interpretar correctament la informació extracel·lular i proliferen descontroladament, formant tumors. Per tant, la desregulació dels receptors ErbB està molt lligada al que podriem anomenar malalties de la informació, és a dir, malalties causades per la pèrdua de la capacitat d’obtenir i interpretar informació extracel·lular. Per tal de quantificar la informació que es transmet a través del sistema ErbB, hem modelitzat matemàticament la dinàmica dels receptors a la membrana mitjançant sistemes d’equacions diferencials ordinàries. Els nostres models incorporen la dimerització (formació d’un complex de dos receptors) entre receptors de diferents tipus. Aquesta interacció és necessària per a l’activació dels receptors i introdueix una no linialitat al sistema. La dimerització i activació són els primers passos en la transducció d’informació a l’interior cel·lular, i vénen seguits de la interacció de proteïnes intracel·lulars amb els receptors actius, que hem modelitzat mitjançant models estocàstics (processos de Poisson). Gràcies a la modelització d’aquestos dos processos hem pogut obtenir una estimació de l’estat intracel·lular en termes probabilístics que ens permet aplicar eines de teoria de la informació per quantificar la transmissió d’informació entre l’exterior i l’interior cel·lular. Els nostres resultats mostren una disminució en la informació transmesa a través del receptors ErbB quan la quantitat de receptors a la membrana augmenta. Aquesta pèrdua de informació depén de la dinàmica entre receptors, així com de la interacció d’aquestos amb les proteïnes intracel·lulars. En particular, hem estudiat la interacció dels receptors actius amb diferents proteïnes intracel·lulars i hem observat que la tendència que es dóna en les proteïnes a interaccionar amb diferents llocs d’unió dels receptors amb afinitats similars es tradueix en un augment en la sinèrgia entre les diferents proteïnes en quant a la informació que detecten. La quantificació i anàlisi d’aquestes interaccions i de la transmissió de informació que en resulta és clau per entendre millor els processos de senyalització cel·lular i serà útil en el diseny d’estratègies per tractar les malaties de la informació. The ability of organisms to extract and store information from their surroundings marked a revolution in the history of life and allowed survival and adaptation to the environment. Cells, from prokaryots to eukaryots, use specific receptors inserted in their membranes to detect extracellular molecules that cannot cross into the cell, where cell decisions are taken. Hence, those membrane receptors represent an information channel through which the environmental information can affect cell behavior and adaptation. In this Thesis, we modeled information transmission through the ErbB system, a family of receptors involved in many different cellular behaviors, such as cell proliferation or migration. Thanks to the study of complex diseases - let us think of cancer – from a molecular perspective, the ErbB receptors have been identified as factors causing the disease: when they are overexpressed (produced in excess), cells cease to interpret correctly extracellular information, which results in uncontrolled cell proliferation forming tumors. Therefore, dysregulation of ErbB receptors is at the core of what can be called information diseases, that is, diseases that arise from the loss of the capacity to obtain and interpret extracellular information. With the aim of quantifying the information transmitted through the ErbB system, we modeled the dynamics of membrane receptors by means of systems of ordinary differential equations. Our models considers the dimerization (formation of pairs of receptors) between receptors of differet types. This interaction is necessary for receptor activation and introduces a nonlinearity in the system. Dimerization and activation are the first steps in the signaling cascade, followed by the interaction of intracellular proteins with the active receptors. We modeled these interactions by means of stochastic models (Poisson processes). Thanks to the modeling of these two processes (receptor dynamics and interactions with the intracellular proteins), we obtained an estimation of the intracellular stat in probabilistic terms which has allowed us to use tools from information theory to quantify information transmission between the exterior and the interior of the cell. Our results show a decrease in the information transmitted through the ErbB channel as the amount of ErbB receptors at the membrane increases. We considered different dynamics of the receptors and showed that the loss of information depends on the dynamics of interaction between the receptors, as well as on their interactions with the intracellular signaling machinery. In particular, we studied the interaction of active receptors with several signaling intracellular proteins and showed that the observed tendency of proteins to bind several binding sites with similar affinities translates into an increased synergy between the signaling proteins. All in all, quantifying and analysing these interactions results in a better understanding of the dynamics and information transmission through ErbB and similar molecular systems and it can be used for the design of therapeutic strategies for information diseases.

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Lüttgen, Maria. "Serotonergic receptor subtypes in learning and memory : focus on 5-HT1A, 5-HT1B and 5-HT2A receptors /." Stockholm, 2004. http://diss.kib.ki.se/2004/91-628-6148-4/.

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Macedo, Cristina Gomes de 1964. "Mecanismos opióides centrais envolvidos no efeito protetor da testosterona no desenvolvimento da dor da ATM em ratos." [s.n.], 2012. http://repositorio.unicamp.br/jspui/handle/REPOSIP/290572.

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Orientador: Claudia Herrera Tambeli Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Odontologia de Piracicaba Made available in DSpace on 2018-08-20T01:36:46Z (GMT). No. of bitstreams: 1 Macedo_CristinaGomesde_M.pdf: 777542 bytes, checksum: 9fba5bed6fd851b4349bf4812dda8d33 (MD5) Previous issue date: 2012 Resumo: Disfunções temporomandibulares são condições dolorosas que envolvem a articulação temporomandibular e os músculos mastigatórios com maior prevalência, severidade e duração no sexo feminino. Recentemente foi demonstrado que a testosterona apresenta um efeito protetor ao diminuir o risco de ratos desenvolverem dor na Articulação Temporomandibular (ATM), o que explica pelo menos em parte, a menor prevalência de dor no sexo masculino. No entanto, o mecanismo através do qual a testosterona induz o efeito protetor em machos não é conhecido. Assim, o objetivo deste trabalho foi investigar se o efeito protetor da testosterona é mediado pela ativação do sistema opióide endógeno no sistema nervoso central e quais os subtipos de receptores opióides estão envolvidos nesse efeito protetor sobre o desenvolvimento de dor na ATM em ratos. Para o procedimento experimental foram usados ratos machos Wistar (230-300 g), intactos, gonadectomizados (Gx) e sham gonadectomizados (sham Gx) e a injeção de formalina 0,5% na ATM foi usada como estímulo nociceptivo. Para testar o envolvimento de um mecanismo neural central dependente da ativação do sistema opióide, os animais receberam injeção de naloxona, antagonista não seletivo de receptores opióides, CTOP, Naltrindole e Nor-BNI, antagonistas opióides seletivos para os subtipos de receptores opióides mu (µ ), delta e capa (µ ), respectivamente na região do núcleo sensorial trigeminal, antes do teste da formalina na ATM. A administração da Naloxona (15?g) antagonista não seletivo ou a combinação dos antagonistas de receptor µ opióide CTOP (30µ g/10µ l) mais o de receptor µ opióide Nor- BNI (90µ g/10µ l) aumentou significativamente a nocicepção induzida pela formalina 0,5% na ATM em ratos sham Gx, mas não em ratos Gx (31.09%, n = 6 e 26,9%, n = 6; respectivamente) A resposta de ratos intactos a estes tratamentos foi semelhante à de ratos sham Gx. Em contraste, a administração de cada antagonista de receptores opióides sozinhos ou a combinação de CTOP (30µ g/10µ l) mais o antagonista do receptor delta opióide Naltrindole (90µ g/10µ l) ou de Nor-BNI (90µ g/10µ l) mais Naltrindole (90µ g/10µ l) não afetou a nocicepção induzida pela formalina 0,5% em ratos Gx, intactos e sham Gx. Estes resultados sugerem que o efeito protetor da testosterona no desenvolvimento da dor na ATM depende da liberação de opióides endógenos e a subseqüente ativação dos receptores opióides mu e capa no sistema nervoso central. Conclui-se que a ativação individual dos subtipos de receptores é insuficiente enquanto que a co-ativação dos receptores opióides µ e k é necessária para mediar o efeito protetor da testosterona Abstract: Temporomandibular Joints (TMJ) dysfunctions are painful conditions involving the masticatory muscles and temporomandibular joint with higher prevalence, severity and duration in females. Recently it was shown that testosterone has a protective effect by reducing the risk of rat develop pain in TMJ, which explains at least in part, the lower prevalence of pain in males. However, the mechanism through which the testosterone induces protective effect in males is not known. Thus, the aim of this study was to investigate whether the protective effect of testosterone is mediated by activation of endogenous opioid system in the central nervous system and what subtypes of opioid receptors are involved in this protective effect on the development of TMJ pain in rats. For the experimental procedure Intact, gonadectomized and sham Wistar (230-300g) male rats were used and all experimental procedures were approved by the Ethics Committee in Animal Research at the UNICAMP. The TMJ injection of 0.5% formalin was used as a nociceptive stimulus. The nociceptive behavior was quantified for 45 minutes and used as a quantitative nociceptive behavior measure that was defined as the cumulative total number of seconds that the animal spent rubbing the orofacial region asymmetrically with the ipsilateral fore or hind paw plus the number of head flinches counted during the observation period. Administration of the opioid receptor antagonist naloxone 15 mg or the combination of the mu-opioid receptor antagonists CTOP (30µ g/10µ l) plus the kappa-opioid receptor antagonist nor-binaltorphimine (90µ g/10µ l), significantly increased TMJ 0.5% formalin-induced nociception in sham (31.09%, n=6 and 26.9%, n=6; respectively) but not in gonadectomized rats. The response of intact rats to these treatments was similar to that of sham rats. In contrast, the administration of each opioid receptor antagonist alone or the combination of CTOP (30µg/10µ l) plus the delta-opioid receptor antagonist Naltrindole (90µ g/10µ l) or of Nor-binaltorphimine (90µ g/10µ l) plus Naltrindole (90µ g/10µ l) did not affect TMJ 0.5% formalin-induced nociception in intact, sham and gonadectomized rats. These findings suggest that the protective effect of testosterone on TMJ pain development depends on the release of endogenous opioids and on the subsequent activation of mu and kappa opioid receptors in the central nervous system. The conclusion is that the selective activation of individual receptor subtypes is insufficient while the co-activation of µ and k opioid receptors is necessary to mediate the protective effect of testosterone Mestrado Fisiologia Oral Mestre em Odontologia

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Jones, Kymry Thereasa. "The role of beta-arrestin in regulating the muscarinic acetylcholine type II receptor." Diss., Atlanta, Ga. : Georgia Institute of Technology, 2007. http://hdl.handle.net/1853/24815.

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Thesis (Ph.D.)--Biology, Georgia Institute of Technology, 2008. Committee Chair: Dr. Nael A. McCarty; Committee Co-Chair: Dr. Darrell Jackson; Committee Member: Dr. Alfred H. Merrill; Committee Member: Dr. Barbara D. Boyan; Committee Member: Dr. Harish Radhakrishna; Committee Member: Dr. Marion B. Sewer

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Pires, Luis Antonio. "Efeitos da quimioterapia neoadjuvante sobre os receptores de lipoproteínas no tecido tumoral em pacientes com carcinoma da mama localmente avançado." Universidade de São Paulo, 2010. http://www.teses.usp.br/teses/disponiveis/5/5139/tde-02092010-173950/.

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Os tumores malignos apresentam um aumento da expressão dos receptores de lipoproteínas, devido ao aceleramento da proliferação celular com consequente aumento da necessidade de lípides para a síntese das membranas celulares. Esse aumento da expressão dos receptores de LDL no câncer pode ser utilizado para concentrar fármacos de ação antineoplásica em tecido tumoral, utilizando lipoproteínas ou nanoemulsões semelhantes a lipoproteínas como veículo. No presente estudo, foram investigados os efeitos da quimioterapia convencional na expressão dos receptores de LDL e LRP-1 em 16 pacientes com carcinoma de mama estádios II ou III, não candidatas à cirurgia conservadora e com indicação de tratamento quimioterápico neoadjuvante. A expressão dos receptores LDLR e LRP-1 foi avaliada por imunoistoquimica em tecido mamário normal e em tecido neoplásico antes e depois da quimioterapia neoadjuvante. Quatro pacientes que apresentaram resposta completa à quimioterapia foram retiradas da análise da expressão de receptores por não existir tumor no fragmento cirúrgico. Em relação ao LDLR, a expressão desse receptor no tecido neoplásico foi maior em comparação ao tecido normal em 8 das 11 pacientes. Após a quimioterapia, a expressão do receptor de LDL diminuiu em 6, aumentou em 4 e não se alterou em 2 pacientes. Do mesmo modo, a expressão do receptor LRP-1 no tecido tumoral estava aumentada em relação ao tecido normal em 4 pacientes das 12 avaliadas. Em comparação com o tecido tumoral antes da quimioterapia, a expressão do receptor LRP-1 diminuiu em 6, aumentou em 4 e permaneceu inalterada em 2 pacientes após a quimioterapia. Esses dados mostram que o efeito da quimioterapia na expressão dos receptores de lipoproteínas foi heterogêneo. A redução da expressão dos receptores não foi o padrão observado, o que indica que o uso de sistemas de carreamento de fármacos via receptores de LDL para o tratamento do câncer pode ser de grande importância. Esses resultados podem contribuir para o desenho de futuros estudos clínicos Proliferative tumor cells present a high expression of LDL receptors due to accelerated mitosis rates which takes to increased need of lipids internalization for building new membranes. Upregulation of LDL receptors may be used as a gate to deliver anticancer drugs to tumor tissues using lipoproteins or artificial nanoemulsions as vehicle. This study investigated the effects of conventional chemotherapy on the expression of LDL and LRP-1 receptors in 16 patients with breast cancer in stage II or III who were not candidates to conservative surgery and with indication of neo-adjuvant chemotherapy. Expression of LDL and LRP-1 receptor was evaluated by immunohistochemistry in normal and neoplastic breast tissue before and after chemotherapy. For absence of tumor in the surgical fragments, 4 patients who presented complete response to chemotherapy were excluded from this analysis. In relation of LDLR, the expression in neoplastic tissue was higher than in normal tissue in 8 of 11 patients. After chemotherapy, LDL receptor expression diminished in 6, increased in 4 and unchanged in 2 patients. Expression of LRP-1 in tumor tissue was higher in 4 of 12 patients when compared to normal tissue. After chemotherapy, the expression of LRP-1 diminished in 6, increased in 4 and showed no difference in 2 patients. These data show that the chemotherapy effects on the tumor expression of LDL receptors were very heterogeneous. The diminution of the receptor expression is not the post-chemotherapy pattern, allowing the use of drug carrier systems that target cancer cells via the LDL receptor pathway. These results may contribute for the design of future clinical assays

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Garcia, Ratés Sara. "Interacció dels derivats amfetamínics amb els receptors nicotínics: Aspectes moleculars i funcionals." Doctoral thesis, Universitat de Barcelona, 2011. http://hdl.handle.net/10803/32009.

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En treballs anteriors del nostre grup de recerca es va demostrar que l’antagonista específic del receptor nicotínic α7, metillicaconitina (MLA), inhibia in vitro la producció d’espècies reactives d’oxigen (EROS) i protegia de la neurotoxicitat in vivo induïda per metamfetamina (METH) i per la 3,4-metilendioxi-N-metamfetamina (MDMA). En aquesta tesi, es descriu un nou mecanisme d’acció dels derivats amfetamínics. Mitjançant assajos de fixació de radiolligands, es va comprovar que ambdós derivats amfetamínics competien amb els radiolligands específics dels receptors nicotínics α7 ([3H]Metillicaconitina), i dels heteromèrics ([3H]Epibatidina), el que indicava que en les cèl•lules PC12, el nostre model experimental, i també en una preparació de cervell total de ratolí, aquestes substàncies interaccionaven directament amb els receptors nicotínics. L’MDMA mostrava més afinitat per ambdós subtipus de receptors. Està descrit que el tractament crònic amb nicotina provoca un augment en la densitat de receptors nicotínics tan in vivo com in vitro en cèl•lules PC12. Ambdós derivats amfetamínics van provocar una regulació a l’alça dels dos subtipus de receptors ja a les 6 hores de pretractament. A la vegada, in vivo, l’MDMA i la Nicotina van provocar la regulació a l’alça que va ser potenciada per la seva associació en determinades zones cerebrals on s’expressen cada subtipus de nAChR. De l’estudi dels mecanismes implicats en aquesta regulació a l’alça, mitjançant inhibidors a diferents nivells, es va concluir que, igual com passa amb la nicotina, es produeixen a nivell postraduccional. A nivell funcional, vam determinar que aquests derivats amfetamínics eren capaços d’activar els receptors nicotínics i, d’acord amb les hipòtesis de treballs anteriors, induir una entrada de calci i de sodi que podria estar implicada en els esdeveniments que comportarien la seva neurotoxicitat. Per una banda, l’MDMA i la METH es van comportar com agonistes parcials dels nAChR α7 induïnt un increment de Ca2+ citosòlic. Per altra banda, l’MDMA es va comportar com antagonista dels nAChR heteromèrics i la METH com agonista parcial induint l’entrada de Na+ de la mateixa manera, el qual explicaria diferències a nivell de dependència, ja que els nAChR α4β2 estan implicats en la via mesolímbica o de recompensa. Paral•lelament a l’increment de fixació de radiolligands, es va determinar que la preincubació amb MDMA indueix un increment en la resposta per activació de receptors nicotínics, demostrant que l’ MDMA també indueix regulació a l’alça funcional. Alhora, es va observar que la preincubació de les cèl•lules durant 24 hores amb MDMA dona lloc a un increment perllongat dels nivells basals de Ca2+, el qual indica que l’MDMA inhibeix la desensibilització dels receptors i fa que entri calci durant un temps més llarg. Aquesta entrada persistent podria estar implicada en fenòmens de neurotoxicitat ja que va seguida de l’activació de vies dependents de calci com la calpaïna i la caspasa-3. During the last years, our emphasis has focused in the study of the neurotoxic effects of MDMA and methamphetamine (METH) on central nervous system and their pharmacological prevention. It has been demonstrated that these amphetamine derivatives produce oxygen species (ROS) in an in vitro model of synaptosomes. In previous works, we demonstrated that blockade of alpha7 nicotinic receptors with methyllycaconitine (MLA) prevented ROS production induced by MDMA and METH, consequently the alpha7 receptor would be involved in the neurotoxicity induced by these drugs. Studies at molecular level, using radioligand binding assays, showed the interaction of METH and MDMA with homomeric alpha7 nAChR and heteromeric subtypes of nicotinic receptors, such as aplha4 beta2. In addition, we investigated the effects of pretreatment with METH and MDMA on nAChR densities. We used PC 12 cells as an experimental model due to the fact other authors have similarly utilised them to evaluate the neurotoxicity of amphetamines. Moreover, they not only express nAChR, including the alpha7 subtype, but also provide an in vitro model for the up-regulation of nAChR, which occurs in vivo following chronic exposure to nicotine. In recent works, we demonstrated in vitro that Ca2+ chelation with EGTA prevented the production of reactive oxygen species (ROS) to a similar extent as nAChR blockade. This indicates that calcium influx, probably through alpha7 nAChR, is a key step in this process. Consequently, one of the objectives of this work was to use a fluorimetric method to investigate the effect of MDMA on Ca2+ and Na+ levels in cultured PC12 cells and the involvement of different nAChR subtypes and other cell pathways related to Ca2+ mobilization. In addition, we used electrophysiology in transfected Xenopus oocytes to corroborate the effects on alpha7 and alpha4 beta2 nAChR. Moreover, pretreatment with MDMA induced functional upregulation by potentiating the effects of specific nAChR agonists or whether it provoked a persistent Ca2+ increase, leading to calpain, caspase 3, NFκB, GSK-3 and Cyt C activation, which was involved in toxicity.

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Casadó, Anguera Verònica. "Allosteric interactions between catecholamine receptors and other G protein-coupled receptors: Pharmacological and functional characterization." Doctoral thesis, Universitat de Barcelona, 2018. http://hdl.handle.net/10803/586262.

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Catecholamines, including dopamine (DA) and norepinephrine (NE), are widely distributed in the body and constitute a class of conventional neurotransmitters and hormones that occupy key positions in the regulation of physiological processes and in the development of neurological, psychiatric, endocrine and cardiovascular diseases. There is a linkage between a variety of genes related to DA (e.g. D4 receptor) and NE (e.g. α2A-adrenoceptor) and the vulnerability for developing attention deficit hyperactivity disorder (ADHD), which is characterized by pervasive symptoms of inattention, impulsivity and/or hyperactivity. In addition, adenosine, acting on adenosine receptors (AR), is a modulator of other receptors such as D1-like and D2-like DA receptors (DR). DA and adenosine receptor complexes are involved in the control of the direct and indirect pathway of motor control in basal ganglia, in which adrenergic receptors are also involved. NE, DA and adenosine receptors belong to the GPCR family, also known as seven transmembrane domain receptors. GPCRs have an enormous biomedical importance. It is estimated that about 35% of approved drugs target GPCRs. Thus, is not surprising that lots of models have been developed in order to explain the pharmacological behavior of these receptors. A large number of GPCRs have been described to form homodimers, heterodimers and higher order oligomers with different pharmacological and functional properties than of its individual components. The aim of this Thesis has been to study and characterize the molecular interactions at pharmacological and functional level of heterodimers between catecholamine receptors and between catecholamine and adenosine receptors involved in several neurological pathologies related to imbalances in attention, impulsivity and motor control. For simplicity, for pharmacologically characterize GPCRs, most of the developed models consider them as monomeric entities. Thus, it is not surprising that, when working with receptor dimers but using monomeric models, some parameters obtained may be erroneous. Then, first of all, we went deeper into the study of allosteric interactions within GPCRs using the dimer receptor model, which considers GPCRs as dimers. Along our study, we have given further evidences that homodimers are the GPCR predominant species, and that allosteric interactions between orthosteric ligands of the different protomers of a GPCR heteromer, have important implications in the field of catecholamine receptor pharmacology. A paradigmatic example of complex allosteric interactions is the A2AR-A2AR-D2R-D2R-Gs-Gi-AC5 heteromer. Moreover, since bivalent ligands are the best example of oligomer selective-ligands that can interact simultaneously with GPCR dimers with high affinity and subtype selectivity, we have developed a precise strategy for developing them. Using computational tools that considered the TM interfaces, distances between orthosteric binding sites and the mode of interaction of the pharmacophore units, we have higher success in affinity results. In particular, the obtained GPCR bivalent ligand had a picomolar binding affinity for the dopamine D2 receptor (D2R) homodimer. However, to obtain oligomer-selective bivalent ligands, the selected pharmacophores must be highly specific. This is not always easy to find. As an example, we have demonstrated that catecholamine receptors constitute a “functional” family of GPCRs. Specifically, in this study we have shown that DA and synthetic DA receptor ligands are able to bind to α2Rs and activate the same signaling pathways as NE. In addition, we have demonstrated the existence of functional D4R-D2SR in vitro and, for the first time, functional D4R-α2AR heteromers in vitro and in rodent brain tissues not only with the D4.4R but also with the D4.7R variant, prevalent in ADHD. Significant different properties of these heteromers were D4R variant-dependent. Finally, given that D2R, D4R and α2AR, are involved in the pathophysiology of ADHD, we suggest that D4R-D2R and α2AR-D4R heteromers could be target for the therapeutic treatment of such neurological disorders. Les catecolamines dopamina (DA) i norepinefrina (NE) tenen una funció clau en la regulació de processos fisiològics i en el desenvolupament de diverses patologies. Existeix una correlació entre gens relacionats amb la DA (com el receptor D4) i amb la NE (com el receptor α2A) i la vulnerabilitat per desenvolupar el trastorn per dèficit d’atenció i hiperactivitat (TDAH). A més, l’adenosina, actuant sobre els receptors d’adenosina (AR), és un modulador dels receptors de DA tipus D1 i D2, que controlen el moviment als ganglis basals, on també es troben implicats els adrenoreceptors. Els receptors de NE, DA i adenosina pertanyen a la família dels GPCR, que té una gran importància biomèdica, essent diana d’un 35% dels fàrmacs aprovats. És conegut que els GPCRs formen homodimers, heterodimers i oligòmers més complexos amb noves propietats farmacològiques i funcionals. En aquesta Tesi hem caracteritzat les interaccions moleculars entre receptors de catecolamines i entre receptors de catecolamines i d’adenosina, involucrats en patologies neurològiques relacionades amb l’atenció, la impulsivitat i el control motor. Concretament, hem donat evidències que els homodimers de GPCRs són les espècies predominants a l’organisme i que les interaccions alostèriques entre lligands ortostèrics dins un heteròmer tenen importants implicacions farmacològiques. També hem generat un protocol de síntesis de lligands bivalents molt eficient. Aquests lligands permeten actuar sobre un oligòmer concret, minimitzant els efectes secundaris en comparació amb fàrmacs dirigits a monomèrs. Hem demostrat que els receptors de catecolamines constitueixen una mateixa família funcional donada la promiscuïtat entre els seus lligands. Finalment, hem descrit l’existència de complexos entre els receptors D4 i D2S i entre D4 i α2A, trobant diferències funcionals segons la variant del receptor D4 involucrada. Donat que els receptors D2R, D4R i α2AR estan involucrats en el TDAH, aquests heteròmers poden ser una nova diana terapèutica per a aquesta patologia.

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33

Lynch, Nick. "The C1q receptors." Thesis, University of Leicester, 1997. http://hdl.handle.net/2381/29753.

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Calreticulin is widely, abundantly and constituatively expressed; it has no transmembrane domain and it is found mainly in the endoplasmic reticulum. These features are characteristic of a house-keeping protein, not of a cell surface receptor. Moreover, the pI of the calreticulin is very low, while that of C1q is very high, suggesting that its retention on C1q affinity columns might be the result of non-specific interactions. This study sought to identify a membrane-targeted isoform of calreticulin that might represent a functional C1q receptor. Northern blot analyses, genomic Southern blots and extensive screening of cDNA libraries indicate that no such isoform exists. However, we have been able to localise the C1q binding sites within calreticulin and to demonstrate that binding is specific.;gC1qBP, a 33 kDa protein that binds to the globular heads of C1q has also been reported to be present in the plasma membrane. However, like calreticulin, gC1qBP is very acidic, raising the possibility that its binding to C1q is non-specific. Results presented here show that gC1qBP is an abundant, ubiquitous, constitutative and highly conserved protein: features of a house-keeping protein. Most importantly, our results, and those of two independent groups, indicate that gC1qBP is an intracellular protein, not a membrane protein, and therefore cannot be a functional C1q receptor. Recent work clearly shows that gC1qBP is located exclusively in the mitochondria.;C1q also binds a various components of the extracellular matrix (ECM), leading to the suggestion that it plays a role in tissue repair by immobilising cells at sites of injury or inflammation until the normal structure of the ECM is restored. We have shown that a newly identified microfibril-associated protein, MFAP4, belongs to the class of ECM proteins that bind to C1q.

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Zeng, Binqi. "Flexible ditopic receptors." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk2/tape16/PQDD_0007/NQ32775.pdf.

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35

Whitford, C. "Mammalian somatostatin receptors." Thesis, University of Newcastle Upon Tyne, 1985. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.356818.

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Kyte, A. B. "Chiral macrocyclic receptors." Thesis, University of Liverpool, 1985. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.354552.

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37

Chinni, Carla. "Proteolytically activated receptors." Thesis, University of Cambridge, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.627093.

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38

Kellenberger, Stephan Beat. "Recombinant GABAA receptors /." [S.l : s.n.], 1994. http://www.ub.unibe.ch/content/bibliotheken_sammlungen/sondersammlungen/dissen_bestellformular/index_ger.html.

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39

Wang, Jixin. "Bioinformatic analysis of chicken chemokines, chemokine receptors, and Toll-like receptor 21." Texas A&M University, 2006. http://hdl.handle.net/1969.1/4212.

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Chemokines triggered by Toll-like receptors (TLRs) are small chemoattractant proteins, which mainly regulate leukocyte trafficking in inflammatory reactions via interaction with G protein-coupled receptors. Forty-two chemokines and 19 cognate receptors have been found in the human genome. Prior to this study, only 11 chicken chemokines and 7 receptors had been reported. The objectives of this study were to identify systematically chicken chemokines and their cognate receptor genes in the chicken genome and to annotate these genes and ligand-receptor binding by a comparative genomics approach. Twenty-three chemokine and 14 chemokine receptor genes were identified in the chicken genome. The number of coding exons in these genes and the syntenies are highly conserved between human, mouse, and chicken although the amino acid sequence homologies are generally low between mammalian and chicken chemokines. Chicken genes were named with the systematic nomenclature used in humans and mice based on phylogeny, synteny, and sequence homology. The independent nomenclature of chicken chemokines and chemokine receptors suggests that the chicken may have ligand-receptor pairings similar to mammals. The TLR family represents evolutionarily conserved components of the patternrecognizing receptors (PRRs) of the innate immune system that recognize specific pathogen-associated molecular patterns (PAMPs) through their ectodomains (ECDs). TLR's ECDs contain 19 to 25 tandem copies of leucine-rich repeat (LRR) motifs. TLRs play important roles in the activation of pro-inflammatory cytokines, chemokines and modulation of antigen-specific adaptive immune responses. To date, nine TLRs have been reported in chicken, along with a non-functional TLR8. Two non-mammalian TLRs, TLR21 and TLR22, have been identified in pufferfish and zebrafish. The objectives of this study were to determine if there is the existence of chicken genes homologous to fish-specific TLRs, and if possible ligands of these receptors exist. After searching the chicken genome sequence and EST database, a novel chicken TLR homologous to fish TLR21 was identified. Phylogenetic analysis indicated that the identified chicken TLR is the orthologue of TLR21 in fish. Bioinformatic analysis of potential PAMP binding sites within LRR insertions showed that CpG DNA is the putative ligand of this receptor.

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40

Tong, Huaxia. "Modulation of NMDA receptor activity by dopamine receptors in the rat striatum." Thesis, University College London (University of London), 2006. http://discovery.ucl.ac.uk/1445880/.

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NMDA receptors are of particular importance in the control of synaptic strength and integration of synaptic activity. Dopamine receptor modulation of NMDA receptors in the striatum may influence the efficacy of synaptic transmission in the cortico-striatal pathway (Calabresi et al., 2000c Centonze et al., 2003) and if so, this modulation will be lost in Parkinson's disease. This change may be an important factor in the changes in the basal ganglia neural network that occur in Parkinson's Disease. In this thesis I have studied dopamine D1 and D2 receptor modulation of NMDA receptors in medium spiny neurons of 7-21 day old rat striatum. The dopamine D1 receptor agonist, SKF-82958, significantly decreased rat striatal NMDA receptor currents in patch-clamp whole-cell recordings from 7 day old rats. This inhibition was not abolished by application of a G protein inhibitor (GDP-p-S) or irreversible activator (GTP-y-S) suggesting a G protein-independent mechanism. In addition, intracellular application of protein tyrosine kinase inhibitors (lavendustin A or PP2) abolished D1 inhibition of NMDA currents. Functional NR2A receptors were absent in 7 day old rat striatum according to my experiments. Single-channel recordings showed that direct D1 receptor inhibition of NMDA receptors can not be observed in isolated membrane patches, which may indicate that D1 inhibition in whole-cell recordings is mediated by a change in NMDA receptor trafficking. Consistent with this hypothesis, intracellular application of a dynamin inhibitory peptide (QVPSRPNRAP) abolished D1 inhibition of NMDA receptor currents. I therefore conclude that a tyrosine kinase-dependent alteration of NMDA receptor trafficking underlies D1 dopamine receptor-mediated down-regulation of NMDA receptor currents in the striatum. The D2 class dopamine receptor agonist, quinpirole, significantly inhibited the NMDAR responses at 1 uM, but at a lower concentration (40 nM) there was no significant effect in 7 day old rat striatum. Replacement of GTP with GDP-P-S in the pipette solution abolished the inhibition induced by 1 uM quinpirole suggesting a G protein-dependent mechanism underlies the D2 family dopamine receptor modulation of NMDA receptors in the striatum.

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41

Szekeres, Philip Graham. "Studies on the activation of G proteins by opioid receptors and receptor-mimetic peptides." Thesis, Loughborough University, 1995. https://dspace.lboro.ac.uk/2134/12440.

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42

Beleza, Meireles Ana Maria. "Hypospadias : analysis of a complex genetic disorder /." Stockholm, 2007. http://diss.kib.ki.se/2007/978-91-7357-249-1/.

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43

Hazell, Georgina Grace Joan. "Deorphanising G protein-coupled receptors : the search for fast steroid receptors." Thesis, University of Bristol, 2011. http://hdl.handle.net/1983/12fbf473-f360-4831-8123-42698aff4950.

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G protein coupled receptors (GPCRs) are the largest family of transmembrane receptors in the genome and are activated by a multitude of ligands including neuropeptides, hormones and sensory signals. The paraventricular nucleus (PVN) and supraoptic nucleus (SON) of the hypothalamus are important mediators in homeostatic control. Many modulators of PVN/SON activity, including neurotransmitters and hormones act via GPCRs - in fact over 100 non-chemosensory GPCRs have been detected in either the PVN or SON. The introduction to this thesis begins with a comprehensive summary of GPCR expression within the PVN/SON, with a critique of the detection techniques used within the literature. Also discussed are some aspects of the regulation and known roles of GPCRs in the PVN/SON, as well the possible functional significance of orphan GPCRs. Particular interest is paid to the recently 'deorphanised' G protein-coupled oestrogen (E2) receptor, GPER, which is the first receptor to be acknowledged as a steroid binding GPCR (although there are conflicting studies regarding its affinity for E2) and is expressed in the PVN and SON. Steroids are known to have fast non-genomic effects that are thought to be mediated in-part by membrane-associated forms of the traditional steroid receptors (members of a family of transcription factors). However, the possible discovery of a fast E2 GPCR has raised speculation regarding the existence of other steroid binding GPCRs. Thus the experimental Chapters were undertaken to explore the concept of fast steroid receptors, with particular emphasis on their possible roles in neuroendocrine systems. Firstly, the distribution of the putative E2 receptor was investigated to give further insight into its possible in vivo roles. In the rodent, high levels of GPER gene and protein expression were detected in the oxytocin and vasopressin neurones in the PVN and SON, the anterior and intermediate lobe of the pituitary, adrenal medulla and renal medulla and pelvis, suggesting roles for GPER in multiple functions including hormone release. To clarify the controversy surrounding GPER as an E2 receptor, we investigated GPER function in vitro using a series of cell signalling assays. However, E2 did not stimulate GPER-mediated signalling, suggesting that either GPER remains an orphan GPCR, or the cell lines used in this study lacked a vital component for E2 activation of GPER. As the rapid effects of glucocorticoid have been reported in numerous brain regions (including the PVN and SON), endocrine, and other tissues, the second part of this thesis focussed on the search for a possible fast glucocorticoid receptor. We compared the tissue distribution gene expression profiles of approximately 125 orphan GPCRs common to human and rodent with tissues that are known to exhibit fast effects of steroids (e.g., hippocampus, PVN, SON, thymus, kidney, etc.). Of the 125 orphans,3 GPCRs (GPR108, GPR146, and TMEM87B) had distribution profiles that closely matched the regions/tissues of interest. These orphans were tested for glucocorticoid activation using a universal deorphanisation assay. However, the identity of the fast glucocorticoid receptor remains unknown, as none of the candidate orphan GPCRs responded to glucocorticoids.

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44

Ramos, Vicente David. "Phylogenetic Studies of Glutamate Receptors and their Auxiliary Subunits Update their Classifications and Uncover their Diverse Metazoan Evolutionary Histories." Doctoral thesis, Universitat Autònoma de Barcelona, 2021. http://hdl.handle.net/10803/673959.

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El glutamat és el principal neurotransmissor excitatori en el sistema nerviós dels vertebrats i invertebrats. Les proteïnes involucrades en la neurotransmissió glutamatèrgica, i especialment els receptors de glutamat i les seves subunitats auxiliars, juguen un paper clau en el funcionament del sistema nerviós. Així, entendre la seva evolució i revelar la seva diversitat és essencial per comprendre com ha evolucionat el sistema nerviós, donant forma a la funció cognitiva. L'anàlisi integral de la filogènia d'aquestes proteïnes en els metazous ha revelat que la seva evolució és molt més complexa del que es podia anticipar en base al genoma dels vertebrats. Això és particularment cert per als receptors ionotròpics de glutamat, doncs la seva classificació actual en sis classes (AMPA, Kainat, Delta, NMDA1, NMDA2 and NMDA3) seria altament incompleta. El treball presentat aquí proposa una classificació en 4 subfamílies que engloben 10 classes. Els receptors AMPA, Kainat i Delta de vertebrats pertanyerien a una d'aquestes subfamílies, anomenada AKDF, i les subunitats NMDA constituirien una altra subfamília. A més, també podrien existir dues subfamílies no descrites previament, que són referides com a Epsilon i Lambda. D'una altra banda, les famílies de proteïnes que contenen subunitats auxiliars de receptors AMPA (ARAS) han experimentat històries evolutives menys complexes. No obstant, els vertebrats haurien reclutat per actuar com ARAS a la sinapsi proteïnes d'aquestes famílies per processos de neo i/o subfuncionalització donats després d'events de duplicació gènica ocorreguda en aquest llinatge. Així aquest treball afavoreix la hipòtesi que la complexitat del sistema nerviós podria haver evolucionat no pas incrementant el conjunt de receptors de neurotransmissors en el genoma, sinó augmentant la regulació d'aquests receptors a la sinapsi. El glutamato es el principal neurotransmisor excitatorio del sistema nervioso de los vertebrados e invertebrados. Las proteínas involucradas en la neurotransmisión glutamatérgica, y especialmente los receptores de glutamato y sus subunitades auxiliares, juegan un papel clave en el funcionamiento del sistema nervioso. Así, entender su evolución y revelar su diversidad es esencial para comprender como ha evolucionado el sistema nervioso, dando forma a la función cognitiva. El análisis integral de la filogenia de estas proteínas en los metazoos ha revelado que su evolución es mucho más compleja de lo que se podia anticipar en base al genoma de los vertebrados. Esto es particularmente cierto para los receptores ionotrópicos de glutamato, pues su clasificación actual en seis clases (AMPA, Kainato, Delta, NMDA1, NMDA2 and NMDA3) estaría altamente incompleta. El trabajo aquí presentado propone una clasificación en 4 subfamilias que engloban 10 clases. Los receptores AMPA, Kainato y Delta de vertebrados pertenecerían a una de estas subfamilias, llamada AKDF, y las subunidades NMDA constituirían otra subfamilia. Además, también podrían existir dos subfamilias no descritas previamente, que son referidas como Epsilon y Lambda. Por otro lado, las familias de proteínas que contienen subunidades auxiliares de receptores AMPA (ARAS) han experimentado historias evolutivas menos complejas. No obstante, los vertebrados habrían reclutado para actuar como ARAS a la sinapsis proteínas de estas familias mediante procesos de neo y/o subfuncionalización que se dieron después de eventos de duplicación génica ocurridos en este linaje. Así este trabajo favorece la hipótesis de que la complejidad del sistema nervioso podría no haber evolucionado incrementando el conjunto de receptores de neurotransmisores en el genoma, sino augmentando la regulación de estos receptores en la sinapsis. Glutamate is the major excitatory neurotransmitter in vertebrate and invertebrate nervous systems. Proteins involved in glutamatergic neurotransmission, and chiefly glutamate receptors and their auxiliary subunits, play key roles in nervous system function. Thus, understanding their evolution and uncovering their diversity is essential to comprehend how nervous systems evolved, shaping cognitive function. Comprehensive phylogenetic analysis of these proteins across metazoans have revealed that their evolution is much more complex than what can be anticipated from vertebrate genomes. This is particularly true for ionotropic glutamate receptors, as their current classification in six classes (AMPA, Kainate, Delta, NMDA1, NMDA2 and NMDA3) would be largely incomplete. New work proposes a classification into 4 subfamilies that encompass 10 classes. Vertebrate AMPA, Kainate and Delta receptors would belong to one of these subfamilies, named AKDF, and the NMDA subunits would constitute another subfamily. Furthermore, two previously unreported subfamilies would also exist, these are referred to as Epsilon and Lambda. On the other hand, protein families containing AMPA receptor auxiliary subunits (ARAS) have experienced less complex evolutionary histories. Nevertheless, vertebrates would have recruited to function as ARAS in the synapse proteins from these families by neo and/or subfunctionalization after gene duplication events occurred in this lineage. Thus, this work favours the hypothesis that nervous system complexity could have evolved not by increasing the set of neurotransmitter receptors in the genome, but by increasing the regulation of such receptors in the synapse. Universitat Autònoma de Barcelona. Programa de Doctorat en Neurociències

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45

Sjödin, Paula. "Pharmacological studies of four neuropeptide Y-family receptor subtypes /." Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2005. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-5925.

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46

Hild-Petito, Sheri Ann. "Distribution of estrogen and progesterone receptors in the primate ovary, with emphasis on subpopulations of cells within the corpus luteum." Diss., The University of Arizona, 1988. http://hdl.handle.net/10150/184485.

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Both estradiol and progeterone are proposed autocrine or paracrine regulators of ovarian function in primate species. However, specific receptors for these steroids have not been localized to individual compartments of the primate ovary. Using immunocytochemical techniques, estradiol receptors were detected in the germinal epithelium, but not other structures, of ovaries obtained from rhesus or cynomolgus monkeys during the follicular and luteal phases of the menstrual cycle. In contrast, progesterone receptors were present in stromal and interstitial tissue, the thecal layers of healthy and atretic follicles, as well as the functional corpus luteum. These results are consistent with the concept of a receptor-mediated role for progesterone, but not estrogen, within the predominant gametogenic and endocrine structures, e.g., the follicle and corpus luteum, of the primate ovary. The recent discovery of distinct cell types in the corpus luteum of domestic ungulates has revised concepts on the control of luteal function in these species. Studies were designed to test the hypothesis that the primate corpus luteum consists of cell subpopulations that differ in physical characteristics, function and regulation. Cells enzymatically-dispersed from the monkey corpus luteum at mid-luteal phase of the menstrual cycle differed in size (diameter) and the presence of the steroidogenic enzyme, 3β-hydroxysteroid dehydrogenase (3β-HSD). Analysis of dispersed cells for forward and 90° light scatter properties by flow cytometry revealed two distinct continua (Cα and Cβ). These continua were isolated using the sorting capabilities of the flow cytometer. Cα contained single cells of ≤ 15 μm and cell clusters; the cells were typically 3β-HSD-negative nonsteroidogenic. Cβ consisted of single cells that increased in size up to 40 μm and were 3β-HSD-positive. Cβ was divided into two regions (R₁ and R₃) and the cells isolated. R₁ cells were ≤ 15 μm whereas R₃ cells were ≥ 20 μm. Basal progesterone and estrogen production by R₃ cells was greater than that produced by R₁ cells (as determined by radioimmunoassay of the incubation media). Relative stimulation of progesterone production by hCG, cAMP or PGE₂ was not different between R₁ and R₃ luteal cells. These results support the hypothesis that the primate corpus luteum consists of distinct cell subpopulations which differ in size and steroidogenic capacity. However, the cell types which secrete progesterone are typically responsive to gonadotropin and PGE₂, possibly via a cAMP-mediated pathway.

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47

Ribeiro, Carlos Alberto da Silva [UNESP]. "Investigação do envolvimento de subtipos de adrenoceptores α1 no efeito anti-imobilidade da imipramina no teste de suspensão pela cauda". Universidade Estadual Paulista (UNESP), 2015. http://hdl.handle.net/11449/123303.

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Made available in DSpace on 2015-05-14T16:53:19Z (GMT). No. of bitstreams: 0 Previous issue date: 2015-02-27Bitstream added on 2015-05-14T16:59:01Z : No. of bitstreams: 1 000828052_20150610.pdf: 305956 bytes, checksum: 7369e2c8e287bd85ed19449e6cb2b2e6 (MD5) Bitstreams deleted on 2015-06-12T11:19:08Z: 000828052_20150610.pdf,. Added 1 bitstream(s) on 2015-06-12T11:19:39Z : No. of bitstreams: 1 000828052.pdf: 458163 bytes, checksum: 8f3277eff5562c7da6c209cf3706a1c0 (MD5) A imipramina é antidepressivo tricíclico cujo principal mecanismo é a inibição da captura neuronal de noradrenalina e/ou serotonina, aumentando os níveis sinápticos dessas monoaminas. Além disso, a imipramina, bem como outros antidepressivos tricíclicos, antagonizam os adrenoceptores α1 na mesma faixa de concentração em que inibem o transportador de noradrenalina. Por outro lado, estudos recentes mostraram que a imipramina tem afinidades distintas para os três subtipos de adrenoceptores α1, (α1A, α1B e α1D), ou seja, aproximadamente 25 vezes mais seletiva para α1A em relação aos adrenoceptores α1B e 10 vezes para adrenoceptores α1D em relação aos adrenoceptores α1B. Isso sugere que seu mecanismo de ação possa estar relacionado com essa característica, uma vez que, ao aumentar os níveis sinápticos de noradrenalina, antagoniza α1A e α1D, mas deixa relativamente livre α1B. Então, o objetivo desta tese foi investigar a participação dos adrenoceptores α1A, α1B e α1D no efeito anti-imobilidade da imipramina no teste de suspensão pela cauda em camundongos. Para isso, camundongos foram submetidos ao teste de suspensão pela cauda, com a administração de diversos antagonistas seletivos e não-seletivos para subtipos α1. Os testes foram realizados utilizando a imipramina associada ao prazosin, antagonista não-seletivo para adrenoceptores α1, RS-100329, antagonista seletivo pra α1A, L-765314, seletivo par α1B e BMY-7378, seletivo para α1D. Os animais também foram avaliados com administrações únicas dos antagonistas. Esta tese mostrou que a administração concomitante de prazosin ou o L-765314 reverteram o efeito anti-imobilidade da imipramina. Por outro lado, nem o RS-100329 ou BMY-7378 modificaram o efeito anti-imobilidade da imipramina. Além disso, a administração de apenas o RS-100329 ou BMY-7378 apresentou efeito anti-imobilidade no teste de suspensão pela cauda. Isso indica que o efeito ... Imipramine is a tricyclic antidepressant inhibitor of norepinephrine and serotonin neuronal reuptake. In addition, the imipramine antagonizes α1-adrenoceptors in the same concentration range that inhibited norepinephrine transporter. However, the imipramine has different affinity to α1-adrenoceptor subtypes presenting higher affinity (10-25-fold) towards α1A- and α1D-adrenoceptors compared to α1B-adrenoceptors. This study investigates the α1-adrenoceptor subtypes involved in the anti-immobility effect of imipramine in the tail suspension test in mice. The anti-immobility effect of imipramine was significantly antagonized by the non-subtype-selective α1-adrenoceptor antagonist prazosin. Neither the selective α1A adrenoceptor antagonist RS-100329 nor the selective α1D-adrenoceptor antagonist BMY-7378 changed the anti-immobility effect of imipramine. However, the selective α1B-adrenoceptor antagonist L-765314 antagonized the anti-immobility effect of imipramine. In addition, mice treated only with RS-100329 or BMY-7378 showed reduced immobility time in comparison to mice treated with vehicle, whereas L-765314 increased the immobility time. These results suggests that the α1B-subtype is the main target for the increased levels of norepinephrine caused by imipramine, and that the selective antagonism of α1A- and α1D-adrenoceptors results in anti-immobility effects

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48

Ribeiro, Carlos Alberto da Silva. "Investigação do envolvimento de subtipos de adrenoceptores α1 no efeito anti-imobilidade da imipramina no teste de suspensão pela cauda /". Botucatu, 2015. http://hdl.handle.net/11449/123303.

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Orientador: André Sampaio Pupo Banca: Ana Lúcia Severo Rodrigues Banca: Ricardo Luiz Nunes de Souza Banca: Márcia Gallacci Banca: Leonardo Resstel Barbosa Moraes Resumo: A imipramina é antidepressivo tricíclico cujo principal mecanismo é a inibição da captura neuronal de noradrenalina e/ou serotonina, aumentando os níveis sinápticos dessas monoaminas. Além disso, a imipramina, bem como outros antidepressivos tricíclicos, antagonizam os adrenoceptores α1 na mesma faixa de concentração em que inibem o transportador de noradrenalina. Por outro lado, estudos recentes mostraram que a imipramina tem afinidades distintas para os três subtipos de adrenoceptores α1, (α1A, α1B e α1D), ou seja, aproximadamente 25 vezes mais seletiva para α1A em relação aos adrenoceptores α1B e 10 vezes para adrenoceptores α1D em relação aos adrenoceptores α1B. Isso sugere que seu mecanismo de ação possa estar relacionado com essa característica, uma vez que, ao aumentar os níveis sinápticos de noradrenalina, antagoniza α1A e α1D, mas deixa relativamente livre α1B. Então, o objetivo desta tese foi investigar a participação dos adrenoceptores α1A, α1B e α1D no efeito anti-imobilidade da imipramina no teste de suspensão pela cauda em camundongos. Para isso, camundongos foram submetidos ao teste de suspensão pela cauda, com a administração de diversos antagonistas seletivos e não-seletivos para subtipos α1. Os testes foram realizados utilizando a imipramina associada ao prazosin, antagonista não-seletivo para adrenoceptores α1, RS-100329, antagonista seletivo pra α1A, L-765314, seletivo par α1B e BMY-7378, seletivo para α1D. Os animais também foram avaliados com administrações únicas dos antagonistas. Esta tese mostrou que a administração concomitante de prazosin ou o L-765314 reverteram o efeito anti-imobilidade da imipramina. Por outro lado, nem o RS-100329 ou BMY-7378 modificaram o efeito anti-imobilidade da imipramina. Além disso, a administração de apenas o RS-100329 ou BMY-7378 apresentou efeito anti-imobilidade no teste de suspensão pela cauda. Isso indica que o efeito ... Abstract: Imipramine is a tricyclic antidepressant inhibitor of norepinephrine and serotonin neuronal reuptake. In addition, the imipramine antagonizes α1-adrenoceptors in the same concentration range that inhibited norepinephrine transporter. However, the imipramine has different affinity to α1-adrenoceptor subtypes presenting higher affinity (10-25-fold) towards α1A- and α1D-adrenoceptors compared to α1B-adrenoceptors. This study investigates the α1-adrenoceptor subtypes involved in the anti-immobility effect of imipramine in the tail suspension test in mice. The anti-immobility effect of imipramine was significantly antagonized by the non-subtype-selective α1-adrenoceptor antagonist prazosin. Neither the selective α1A adrenoceptor antagonist RS-100329 nor the selective α1D-adrenoceptor antagonist BMY-7378 changed the anti-immobility effect of imipramine. However, the selective α1B-adrenoceptor antagonist L-765314 antagonized the anti-immobility effect of imipramine. In addition, mice treated only with RS-100329 or BMY-7378 showed reduced immobility time in comparison to mice treated with vehicle, whereas L-765314 increased the immobility time. These results suggests that the α1B-subtype is the main target for the increased levels of norepinephrine caused by imipramine, and that the selective antagonism of α1A- and α1D-adrenoceptors results in anti-immobility effects Doutor

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49

Mineo, Alessandro. "Mechanisms of restricted activation of the Torso receptor: from the eggshell to the embryo." Doctoral thesis, Universitat de Barcelona, 2016. http://hdl.handle.net/10803/402625.

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The establishment of the embryonic axis in the Drosophila embryo relies on four maternal systems. Anterior and posterior axes rely on morphogens located at the poles that will generate a gradient of activity along the embryo. In contrast, terminal and dorsoventral system rely on cues that are generated by follicle cells in the egg chamber to induce the restricted activation of their receptors, Torso and Toll respectively. In the case of the terminal signaling, the torso (tor) gene encodes for a tyrosine kinase receptor uniformly localised all around the membrane of the embryo but exclusively activated at the poles upon the activity of the Torso-like (Tsl) protein. Restricted activation of the Torso receptor at the embryonic poles relies on the tsl gene. Indeed, Tsl is expressed at the poles of the egg chamber during oogenesis and, in embryogenesis, accumulates at both poles of the inner side of the vitelline membrane, the innermost eggshell layer, by means of three protein encoded by the Nasrat (f(s) N), Polehole (f(s) Ph) and Closca (clos) genes. f(s) N, f(s) Ph and clos encode for proteins that localise in the vitelline membrane and are involved in the crosslinking of the vitelline membrane converting the eggshell into a stiff and insoluble layer. Indeed, females bearing mutations in any of these genes produce collapsed eggs due to defects in their eggshell. fs(1)N12, fs(1)ph1901 and clos1 are the only point mutation alleles which do not abolish the integrity of the vitelline membrane but cause the lack of terminal structures. The main objective of this work was to shed light on the role of Tsl, Nasrat, Polehole and Closca in ensuring restricted of Tor activation at the embryonic poles. In the case of Tsl, we found that, during oogenesis, it accumulates at the vitelline membrane while, in embryogenesis it localises at both ends of the embryonic plasma membrane probably at egg activation. These results suggest a a mechanism to transfer the Tsl from the egg chamber to the early embryo. This mechanism relies on the initial anchoring of Tsl at the vitelline membrane as it is secreted by the follicle cells, followed by its later translocation to the egg plasma membrane. In the case of Nasrat, Polehole and Closca,we found that embryo laid by fs(1)N12, fs(1)ph1901 and clos1 mutant females display defects in dorsoventral patterning specification besides their terminal phenotype. Nasrat, Polehole and Closca, are required for proper anchorage and activity of Nudel, a protease acting both in embryonic dorsoventral patterning and vitelline membrane integrity, thus providing a mechanism for the role of Nasrat, Polehole and Closca in vitelline membrane cross linking and dorsoventral patterning. Therefore, the dorsoventral and terminal systems, hitherto considered independent, share a common extracellular mechanism constituted by the Nasrat, Polehole and Closca proteins. Moreover, we found that these proteins have a new Tsl-independent role in terminal signaling. In the embryonic terminal system, Tor is activated only at the poles by its ligand Trunk while, in Drosophila larvae, Tor is also expressed and activated by another ligand called Prothoracicotropic hormone (PTTH) in the Prothoracic Gland. Ectopic expression of PTTH in the embryo is able to activate Tor ectopically even in the absence of Tsl but requires Nasrat, Polehole and Closca. From these results, we propose that a Nasrat/Polehole/Closca complex acts as a multifunctional hub to anchor various proteins synthesized at oogenesis, ensuring their spatial and temporal restricted function. These findings shed light on the eggshell not just as protective layer but as a specialised extracellular matrix that regulates the spatial and temporal control of early embryonic developmental processes. El eje antero-posterior del embrión de Drosophila se especifica por acción de tres sistemas maternos: el sistema anterior, el sistema posterior y el sistema terminal. En el sistema terminal el receptor tirosina quinasa Torso (Tor) está localizado uniformemente en la membrana del embrión temprano pero se activa sólo en los polos por acción de la proteína Torso-like (Tsl). Aunque el papel de Tsl en la activación de Tor no está del todo claro, se ha descrito que Tsl es la única proteína de todo el sistema terminal localizada en los polos. De hecho, Tsl se acumula en la cara interna de la membrana vitelina (MV), anclado a las proteínas Nasrat, Polehole y Closca. El papel molecular de estas proteínas es poco conocido, pero análisis genéticos han demostrado que se necesitan para una correcta estructura de la MV y también para la activación de Tor. En esta tesis, nos hemos focalizado en la función de las proteínas Tsl, Nasrat, Polehole y Closca y su papel en la activación de Tor en los polos. Respecto a Tsl, descubrimos que esta proteína se acumula en la MV durante la oogénesis y, al principio de la embriogénesis, transloca de la MV a la membrana plasmática del embrión. En cuanto a Nasrat, Polehole y Closca descubrimos que estas proteínas se necesitan también para la correcta localización y función de Nudel, una proteína involucrada en la especificación del eje dorso ventral del embrión. Además encontramos que Nasrat, Polehole y Closca tienen una función adicional en el sistema terminal independiente de Tsl. De los resultados aquí descritos proponemos que un complejo formado por las proteínas Nasrat, Polehole y Closca podría funcionar en la MV como un centro multifuncional para anclar proteínas importantes por la especificación de los ejes del embrión.

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50

Marttila, Marko. "Cellular receptors for species B adenoviruses." Doctoral thesis, Umeå : Univ, 2007. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-1351.

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Dissertations / Theses on the topic 'Receptors'

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