Dissertations / Theses on the topic 'Kv3.3'
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Kemp, Laurens [Verfasser], Tobias [Akademischer Betreuer] Huth, and Tobias [Gutachter] Huth. "Elektrophysiologische Untersuchung von Kv3.3/Kv3.4 Kanalkomplexen und deren Interaktion mit der β-Sekretase BACE1 / Laurens Kemp ; Gutachter: Tobias Huth ; Betreuer: Tobias Huth." Erlangen : Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 2021. http://d-nb.info/1228627606/34.
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Vallejo, Gracia Albert. "Kv1.3 and Kv1.5 channels in leukocytes." Doctoral thesis, Universitat de Barcelona, 2016. http://hdl.handle.net/10803/397797.
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Voltage dependent potassium channels are a group of plasma membrane ion channels with a key role in the immune system as the predominant ion channels controlling the resting membrane potential and tuning intracellular Ca2+ signaling in lymphocytes, monocytes, macrophages, and dendritic cells. Leukocytes present a limited Kv repertoire, including Kv1.3 and Kv1.5 channel isoforms. Kv1.3 is expressed in the immune system, and the blockade of this channel is associated with selective inhibition of T cell activation and proliferation.
A functional Kv channel is an oligomeric complex composed of pore-forming and ancillary subunits. The KCNE gene family (KCNE1-5) is a novel group of modulatory Kv channel elements expressed in several tissues including leukocytes. KCNE peptides are small single spanning membrane proteins known to modulate Kv channels trafficking and biophysical properties.
The hypothesis of the present PhD thesis entitled “Kv1.3 and Kv1.5 channels in leukocytes” was that changes in the channelosome composition by modulating the heterooligomeric combinations of the Kv1.3 channelosome control physiological and neoplastic cell growth as well as leukocyte responses.
Evidence suggests that Kv channels are involved in cell differentiation and cell cycle control (because non-specific drugs, such as 4-AP and TEA, impaire proliferation), and they are also known to be remodeled during carcinogenesis. Thus, we elucidated the role of Kv1.3 and Kv1.5 channels in cell growth and their relationship with cancer, in models such as B lymphocytes and lymphomas (non-Hodgkin lymphomas), pancreatic ductal adenocarcinoma (PDAC) and glioblastomas.
In spite of its significance, the mechanisms that regulate Kv1.3 and its role in the T cell activation are not well known. To that end, we analyzed the expression of KCNEs ancillary subunits upon different states of activation and proliferation of leukocytes (macrophages, T and B lymphocytes).
In addition, recent data from our laboratory demonstrate that KCNE4, acting as a dominant negative ancillary subunit, physically interacts with Kv1.3 inhibiting K+ currents and retaining the channel intracellularly. Therefore, we studied the Kv1.3 modulation by the auxiliary subunit KCNE4 in leukocytes.
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Roig, Merino Sara Raquel. "Heteroligomeric interactions of the Kv1.3 channelosome." Doctoral thesis, Universitat de Barcelona, 2017. http://hdl.handle.net/10803/404756.
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Voltage-gated potassium channels are proteins that allow the flux of potassium ions across the plasma membrane in response to a voltage stimulus. Those proteins were initially described in nervous system as the repolarization entities posterior to a depolarization. However, several different roles have been discovered to be enhanced, mediated or influenced by those entities. Cell cycle progression, homeostasis, proliferation or activation and apoptosis program are some of those functions.
Kv1.3 is the third member of the first family of voltage-gated potassium channels in humans. This specific entity is mainly expressed in nervous and immune system. It has been associated with the repolarization of neurons, the activation and proliferation of leukocytes and apoptosis. Moreover, its dysfunctionality has been related to some autoimmune disease. The fine-tunning of the channel is highly relevant to control the final cell decision. The subunits that accompany the channel were classically named as β- subunits. Several different families have been described to modulate some channel features. Kvβ family are cytoplasmic proteins that can enhance the traffic to the plasma membrane and promote a switch towards negative voltages of the channel activation. However, few are known about alternative locations and Kv1.3 modulation. KCNE family are single spanning proteins highly promiscuous that modulate several different Kvα-subunits. Depending on the KCNE subtype, the effect on the channels can present different natures. This dissertation is focused on KCNE4 member, a peptide which generally negatively regulates Kv channels.
This thesis described the positioning of Kvβ2.1, but not Kvβ1.1, in specific regions of the plasma membrane: lipid raft microdomains. Those are considered as signalling platforms at the plasma membrane highly relevant for several cellular processes. The possible mechanism that drives Kvβ2.1 is the palmitoylation of its amino acidic sequence; even other causes are not discarded. Proliferation signals are enhancing this localization while PMA treatment generates the opposite effect. This protein, as well as its partner Kvβ1.1, can form homo and heteroligomers. Their affinity and stoichiometry was addressed. Furthermore, multiprotein complexes were detected at membrane associated environments. Traffic and electrophysiological consequences on the channel were analysed upon coexpression with those subunits. Kv1.3 was removed from lipid raft microdomains and Kvβs prevented partially its PMA-dependent internalization.
The molecular determinants involved in the Kv1.3 traffic to the plasma membrane were localised at the C-terminal domain. Previous results from the laboratory determined that KCNE4 is impairing the traffic of the channel. This thesis deciphered the molecular mechanisms involved in this effect concluding a bipartite system: (i) the masking of Kv1.3 export signal and (ii) the transference of a retention signal to the channelosome. Moreover, the specific domains of Kv1.3 and KCNE4 implicated in their interaction were mapped and pointed out to the C-terminal regions of both peptides. KCNE4 was also found to form oligomers and present several signals for its retention at the endoplasmic reticulum.
Finally, the combination of both subunits (Kvβ2.1 and KCNE4) on the channel showed a dominance of KCNE4 effects, but an electrophysiological function of Kvβ2.1 on Kv1.3 kept preserved. Thus, the present thesis brought light to the comprehension of Kv1.3 channelosome.
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Solé, i. Codina Laura. "Role of KCN E4 on the voltage gated potassium channel Kv1.3 = Paper de KCNE4 en el canal de potassi dependent de voltage Kv1.3." Doctoral thesis, Universitat de Barcelona, 2013. http://hdl.handle.net/10803/129685.
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Voltage gated potassium channels (Kv) play important roles in different biological process such as generation and propagation of the nerve pulse and the cardiac action potential, promotion of insulin secretion, cell volume control, induction of cell proliferation, apoptosis, migration and initiation of many signaling pathways. Kv channels can homo- or hetero- tetramerize. The composition of the channel modulates their surface expression and serves as a mechanism for regulating channel activity. Kv channel interaction with accessory subunits provides mechanisms for channels to respond to stimuli beyond changes in membrane potential. The present dissertation is focused in the analysis of the effect of one regulatory subunits family (KCNEs) on different Kv channels. The first channel analyzed is Kv7.1, which is one of the most well-known channels to interact with all the KCNE family members. In fact KCNE1-Kv7.1 complex is focus of a huge number of studies, due to its important role in heart. Most of the studies though are focused to their electrophysiological properties and molecular determinants involved in the interaction. We performed traffic analysis experiments of Kv7.1 in the present of KCNE1-5 and demonstrated that Kv7.1 membrane surface localization is modified by some of them. Next, analysis was expanded to another channel from the same family, less characterized: Kv7.5. We demonstrated that from the five KCNEs members, only KCNE1 and KCNE3 modulate Kv7.5 activity. Furthermore, we demonstrated that Kv7.5 association to KCNE3 modifies the targeting of the regulatory subunit. Next, we moved to a non-related Kv channel such as Kv1.3, which plays a crucial role in the immune system. We first focused into characterizing the modulation of Kv1.3. We demonstrated that KCNE4, but not KCNE2, functions as an inhibitory Kv1.3 partner. Kv1.3 trafficking, targeting and activity are altered by the presence of KCNE4. Furthermore, by the combination of a plethora of approaches such as electrophysiological experiments from chimeric proteins and GFP single bleaching counting steps methodology we deciphered the stoichiometry of the Kv1.3-KCNE4 complex. Next, by immunoprecipitation experiments, traffic analysis and electrophysiological experiments, we analyzed the molecular determinants involved in the association between Kv1.3 and KCNE4. We have map a domain of Kv1.3 and a specific motif of KCNE4 involved in the formation of Kv1.3-KCNE4 complex, but not in the modulation of the channel. We also proposed a 3D docking model of Kv1.3 and KCNE4. Finally, due to the importance of Kv1.3 in the immune system, the expression of all the KCNE family has been analyzed in several cell lines of leukocytes. We have demonstrated that all KCNEs suffer a differential regulation among proliferation of leukocytes. Furthermore, a different regulation can be observed, depend on the mode of leukocytes’ activation. Our results further suggest a new and yet unidentified physiological role for KCNE subunits in the immune system. Putative associations of these ancillary proteins with Kv channels would yield a wide variety of biophysically and pharmacologically distinct channels that fine-tune the immunological response.Els canals de potassi dependents de voltatge (Kv) juguen un paper molt important tant en cèl•lules excitables com no excitables. La possibilitat de formar hetero-oligomers i la d’associació amb subunitats reguladores són uns dels mecanismes que existeixen per tal de proveir de diferents mecanismes per a respondre de manera diferent enfront a canvis en el potencial de membrana. La composició del canalosoma modula tant la seva expressió a superfície com l’activitat d’aquests. Aquesta tesi es centra en l’estudi de l’efecte del la família de les subunitats reguladores KCNE sobre diferents Kv. Primerament s’estudià l’efecte que causaven en el tràfic del canal Kv7.1 (canal model per a l’estudi dels KCNEs) i posteriorment s’amplià l’estudi a un altre membre de la mateixa família, Kv7.5. A continuació s’estudià un canal d’elevada importància per a l’activació i proliferació leucocitària: Kv1.3, centrant-nos sobretot en l’efecte causat per un dels KCNEs: KCNE4. Aquesta subunitat no només inhibeix dràsticament el corrent del canal Kv1.3, sinó que a més a més, modifica el seu tràfic i localització. Aquests canvis són deguts a una interacció directa entre ambdues proteïnes. A continuació s’estudià en detall el complex Kv1.3-KCNE4. Mitjançant la combinació d’experiments d’electrofisiologia i monitorització de fluorescència de molècules individuals en la membrana, es va poder establir l’estequiometria d’aquest complex. Posteriorment, mitjançant l’anàlisi de diverses proteïnes quimèriques i mutants, tant del canal com de la subunitat reguladora, es van cercar els determinants moleculars implicats en l’associació entre ambdues proteïnes. S’han pogut determinar els motius claus en KCNE4 i Kv1.3 implicats en la formació del complex, però no en la modulació del canal. Finalment, degut a la importància de Kv1.3 en el sistema immunitari, s’han analitzat els nivells d’expressió dels KCNEs en diferents línies leucocitàries. S’ha observat que aquestes subunitats pateixen una regulació diferencial en funció de la manera d’activació i al llarg de la proliferació del leucòcits, suggerint un possible paper en la regulació precisa de la resposta immunològica.
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Schilling, Tom. "Morphologische, immunphänotypische und elektrophysiologische Eigenschaften deaktivierter muriner Mikroglia in vitro." Doctoral thesis, Humboldt-Universität zu Berlin, Medizinische Fakultät - Universitätsklinikum Charité, 2001. http://dx.doi.org/10.18452/14649.
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Murine Mikrogliakulturen wurden mit Astrozyten-konditioniertem Medium (ACM) in einen deaktivierten Zustand überführt. Dies wurde anhand morphologischer (Grad der Ramifizierung) und immunologischer (Expression von Adhäsionsmolekülen) Parameter verifiziert. Durch den Einsatz von Makrophagen-koloniestimulierenden Faktor (M-CSF), Granulozyten/Makrophagen-koloniestimulierenden Faktor (GM-CSF), transformierenden Wachstumsfaktor beta (TGF-beta) und den gegen sie gerichteten Antikörpern wurde gezeigt, daß alle untersuchten Zytokine in unterschiedlichem Maße an der Deaktivierung der Mikrogliazellen durch ACM beteiligt sind. Außerdem wurde nach Stimulation mit ACM an murinen Mikrogliazellen eine transiente Hochregulation eines Kaliumauswärtsstromes beobachtet Das Auftreten dieses Kalium-stromes nach Inkubation der Mikrogliazellen mit ACM konnte auf die Wirkung von TGF-beta, welches im ACM enthalten ist, zurückgeführt werden. Der durch ACM in deaktivierter Mikroglia induzierte Kaliumkanal entsprach in seinen kinetischen und pharma-kologischen Eigenschaften am ehesten dem klonierten Kanal Kv1.3. Die Kv1.3 Expression durch TGF-beta oder ACM war durch den unspezifischen Proteinkinaseinhibitor H7 unterdrückbar. Diese Ergebnisse zeigen, daß die Expression des Kv1.3 Kanals nicht, wie bisher angenommen, ein Indikator für aktivierte Mikroglia ist.Murine microglial cultures were deactivated with astrocyte-conditioned medium (ACM). The deactivation process was verified measuring morphological (ramification index) and immunological (expression level of adhesion molecules) parameters. By using macrophage-colony stimulating factor (M-CSF), granulocyte/macrophage-colony stimulating factor (GM-CSF), transforming growth factor beta (TGF-beta) and their corresponding antibodies it was shown, that to a different extent all of these cytokines influence the deactivation process of microglial cells by ACM. ACM treatment of microglial cultures also lead to a transient upregulation of a delayed potassium outward current. This upregulation was due to the impact of TGF-beta contained in ACM. The ACM induced potassium channel resembled in its kinetic and pharmacological properties the cloned Kv1.3 channel. Expression of Kv1.3 in microglial cells by TGF-beta or ACM was inhibited by the unspecific protein kinase inhibitor H7. These results show, that expression of Kv1.3 channels is not a special feature of activated microglia, which has been proposed in recent publications.
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Arnoux, Isabelle. "Rôles et caractérisation de la microglie dans le développement du néocortex somatosensoriel de la souris." Phd thesis, Université René Descartes - Paris V, 2014. http://tel.archives-ouvertes.fr/tel-01070271.
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Les cellules microgliales, qui sont les macrophages du système nerveux central, ont été principalement étudiées en conditions pathologiques. Néanmoins, l'étude de la microglie aux stades périnataux indique qu'elle influence le développement normal du système nerveux central. Des interactions directes et indirectes entre la microglie et les synapses existent mais les mécanismes par lesquels ces cellules immunitaires ciblent les synapses et modulent leur maturation fonctionnelle durant le développement postnatal sont peu connus. Au cours de mon travail de thèse, je me suis intéressée aux cellules microgliales et à leurs fonctions dans le développement postnatal du cortex somato-sensoriel de la souris. Dans une première étude, nous avons montré qu'au cours de la première semaine post-natale le recrutement des cellules microgliales aux sites synaptiques en maturation met en jeu une voie de signalisation impliquant la chimiokine neuronale fractalkine et de son récepteur microglial CX3CR1. En effet, un défaut d'expression de ce récepteur retarde le recrutement des cellules microgliales aux sites synaptiques et entraine un retard de maturation fonctionnelle des synapses thalamocorticales. Dans une seconde étude, nous avons caractérisé le phénotype des cellules microgliales lors de la maturation fonctionnelle des réseaux synaptiques corticaux. Nous avons montré que les cellules microgliales adoptent un phénotype particulier lorsqu'elles sont recrutées aux synapses en maturation. Ce phénotype diffère de celui exprimé par la microglie adulte en conditions physiologiques et pathologiques et pourrait permettre aux cellules microgliales d'accomplir des fonctions spécifiques nécessaires à la maturation synaptique. Dans une troisième étude, nous avons testé les effets de la minocycline sur le développement cortical. Cette tétracycline est connue pour bloquer l'activation microgliale chez l'adulte. De façon surprenante, nous avons observé que pendant une période critique se situant à la fin de la première semaine post-natale la minocycline induit une importante mort cellulaire qui s'accompagne d'une altération de la distribution des cellules microgliales et déclenche leur activation. L'ensemble de mes données montrent que les cellules microgliales sont très sensibles aux changements de leur environnement, que leur phénotype fonctionnel change en conditions physiologiques en fonction de cet environnement et que des interactions réciproques entre neurones et microglie influencent la maturation fonctionnelle des réseaux synaptiques corticaux lors du développement postnatal.
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Serrano, Albarrás Antonio. "Heteromeric composition of the Kv 1.3 channelosome = Composició heteromèrica del canalosoma Kv1.3." Doctoral thesis, Universitat de Barcelona, 2018. http://hdl.handle.net/10803/665245.
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Ion channels are transmembrane proteins containing aqueous pores which, once open, permit the pass of ions through the plasma membrane. This ion flux takes places following the electrochemical gradient for the specific ion.
Kv1.3 is a voltage-gated potassium channel which is member of the Shaker superfamily. Its basic structure consists in a protein with six transmembrane domains, while the functional channel is formed by 4 copies of this protein.
Kv1.3 participates in a great amount of physiological functions: nervous system, immune system, insulin signaling or cell proliferation. In the immune system, Kv1.3 is highly expressed both in lymphocytes as well as in mononuclear phagocytes. In both cell types, Kv1.3 regulates the immune activation and cell proliferation. Moreover, Kv1.3 is coexpressed with other ion channel proteins like Kv1.5 or KCNE4 in the immune cells.
Kv1.5 is able to heteromerize with Kv1.3, generating heterotetramers with variable stoichiometries. Those heterotetramers produce intermediate phenotypes depending on the ratio of the subunits that generate them. On the other side, KCNE4 may interact with Kv1.3, but not with Kv1.5. Kv1.3 is greatly inhibited by the association with either of the two proteins.
In the present thesis we focus in characterizing these interactions and the importance of stoichiometry in their effects. We demonstrate that the associations between Kv1.3 and Kv1.5; and between Kv1.3 and KCNE4 take place in immune cells. Moreover, by using a fusion protein we get to fix the stoichiometry of the Kv1.3-Kv1.5 complex to 1:1. With this stoichiometry, Kv1.5 acts as a dominant negative toward Kv1.3 in the complex. Further interactions are characterized by using several chimeric proteins. By using those chimaeras, it is revealed that the carboxyterminal domain is necessary for the correct function of the channel.
On the other hand, we demonstrate that KCNE4 is able to interact with Kv1.3 regardless of Kv1.5 presence. Furthermore, the presence of Kv1.5 in the Kv1.3-KCNE4 interaction results in this association potentiating the function of the channel, instead of inhibiting it. These results are replicated both in heterologous systems as well as in native cells. This discovery presents a new paradigm by which the association with several modulatory proteins may result in the modification of the effect of each one of them. Taking into account the sheer number of different ion channel subunits, the number of different potential phenotypes is increased by a huge margin.
KCNE1 is a regulatory subunit, as well as KCNE4. Unlike KCNE4, though, KCNE1 can interact with Kv1.5. In the present thesis we demonstrate for the first time that KCNE1 is not only able to associate with Kv1.5, but to potentiate its activity by a huge amount. This interaction also seems to affect the membrane microdomain targeting of Kv1.5
Finally, the 4 studied proteins are expressed in T lymphocytes, which are the main actors in the pathogenicity of autoimmune diseases. Therefore, we genotyped those genes in multiple sclerosis patients to identify different polymorphisms which could be linked to immune overactivity. After analyzing the different polymorphisms, we located some which could be of special relevance for the physiopathology of autoimmune diseases.Los canales iónicos son proteínas transmembrana que contienen poros acuosos que permiten el paso de iones a través de la membrana plasmática a favor de gradiente electroquímico. Kv1.3 es un canal de potasio dependiente de voltaje de la superfamilia Shaker. La estructura básica consiste en una proteína con seis dominios transmembrana y el canal funcional está formado por cuatro copias de esta proteína. Kv1.3 participa en multitud de funciones del organismo: sistema nervioso, sistema inmunitario, señalización de la insulina o proliferación celular. En el sistema inmunitario está altamente expresado tanto en linfocitos como en fagocitos mononucleares. En ambos tipos celulares regula la activación inmunitaria y la proliferación celular. Además, se ve coexpresado con otras proteínas de relevancia como Kv1.5 o KCNE4. Kv1.5 puede heteromerizar con Kv1.3, dando lugar a heterotrámeros de estequiometrias variables. Por otro lado, KCNE4 puede interaccionar con Kv1.3, pero no con Kv1.5. Kv1.3 se ve potentemente inhibido por ambas asociaciones. En la presente tesis nos centramos en caracterizar estas interacciones y el peso de la estequiometría en sus efectos. Demostramos que ambas asociaciones tienen lugar en células del sistema inmunitario. Además, mediante una proteína de fusión logramos fijar la estequiometría del complejo Kv1.3-Kv1-5 en 1:1. Así, Kv1.5 demuestra ejercer como dominante negativo respecto a Kv1.3 en el complejo. Estas interacciones intramoleculares son estudiadas mediante el uso de diversas proteínas quiméricas para dilucidar el peso de los extremos carboxiterminales en la formación del canal y su función. Por otro lado, demostramos que KCNE4 afecta el canal de estequiometría 1:1 aumentado su actividad, en lugar de reducirla. Este descubrimiento presenta un nuevo paradigma en que la asociación con varias proteínas reguladoras puede resultar en la modificación del efecto de cada una de ellas. KCNE1 es una proteína reguladora al igual que KCNE4, pero que interactúa con Kv1.5. En la presente tesis demostramos como KCNE1 no solo interacciona con Kv1.5, sino que aumenta en gran medida su actividad. Finalmente, también genotipamos estos genes en pacientes de una enfermedad autoinmune como es la esclerosis múltiple, llegando a localizar diversos polimorfismos de posible interés fisiopatológico.
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Venturini, Elisa [Verfasser], and Erich [Akademischer Betreuer] Gulbins. "Kv1.3 inhibitors in the treatment of glioma and melanoma / Elisa Venturini. Betreuer: Erich Gulbins." Duisburg, 2015. http://d-nb.info/108047885X/34.
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Martel, Julie. "Expression et caractérisation du canal potassique voltage-dépendant lymphocytaire Kv1.3 chez les cellules HEK 293." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp04/nq26390.pdf.
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Martel, Julie. "Expression et caractérisation du canal potassique voltage-dépendant lymphocytaire Kv1.3 chez les cellules HEK 293." Sherbrooke : Université de Sherbrooke, 1997.
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Bodendiek, Silke [Verfasser]. "4-Phenoxybutoxy-substituierte, anellierte Heterozyklen : Synthese und elektrophysiologische Testung am lymphozytären Kaliumkanal Kv1.3 / Silke Bodendiek." Kiel : Universitätsbibliothek Kiel, 2008. http://d-nb.info/1019670282/34.
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Bezine, Maryem. "Implication du canal potassium Kv3.1 dans la lipotoxicité du 7-cétocholestérol, 24S-hydroxycholestérol et de l’acide tétracosanoïque sur des cellules nerveuses 158N et BV-2 : Etude des relations entre Kv3.1, homéostasie potassique et métabolisme peroxysomal dans la maladie d’Alzheimer." Thesis, Bourgogne Franche-Comté, 2017. http://www.theses.fr/2017UBFCI010/document.
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Le potassium (K+) est impliqué dans la régulation de l’excitabilité cellulaire, la régulation du cycle cellulaire, la viabilité cellulaire, la neuroprotection et le maintien des fonctions microgliales et oligodendrocytaires. Le dysfonctionnement des canaux potassiques, décrit dans plusieurs maladies neurodégénératives comme la Maladie d’Alzheimer (MA), la sclérose en plaques (SEP), la maladie de Parkinson et la maladie de Huntington, pourrait être une potentiel cible thérapeutique. Les mécanismes toxiques sous-jacents de ces pathologies neurodégénératives impliquent des oxystérols, dérivés oxydés du cholestérol, et des acides gras en relation avec le métabolisme peroxysomal. Le 7-cétocholestérol (7KC), le 24S-hydroxycholestérol (24S-OHC) et l'acide tétracosanoïque (C24: 0), souvent trouvés à des taux élevés au niveau du cerveau et dans le plasma de patients atteints de maladies neurodégénératives (MA, maladie de Nieman-Pick, SEP, maladie de Parkinson, maladie de Huntington et X-ALD conduisent une rupture de l’équilibre Redox qui aboutirait à la neurodégénérescence. Dans ce contexte, il est intéressant de déterminer l’éventuelle connexion entre environnement lipidique et homéostasie potassique. L’étude in vitro a été réalisée sur des olygodendrocytes murins 158N et les cellules microgliale BV-2. Nous avons montré que la lipotoxicité du 7KC, 24S-OHC et C24:0 implique une rétention du K+ faisant intervenir les canaux potassium voltage dépendant (Kv). Ces résultats ont montré que l'inhibition des canaux Kv conduisant à une augmentation la [K+]i contribue à la cytotoxicité du 7KC, 24S-OHC et C24:0. Nous nous sommes focalisés sur le canal Kv3.1b. La retention du K+ induite par les oxystérols (7KC et 24S-OHC) serait sous le contrôle de Kv3.1b. L’étude clinique réalisée sur du plasma de MA a révélé une corrélation négative entre le taux d’acide docosahexaénoïque (DHA) et la concentration de K+. Chez les souris transgéniques J20, modèle de la MA, l’étude de la topographie d’expression de Kv3.1b et d’Abcd3, au niveau de l’hippocampe et du cortex, a montré une baisse de l’expression de ces deux marqueurs. Dans leur ensemble, les résultats obtenus ont établi des relations entre lipotoxicité, métabolisme peroxysomal et altération de l’homéostasie potassique dans la neurodégénérescence et suggèrent une possible modulation de l’expression et de l’activité de kv3.1b dans la physiopathologie des maladies neurodégénérativesPotassium (K+) is involved in the regulation of cellular excitability, cell cycle regulation, cell viability, neuroprotection and maintenance of microglial and oligodendrocytic functions. Potassium dysfunction, described in several neurodegenerative diseases such as Alzheimer's Disease (AD), multiple sclerosis (MS), Parkinson's disease and Huntington's disease, may be a potential therapeutic target. The underlying toxic mechanisms of these neurodegenerative pathologies involve oxysterols, which are oxidized cholesterol derivatives, and fatty acids including those associated with peroxisomal metabolism. 7-ketocholesterol (7KC), 24S-hydroxycholesterol (24S-OHC) and tetracosanoic acid (C24:0), often found at increased levels in the brain and plasma of patients with neurodegenerative diseases (Nieman-Pick disease, MS, Parkinson's disease, Huntington's disease and X-ALD) lead to a breakdown of the redox equilibrium leading to neurodegeneration. In this context, it is interesting to determine the possible connection between the lipid environment and potassium homeostasis The in vitro study was carried out on 158N murine oligodendrocytes and microglial BV-2 cells. We have shown that the lipotoxicity of 7KC, 24S-OHC and C24:0 implies retention of K+ involving the voltage dependent potassium channels (Kv). These results have shown that inhibition of Kv channels lead to an increase in [K +] i contributing to the cytotoxicity of 7KC, 24S-OHC and C24:0. The retention of K+ induced by oxysterols (7KC and 24S-OHC) would be under the control of Kv3.1b. A clinical study, on plasma of patients with Alzheimer’s disease, revealed a negative correlation between docosahexaenoic acid (DHA) and K+ concentration. In the J20 mice, a transgenic model of Alzheimer’s disease, the expression of Kv3.1b and Abcd3 was decreased in the hippocampus and cortex. Overall, the results obtained established relationships between lipotoxicity, peroxisomal metabolism and potassium homeostasis in neurodegeneration and suggest a possible modulation of the expression and activity of kv3.1b in the pathophysiology of neurodegenerative diseases. So, modulation of Kv3.1 could constitute a new therapeuthic approach against some neurodegenerative diseases
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Bassetto, Júnior Carlos Alberto Zanutto. "Estudo da atividade bloqueadora de N-Alquilbenzenossulfonamidas em canais iônicos, com enfase em canais para potássio." Universidade Estadual Paulista (UNESP), 2016. http://hdl.handle.net/11449/140287.
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Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
Esta tese teve como objetivo estudar as moléculas orgânicas (N-alquilbenzenossulfonamidas) como inibidoras de canais para potássio do tipo KV3.1, heterologamente expressos em células L-929. Com o presente estudo constatou-se que as moléculas, N-alquilbenzenossulfonamidas, produzem efeitos inibitórios sobre KV3.1. Através da técnica de whole cell patch clamp, observou-se que os valores de IC50 para as moléculas que bloquearam o canal foram 13,5 μM, 16,9 μM, 25,9 μM, 34,2 μM, 34,9 μM e 60 μM, respectivamente, para 4-cloro-3-nitro-N-butilbenzenossulfonamida (SMD2), 4-cloro-3-nitro-N-furfutilbenzenossulfonamida (SMD3), 4-[N-(3’aminopropil)-2-pirrolidona]-3-nitro-N-butilbenzenossulfonamida (SMD2_APP), 4-[N-(3’aminopropil)-2-pirrolidona]-3-nitro-N-furfurilbenzenossulfonamida (SMD3_APP), 4-cloro-N-butilbenzenossulfonamida (SMD2_SN) e 4-cloro-N-furfurilbenzenossulfonamida (SMD3_SN). O efeito de todas as moléculas mostrou-se reversível quanto à ligação com o canal e todas atuaram como bloqueadores de canal aberto. Em SMD2, molécula que mostrou o menor valor de IC50, observou-se um deslocamento de -8 mV em relação ao controle, nas curvas de condutância versus voltagem, nas cinéticas de ativação e na recuperação a partir da inativação em relação à voltagem. O SMD2 não alterou as constantes de tempo de desativação, embora tenha mudado as constantes de ativação e inativação, além de ter induzido o fenômeno de tail crossover. Observou-se que para potenciais mais despolarizados, ocorreu o alívio do bloqueio (Block Relief). Não foi observado o efeito da dependência do pH para o bloqueio e SMD2 não mudou a seletividade do canal. Constatou-se que pulsos despolarizantes de curta duração induzem efeitos menos intensos, ao passo que pulsos despolarizantes mais longos, produzem efeitos mais intensos de SMD2 sobre o canal. Além disso, foi observado que, quanto mais o canal é usado, ou seja, aberto, mais ele é bloqueado por SMD2. Todos esses dados sugerem que SMD2 não interage com o estado fechado e nem com o estado inativado do canal, mas sim com seu estado aberto, apresentando também um efeito dependente de uso. De um ponto de vista farmacológico, isso indica que SMD2 pode ser uma molécula importante na modulação da atividade dos canais KV3.1, presentes em células com altas frequências de disparos de potencial de ação, podendo constituir uma nova classe de moduladores farmacológicos desses canais.
This thesis had the aim of studying the organic molecules (N-alkylbenzenesulfonamides) that block KV3.1 potassium channel heterologously expressed in L-929 cells. It was found that N-alkylbenzenesulfonamides have restrained effects on KV3.1. Through the whole cell patch clamp technique, it was observed that the values of IC50, for molecules that block the channel, were 13,5 μM, 16,9 μM, 25,9 μM, 34,2 μM, 34,9 μM and 60 μM, respectively 4-Chloro-3-nitro-N-butylbenzenesulfonamide (SMD2), 4-Chloro-3-nitro-N-furfurylbenzene-sulfonamide (SMD3), 4-[N-(3′-Aminopropyl)-2-pyrrolidone]-3-nitro-N-butylbenzenesulfona-mide (SMD2_APP), 4-[N-(3′-Aminopropyl)-2-pyrrolidone]-3-nitro-N-furfurylbenzene-sulfonamide (SMD3_APP), 4-Chloro-N-butyllbenzenesulfonamide (SMD2_SN) e 4-Chloro-N-furfurylbenzenesulfonamide(SMD3_SN). The effect of all molecules was reversible regards to the linking with the channel and all act as open channel blocker. In SMD2, molecule which showed the smallest value of IC50, it was observed a displacement of -8 mV compared to control, for conductance curves versus voltage, for the kinetics of activation and for the recovery from inactivation in relation to voltage. SMD2 did not change the deactivation of time constants, although it changed the activation and inactivation constants, and more, SMD2 have induced tail crossover phenomenon. It was observed that, for more depolarized potentials, there was a block relief. It was not observed the effect of pH dependence for the block and SMD2 did not change the channel selectivity. It was observed that, short duration depolarizing pulses prompt less intense effects, whereas long duration depolarizing pulses prompt more intense effects of SMD2 on the channels. Furthermore, it was observed that the more the channel is used, in an open state, the more it is blocked by SMD2. All of these data suggest that SMD2 does not interact neither with the closed state nor the inactivated state of channel, but with its open state presenting an use-dependent manner, also showing a use-dependent effect. In a pharmacological point of view, this indicates that SMD2 may be an important molecule in the modulation of the activity in the KV3.1 channels, presents in cells with high frequency of firing of action potential and may constitute a new class of pharmacological modulators.
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Beck, Sascha Daniel. "Modulation des epithelialen Natriumkanals (ENaC) und des Shaker-Kaliumkanals Kv1.3 durch die Aldosteron-induzierte Serin-Threonin-Kinase SGK." [S.l.] : [s.n.], 2003. http://deposit.ddb.de/cgi-bin/dokserv?idn=96907915X.
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Groen, Christiane [Verfasser], and Robert [Akademischer Betreuer] Bähring. "Modulation des humanen rekombinanten Ito-Kanals Kv4.3/KChIP2 durch die zytoplasmatische Ca2+-Konzentration / Christiane Groen ; Betreuer: Robert Bähring." Hamburg : Staats- und Universitätsbibliothek Hamburg, 2017. http://d-nb.info/1141904969/34.
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Handschuh, Juliane [Verfasser]. "The interaction of Kv1.3 with Dlg-like MAGUKs and its impact on calcium signaling in activated T cells / Juliane Handschuh." Magdeburg : Universitätsbibliothek, 2017. http://d-nb.info/1128726475/34.
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Grabert, Jochen. "Regulation of interneuronal voltage-gated potassium channels Kv3.1b and Kv3.2 and the calcium-binding protein parvalbumin in the rat visual cortex." [S.l.] : [s.n.], 2005. http://deposit.ddb.de/cgi-bin/dokserv?idn=975799088.
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Albers, Florian. "Identifikation charakteristischer Bindungsstrukturen zwischen den T-lymphozytären Kaliumkanälen Kv1.1, Kv1.3 und SKCa2 und Kanalliganden anhand von Chimären des prokaryotischen Kaliumkanals KcsA." [S.l.] : [s.n.], 2005. http://deposit.ddb.de/cgi-bin/dokserv?idn=974849731.
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Caballero, Martínez Amelia [Verfasser], and Elisabeth [Akademischer Betreuer] Deindl. "The role of the potassium channels KV1.3 and KCa3.1 in arteriogenic smooth muscle cell proliferation / Amelia Caballero Martínez ; Betreuer: Elisabeth Deindl." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2019. http://d-nb.info/1201274508/34.
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Haddjeri, Alexis. "Robustesse du phénotype électrique des neurones dopaminergiques de la substance noire compacte à la délétion des canaux potassium Kv4.3 et SK3." Thesis, Aix-Marseille, 2019. http://theses.univ-amu.fr.lama.univ-amu.fr/191211_HADDJERI_482kf140lioz770fao837wbiyys_TH.pdf.
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Ce travail de thèse concerne la caractérisation des variations du phénotype électrique des neurones DA de la SNc chez les animaux KOs SK3 et Kv4.3, en conditions physiologiques et physiopathologiques. Dans une première étude, j'ai analysé un grand nombre de paramètres électrophysiologiques chez ces animaux. En association avec des blocages pharmacologiques aigus de ces canaux, la délétion chronique du canal Kv4.3 conduit à une variation phénotypique semblable au blocage aigu du canal tandis que la délétion du canal SK3 semble compensée par d'autres canaux (notamment le SK2). Dans une seconde étude, préliminaire, nous avons utilisé un modèle de lésion bilatérale partielle pour étudier les répercussions comportementales et électrophysiologiques de la délétion du canal SK3 dans le développement de la maladie de Parkinson. Nos résultats suggèrent qu’en condition "Parkinson", la suppression constitutive du canal SK3 est associée à un léger effet anxiolytique, à l’abolition de l’hypersensibilité aux agonistes dopaminergiques mais aussi à des déficits de l’apprentissage moteur. Du point de vue électrophysiologique, les neurones DA de la SNc présentent un profil de décharge régulier similaire à la condition non-traitée. Ces deux études suggèrent que l'activité électrique des neurones DA de la SNc présente une robustesse partielle et variable à la délétion des canaux potassium qui peut être révélée dans des contextes physiologiques et physiopathologiques. Ce travail devrait permettre de mieux comprendre comment les mutations génétiques de canaux ioniques pourraient altérer la vulnérabilité des neurones DA de la SNc dans le contexte de la maladie de ParkinsonDuring my PhD, I precisely characterized the variations in electrical phenotype of the SNc DA neurons in Kv4.3 and SK3 KO animals, in physiological and pathophysiological conditions. In a first study, I analyzed a large number of electrophysiological parameters in these animals Combined with acute pharmacological blockade of these ion channels, I showed that Kv4.3 chronic deletion leads to a phenotypic change similar to the one induced by acute blockade of the channel while SK3 deletion appears to be compensated by other ion channels (in particular SK2). Motor behavior testing of Kv4.3 and SK3 KO animals confirmed the robustness of SK3 animals and the absence of robustness of Kv4.3 animals. In a second preliminary study, we used a bilateral partial lesion model to assess the behavioral and electrophysiological consequences of SK3 deletion on Parkinson's disease development. Our results suggest that in "Parkinson's" conditions, the chronic deletion of SK3 channel is associated with a slight anti-anxiety effect, the suppression of dopaminergic agonist hypersensitivity but also with motor deficits. From an electrophysiological viewpoint, the SNc DA neurons display a pacemaking behavior similar to the untreated condition. These two studies suggest that SNc DA neuron activity displays a partial and variable robustness to potassium channel deletion (robust to SK3 deletion, sensitive to Kv4.3 deletion) that can be revealed in physiological and pathophysiological conditions. This work will help understanding how ion channel mutations may alter SNc DA neuron vulnerability in Parkinson's disease
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Brevet, Marie. "Diminution de l'expression du canal potassique Kv 1. 3 dans les adénocarcinomes mammaires et pancréatiques : Implication de la méthylation du gène Kv1.3." Amiens, 2008. http://www.theses.fr/2008AMIED013.
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Les canaux potassiques (K+) jouent un rôle dans les mécanismes de prolifération cellulaire et d’apoptose et sont impliqués dans la cancérogenèse. Le canal K+ G-Protein Inwardly Rectifying K+ Channel 1 (Kir3. 1 ou GIRK1) et le canal voltage-dépendant KV1. 3 ont été particulièrement étudiés dans ce travail. Par une étude immunohistochimique sur 33 cancers du sein et 31 échantillons de tissu mammaire sain, nous avons mis en évidence une augmentation d’expression du canal GIRK1 et une diminution d’expression du canal KV1. 3 dans le cancer du sein. Suite à ces résultats, nous avons émis l’hypothèse que la diminution d’expression du gène KV1. 3 dans les cancers du sein pouvait être secondaire à une hyperméthylation du promoteur du gène KV1. 3. La technique de Methyl-specific PCR a été réalisée sur 52 adénocarcinomes mammaires. Nos résultats mettent en évidence une méthylation du promoteur du gène KV 1. 3 dans 42,3% des cancers du sein étudiés. Cette méthylation était retrouvée plus fréquemment dans les tumeurs de grade III. Les résultats de l’étude immunohistochimique confirmaient une diminution d‘expression du canal KV1. 3 de façon plus marquée dans les tumeurs de grade III. Des travaux similaires ont été réalisés sur le cancer du pancréas. Nos résultats sont identiques avec une augmentation de l’expression de GIRK1 et une diminution de l’expression du canal KV1. 3 dans les cancers comparativement au tissu pancréatique sain. La méthylation du promoteur du gène KV1. 3 a été retrouvée dans 66,1% des 33 cancers du pancréas étudiés. Il semble exister une association entre la méthylation du gène, le caractère métastatique des tumeurs et la faible survie des patients. Ce travail a permis de conforter le rôle du canal K+ GIRK1 dans la prolifération cellulaire, faisant de ce canal un possible candidat aux thérapies ciblées. Enfin, l’implication de la méthylation du canal KV1. 3 dans la cancérogenèse fait entrevoir d’autres voies thérapeutiques telles que les inhibiteurs de DNA methyltransferasesPotassium (K+) channels play a crucial role in cell proliferation and apoptosis and are implicated in carcinogenesis. G-Protein Inwardly Rectifying K+ Channel 1 (Kir3. 1 or GIRK1) and the voltage-activated KV1. 3 channels are considered in this study. Using immunohistochemistry on 33 cancer and 31 normal breast samples, we showed an increase of GIRK1 and a decrease of KV1. 3 expression in breast cancer. Because methylation could repress gene transcription thereby affecting the protein expression, we hypothesized that KV1. 3 gene promoter was methylated in breast cancers. Methyl-specific PCR was realized on 52 breast cancers. Methylation of KV1. 3 gene promoter was observed in 42. 3% of breast cancers. This methylation was associated with a poor differentiation of the tumor. Immunohistochemical results performed on the same samples confirmed these results with a decrease of KV1. 3 expression especially in grade III tumors. Similar techniques were applied to pancreatic adenocarcinomas. As for breast cancer, GIRK1 expression increased and KV1. 3 expression decreased in pancreatic cancer as compare to normal pancreatic tissue. KV1. 3 promoter methylation was observed in 66. 1% of pancreatic cancers and this methylation seemed to be correlated with metastatic tumors and worse survival for the patients. This work demonstrates an aberrant expression of GIRK1 K+ channel in cancers and suggested that this channel may be used as pharmaceutical target. Finally, implication of KV1. 3 promoter methylation in breast and pancreatic carcinogenesis could permit new pharmaceutical products challenges as DNA methyltransferases inhibitors
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Lange, Wienke [Verfasser], and Thomas [Akademischer Betreuer] Friedrich. "Untersuchungen zu Struktur und Funktion des Spannungssensors und regulatorischer Domänen im Bereich des Carboxy-Terminus von Kv7.3- und Kv7.4-Kanälen / Wienke Lange. Betreuer: Thomas Friedrich." Berlin : Universitätsbibliothek der Technischen Universität Berlin, 2011. http://d-nb.info/1014946670/34.
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Reneer, Mary Catherine. "SIGNALING MECHANISMS INVOLVED IN THE GENERATION OF HUMAN PERIPHERAL iTREGS." UKnowledge, 2012. http://uknowledge.uky.edu/microbio_etds/5.
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Maintaining balance in the human immune system is critical for the body’s ability to discriminate between foreign and self-antigens. This balance is achieved, in part, by a subpopulation of T cells known as induced regulatory T cells (iTregs). Dysregulation of this population may contribute to the onset and progression of cancer, chronic inflammation and autoimmune diseases. Therefore, manipulation of iTreg development holds promising therapeutic potential; however, studying this vital population has proven difficult due to low numbers, heterogeneous cell populations, substantial phenotypic differences between mouse and human cells, and the high plasticity seen in iTregs. These current limitations have prevented a full understanding of the molecular signaling events that govern their development and function. Our lab has established a novel cell culture system that mimics in vivo human iTreg development. This system allows for the discrimination and comparison of naïve, memory and iTreg T cell populations simultaneously within a single donor. These iTregs exhibit high levels of CD25, FoxP3, CTLA4, GITR, low levels of CD127 and display strong suppressor activity. Using this innovative system, we have demonstrated a rewiring of T cell receptor (TCR) signaling in iTregs compared to conventional T cells. We found that the voltage gated K+ ion channel-Kv1.3 is not active in response to TCR engagement in iTregs, even though Ca2+ influx remains intact. Kv1.3 and the linked Src-family kinase Lck were redistributed to the highly active IL2-Receptor (IL2-R) complex. Additionally, we have shown that there is increased AKT protein expression in iTregs versus conventional T cell populations that does not correlate with the TCR-induced increase in its active (phosphorylated) form. This blockage appears to be due to an imbalance of kinase to phosphatase activity in iTregs with a specific TCR-induced inhibition of mTOR activity. We have also demonstrated that AKT accumulation in iTregs leads to its physical association with SMAD3, suggesting a novel, non-enzymatic function of AKT through transcription factor inhibition. This study sheds light on the reciprocal cross talk between the IL-2R and TCR signaling pathways and uncovers the mechanism of AKT blockade in primary human iTregs, thus opening novel avenues for therapeutic manipulation
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Valdor, Markus Verfasser], Hermann [Akademischer Betreuer] [Wagner, and Jens [Akademischer Betreuer] Kurreck. "Functional characterization of the Kv7.2/Kv7.3 ion channel in rat dorsal root ganglion neurons following RNA interference-based knockdown by viral gene transfer / Markus Valdor ; Hermann Wagner, Jens Kurreck." Aachen : Universitätsbibliothek der RWTH Aachen, 2018. http://d-nb.info/1171818645/34.
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Valdor, Markus [Verfasser], Hermann [Akademischer Betreuer] Wagner, and Jens [Akademischer Betreuer] Kurreck. "Functional characterization of the Kv7.2/Kv7.3 ion channel in rat dorsal root ganglion neurons following RNA interference-based knockdown by viral gene transfer / Markus Valdor ; Hermann Wagner, Jens Kurreck." Aachen : Universitätsbibliothek der RWTH Aachen, 2018. http://d-nb.info/1171818645/34.
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Gonzalez, Walter G. "Protein-Ligand Interactions and Allosteric Regulation of Activity in DREAM Protein." FIU Digital Commons, 2016. http://digitalcommons.fiu.edu/etd/2503.
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Downstream regulatory antagonist modulator (DREAM) is a calcium sensing protein that co-assembles with KV4 potassium channels to regulate ion currents as well as with DNA in the nucleus, where it regulates gene expression. The interaction of DREAM with A-type KV4 channels and DNA has been shown to regulate neuronal signaling, pain sensing, and memory retention. The role of DREAM in modulation of pain, onset of Alzheimer’s disease, and cardiac pacemaking has set this protein as a novel therapeutic target. Moreover, previous results have shown a Ca2+ dependent interaction between DREAM and KV4/DNA involving surface contacts at the N-terminus of DREAM. However, the mechanisms by which Ca2+ binding at the C-terminus of DREAM induces structural changes at the C- and N-terminus remain unknown. Here, we present the use of biophysics and biochemistry techniques in order to map the interactions of DREAM and numerous small synthetic ligands as well as KV channels. We further demonstrate that a highly conserved network of aromatic residues spanning the C- and N-terminus domains control protein dynamics and the pathways of signal transduction on DREAM. Using molecular dynamics simulations, site directed mutagenesis, and fluorescence spectroscopy we provide strong evidence in support of a highly dynamic mechanism of signal transduction and regulation. A set of aromatic amino acids including Trp169, Phe171, Tyr174, Phe218, Phe235, Phe219, and Phe252 are identified to form a dynamic network involved in propagation of Ca2+ induced structural changes. These amino acids form a hydrophobic network connecting the N- and C-terminus domains of DREAM and are well conserved in other neuronal calcium sensors. In addition, we show evidence in support of a mechanism in which Ca2+ signals are propagated towards the N-terminus and ultimately lead to the rearrangement of the inactive EF-hand 1. The observed structural motions provide a novel mechanism involved in control of the calcium dependent KV4 and DNA binding. Altogether, we provide the first mechanism of intramolecular and intermolecular signal transduction in a Ca2+ binding protein of the neuronal calcium sensor family.
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Leijon, Sara. "Molecular characterization of cholinergic vestibular and olivocochlear efferent neurons in the rodent brainstem." Thesis, Linköping University, Department of Physics, Chemistry and Biology, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-56844.
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The neural code from the inner ear to the brain is dynamically controlled by central nervous efferent feedback to the audio-vestibular epithelium. Although such efference provides the basis for a cognitive control of our hearing and balance, we know surprisingly little about this feedback system. This project has investigated the applicability of a transgenic mouse model, expressing a fluorescent protein under the choline-acetyltransferase (ChAT) promoter, for targeting the cholinergic audio-vestibular efferent neurons in the brainstem. It was found that the mouse model is useful for targeting the vestibular efferents, which are fluorescent, but not the auditory efferents, which are not highlighted. This model enables, for the first time, physiological studies of the vestibular efferent neurons and their synaptic inputs. We next assessed the expression of the potassium channel family Kv4, known to generate transient potassium currents upon depolarization. Such potassium currents are found in auditory efferent neurons, but it is not known whether Kv4 subunits are expressed in these neurons. Moreover, it is not known if Kv4 is present and has a function in the vestibular efferent neurons. Double labelling with anti-ChAT and anti-Kv4.2 or Kv4.3 demonstrates that the Kv4.3 subunits are abundantly expressed in audio-vestibular efferents, thus indicating that this subunit is a large contributor to the excitability and firing properties of the auditory efferent neurons, and most probably also for the vestibular efferent neurons. In addition, we also unexpectedly found a strong expression of Kv4.3 in principal cells of the superior olive, the neurons which are important for sound localization.
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Moussaud, Simon. "Etude de l'implication des cellules microgliales et de l'α-synucleine dans la maladie neurodégénérative de Parkinson." Phd thesis, Université de Bourgogne, 2011. http://tel.archives-ouvertes.fr/tel-00668186.
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Les maladies neurodégénératives liées à l'âge, telle celle de Parkinson, sont un problème majeur de santé publique. Cependant, la maladie de Parkinson reste incurable et les traitements sont très limités. En effet, les causes de la maladie restent encore mal comprises et la recherche se concentre sur ses mécanismes moléculaires. Dans cette étude, nous nous sommes intéressés à deux phénomènes anormaux se produisant dans la maladie de Parkinson : l'agrégation de l'α-synucléine et l'activation des cellules microgliales. Pour étudier la polymérisation de l'α-synucléine, nous avons établi de nouvelles méthodes permettant la production in vitro de différents types d'oligomères d'α-synucléine. Grâce à des méthodes biophysiques de pointe, nous avons caractérisé ces différents oligomères à l'échelle moléculaire. Puis nous avons étudié leurs effets toxiques sur les neurones. Ensuite, nous nous sommes intéressés à l'activation des microglies et en particulier à leurs canaux potassiques et aux changements liés au vieillissement. Nous avons identifié les canaux Kv1.3 et Kir2.1 et montré qu'ils étaient impliqués dans l'activation des microglies. En parallèle, nous avons établi une méthode originale qui permet l'isolation et la culture de microglies primaires issues de cerveaux adultes. En comparaison à celles de nouveaux-nés, les microglies adultes montrent des différences subtiles mais cruciales qui soutiennent l'hypothèse de changements liés au vieillissement. Globalement, nos résultats suggèrent qu'il est possible de développer de nouvelles approches thérapeutiques contre la maladie de Parkinson en modulant l'action des microglies ou en bloquant l'oligomérisation de l' α-synucléine.
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Marks, David Ronald. "Kv1.3 modulation by PSD-95 and insulin." 2008. http://etd.lib.fsu.edu/theses/available/etd-07032008-124412.
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Thesis (Ph. D.)--Florida State University, 2008.Advisor: Debra Ann Fadool, Florida State University, College of Arts and Sciences, Dept. of Biological Science. Title and description from dissertation home page (viewed Sept. 17, 2008). Document formatted into pages; contains xiv, 217 pages. Includes bibliographical references.
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Schmitz, Alexander. "Phenoxyalkoxypsoralene : eine neue Klasse hochpotenter Blocker des lymphozytären Kaliumkanals Kv1.3 /." 2004. http://www.gbv.de/dms/bs/toc/479946159.pdf.
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Schmidt-Lassen, Kristina. "Nicht-peptidische Blocker des lymphozytären Kaliumkanals Kv1.3 : Untersuchungen zu Struktur-Wirkungsbeziehungen /." 2005. http://www.gbv.de/du/services/toc/bs/486995119.
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Farah, Amin [Verfasser]. "Expression von Kv1.3-Kaliumkanälen in retinalen Pigmentepithelzellen / vorgelegt von Amin Farah." 2008. http://d-nb.info/98940157X/34.
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Fang, Kung-Ping, and 范光平. "A study of voltage-gated potassium channel Kv3.4 during oral carcinogenesis." Thesis, 2001. http://ndltd.ncl.edu.tw/handle/85857594845842206754.
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碩士國立陽明大學
口腔生物研究所
89
Potassium channel have been reported to be involved in the proliferation of many types of cells, including tumor cell lines. Mitogenic stimulation increases the level of expression of potassium channel in T lymphocytes and epithelial cells. In addition, drugs that block potassium channels inhibit the proliferation of mitogen-stimulated normal human T lymphocytes, malignant rat lymphoma cells, human melanoma cells and human breast cancer cells. The over expression of potassium channel and related activity have been observed in neoplasms. Oral cancer is the fifth most common malignancy of the male population in Taiwan and more than 90 % of that are oral squamous cell carcinoma(OSCC) and the incidence and mortality of OSCC are increasing year by year. Our previous studies have shown that the abnormal expression of a voltage-gated potassium channel, Kv3.4 in an OSCC cell line by differential display. Preliminary studies also indicated the differential expression of Kv3.4 in normal appealing oral tissue and OSCC both in mRNA and protein level. We constructed the expression vector carring the Kv3.4 coding sequence, transfected into the OSCC cell line OEC-M1 and determined the high expression of Kv3.4 for subsequent carcinogenic studies. Our results suggest that the increasing expression of Kv3.4 may be beneficial for the cell growth without altering the cell cycle pattern of cancer cells. In addition, over expressing of Kv3.4 increased the chemoreistance of cancer cells. Although, Kv3.4 can not transform the 3T3 cells excluded the direct contribution of Kv3.4 in cell transformation, The potential role of Kv3.4 in carcinogenesis deserved further investigation.
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Dreker, Tobias. "Untersuchung der Verapamil-Bindungsstelle des spannungsabhängigen Kaliumkanals Kv1.3 mit Hilfe von Phenylalkylaminsonden /." 2006. http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&doc_number=015032559&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA.
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Hsu, Yi-Hua, and 許益華. "Expression of A-type K+ Channel Kv4.3 in Rat Cerebellum during Development." Thesis, 2002. http://ndltd.ncl.edu.tw/handle/15443287374723611701.
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碩士國立陽明大學
神經科學研究所
90
Kv4.3, a voltage-gated potassium channel alpha subunit, can evoke A-current in Xenopus oocytes. Previous studies showed that Kv4.3 mRNA exhibited an anterior-posterior (A-P) compartmentalization in granular layer of rat cerebel- lum. Kv4.3 mRNA was highly expressed in the posterior lobules, but at low levels in the anterior lobules. Kv4.3 has been the only ion channel subunit exhibiting A-P compartmentalization in mammalian cerebellum known so far. However, details related to this A-P compartmentalization, as well as the spatial and temporal expression of Kv4.3 in the cerebellum, remained unclear. In this study, with immunohistochemistry and double immunofluorescent staining, we found that granule cell is the only cell type responsible for the A-P compartmen- talization. Kv4.3 was expressed in the somata of posterior granule cells soon after they migrated from the external germinal layer into the internal granular layer at early postnatal stage. Kv4.3 was concentrated on the dendrites after granule cell maturation. Kv4.3 was not expressed in the germinal trigone or the external germinal layer, where granule cell precursors are located. Interestingly, we found that Kv4.3 was transiently expressed in migrating Purkinje cells at em- bryonic stage, and the expression pattern was complementary to calbindin staining. In contrast, in the basket cells, stellate cells, Lugaro cells, a subpopu- lation of Golgi cells, and a subset of deep neurons, expression of Kv4.3 was started soon after they arrived at their final destinations and continued through- out adulthood. Kv4.3 was selectively expressed in posterior but not anterior granule cells, suggesting that anterior and posterior granule cells are derived from two different populations of precursors. Transient expression of Kv4.3 in migrating Purkinje cells suggests that Kv4.3 may be important for the migration of Purkinje cells. Expression of Kv4.3 in many types of cerebellar inter- neurons suggests that Kv4.3 could be crucial for modulating signals in the cerebellum.
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Chang, Yu-Cheng, and 張宇晟. "Increased expression of Kv4.3 channel complex in nociceptors reduces peripheral neuropathic pain." Thesis, 2015. http://ndltd.ncl.edu.tw/handle/80811175800238951774.
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碩士國立陽明大學
神經科學研究所
103
Kv4 channels, a subfamily of voltage-gated K+ (Kv) channels that evoke A-type potassium currents, play a crucial role in controlling neuronal excitability. Accumulative evidence suggest that native Kv4 channels function in ternary complex comprising Kv4 α-subunits and accessory β-subunits, including cytosolic Kv channel-interacting proteins (KChIPs) and transmembrane dipeptidyl peptidase-like proteins (DPPLs). Compared with Kv4 α-subunits alone, A-type potassium currents are robustly increased when they are coexpressed with β-subunits in heterologous systems. Neuropathic pain is often induced by peripheral nerve injury. Our previous studies have demonstrated that Kv4.3 is expressed in the somata of a subset of non-peptidergic nociceptors within the dorsal root ganglion (DRG), Kv4.3 protein level is greatly reduced after peripheral nerve injury, and knockdown of Kv4.3 expression in nociceptors can induce pain in naïve rats. Here, to investigate whether increasing Kv4.3 protein level can relieve neuropathic pain, we used unilateral L5/L6 spinal nerve ligation (SNL) in rats as an animal model. Kv4.3 cDNA was transfected into rat lumbar DRG neurons by a nonviural vector polyethylenimine (PEI) through intrathecal injection. Intrathecal injection of Kv4.3 cDNA slightly attenuated SNL-induced mechanical hypersensitivity (a major symptom of neuropathic pain) by increasing Kv4.3 protein expression in the ipsilateral L5/L6 DRGs. In addition, co-injection of Kv4.3 and its auxiliary subunit cDNAs greatly attenuated SNL-induced mechanical hypersensitivity. Furthermore, SNL-induced nociceptor activity is reduced more by Kv4.3/KChIP1/DPP10 cDNAs than by Kv4.3 cDNA alone. These data suggest that Kv4.3 and its auxiliary subunits KChIP1/DPP10 are potential targets for treating peripheral neuropathic pain.
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Lin, Ming-Xin, and 林明勳. "Transient expression of Kv3.4 potassium channel in migrating hippocampal neurons during development." Thesis, 2007. http://ndltd.ncl.edu.tw/handle/13585157340727202043.
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碩士國立陽明大學
神經科學研究所
95
Neuronal migration is essential for the establishment of normal brain organization during development. Hippocampus is the key brain region for learning and memory. Malformation of hippocampus will result in mental retardation and epilepsy in children. Kv3 channels, a group of voltage-gated K+ (Kv) channels, are required for repetitive firing at high frequency in mature neurons. Recent studies indicated that Kv3 channels were expressed in migrating neurons during chick hindbrain formation. To investigate the role of Kv3 channels in neuronal migration, a useful first step was to map their distributions in rat hippocampus at various developmental stages by immunohistochemistry. We found that Kv3.4 was expressed in new born neurons migrating radially from the ventricular zone to the primordial plexiform layer during the embryonic day E12.5~E15.5. In addition, Kv3.4 appeared in a stream of GABAergic interneurons, which originate from the striatum, migrate tangentially via cerebral cortex, and finally arrive at hippocampus during E15.5~E19.5. Interestingly, Kv3.4 disappeared from both radially and tangentially migrating neurons soon after they arrived at the destinations. In summary, Kv3.4 was transiently expressed in both the radially and tangentially migrating neurons during the development of hippocampus. Our data suggest that dysfunction of Kv3.4 may result in mental retardation and epilepsy in children, due to the malformation of hippocampus during pregnancy. In contrast, Kv3.3 was expressed in parvalbumin- and somatostatin-positive interneurons located in the pyramidal cell layer since the postnatal day 9. These Kv3.3(+) neurons also co-expressed Kv3.1b or Kv3.2. These results suggest that Kv3.3, as well as Kv3.1b and Kv3.2, may protect us from epilepsy resulted from neuronal over-excitation in the hippocampus since the early postnatal stage.
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Ku, Wen-Xin, and 古文昕. "Pharmacophore- and structure-based virtual screening of potential Kv1.3 inhibitors with new scaffolds." Thesis, 2011. http://ndltd.ncl.edu.tw/handle/mtn4zz.
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碩士國立臺北科技大學
生物科技研究所
99
In addition to KCa3.1, Kv1.3 has been regarded as a promising target for the selective inhibition of terminally differentiated effector memory T (TEM) cell in T cell-mediated autoimmune diseases, such as multiple sclerosis and type 1 diabetes. In this study, pharmacophore-based virtual screening was used to search for new lead compounds with new scaffolds that can serve as potential drugs without causing liver toxicity. A total of 106 Kv1.3 inhibitors, which were collected from published literatures, were used to build pharmacophore model. The best pharmacophore model (Hypo3-3), containing of two hydrogen bond acceptor, one hydrophobic, and one aromatic ring, has the highest R2 value (0.763) for the test set. The cross validation method with 95% confidence level was further used to validate Hypo3-3 and proved that this model was reliable in identifying structurally diverse compounds for Kv1.3 inhibition. This model was then employed as a filter to search for lead compounds with new scaffolds from the NCI chemical database. Top 10 hit compounds, selected based on their fit values, were found to share different conformations. On the other hand, the potent and selective Kv1.3 inhibitors can be retrieved by structure-based virtual screening. In the beginning, the Kv1.3 structure was build by homology modeling using the highest resolution structure of Kv1.2 as the template. Then, PAP-1, Psora-4 and 7-substituted khelliones inhibitors with selectivity for Kv1.3 were collected to construct a consensus scoring function with highly predicative ability by molecular docking. After docking ligand from commercially available database, this consensus scoring function was used to discover the novel selective Kv1.3 inhibitors. The resulting hit compounds from both ligand- and structure-based virtual screening can be applied in further in vitro biological evaluation and optimization.
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Amadi, Chiemezie Chianotu. "Attenuation of extracellular potassium concentration effects on cardiac Kv4.3 gating, by conventional KChIP2 isoforms." 2005. http://proquest.umi.com/pqdweb?did=974428841&sid=22&Fmt=2&clientId=39334&RQT=309&VName=PQD.
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Thesis (M.A.)--State University of New York at Buffalo, 2005.Title from PDF title page (viewed on Mar. 21, 2006) Available through UMI ProQuest Digital Dissertations. Thesis adviser: Campbell, Donald L. Includes bibliographical references.
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Ahmed, Ishtiaq. "Ensnaring the pancreatic alpha-cell, and, Syntaxin 1A modulation of the alpha-cell Kv4.3 channel." 2006. http://link.library.utoronto.ca/eir/EIRdetail.cfm?Resources__ID=442243&T=F.
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Skrobek, Lennart [Verfasser]. "Biophysikalischer Einfluss von Kv6.1-, Kv6.3- und Kv6.4-Proteinen auf den spannungsabhängigen Kaliumkanal Kv2.1 / vorgelegt vonLennart Skrobek." 2008. http://d-nb.info/98994431X/34.
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Huang, Chia-Yi, and 黃嘉怡. "Transient expression of A-type K+ channel Kv3.4 in early axonal tracts of developing rat forebrain." Thesis, 2009. http://ndltd.ncl.edu.tw/handle/22270560335509082181.
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碩士國立陽明大學
神經科學研究所
97
The formation of functional neuronal circuits depends on precise axon wiring during development. Appropriate wiring of forebrain circuits is necessary for intellectual, social and emotional dimensions of behavior. Previous studies have found that potassium channels are required for axon extension and guidance of Xenopus retinal ganglion cells in vitro. However, little is known about the spatiotemporal distribution of potassium channels in developing forebrain circuits. In this study, we focus on Kv3.4, an A-type potassium channel, which is important in controlling neuronal spike frequency. Kv3.4 appears more frequently in the axons and nerve terminals of adult brain neurons. To investigate whether Kv3.4 is expressed in growing axons in vivo, we have mapped Kv3.4 in embryonic rat forebrain by immunohistochemistry. Spatially, Kv3.4 is widely expressed in early axonal tracts, such as the lateral olfactory tract, optic nerves, corticofugal fibers, hippocamposeptal projection, and thalamocortical axons. Temporally, Kv3.4 appears in these axonal tracts only during embryonic day (E)14.5-E20.5, a time period coincides with early axon outgrowth. Furthermore, although these early axonal tracts remain visible around birth (E22 in rat), Kv3.4 has become undetectable from them, indicating that Kv3.4 disappears from axons before axons refine synaptic connections with their targets. DCC (deleted in colorectal cancer), a receptor for the axon guidance cue netrin-1, is largely confined to early axonal tracts and crucial for axon guidance. Ca2+ influx through L-type Ca2+ channel mediates axon outgrowth induced by netrin-1. Interestingly, Kv3.4 is co-localized with DCC and Cav1.2 in all early axonal tracts examined during E14.5-E20.5. Taken together, Kv3.4 is expressed in early axonal tracts widely during the phase of axon outgrowth/guidance, implicating that Kv3.4 may regulate axon outgrowth via controlling neuronal spike frequency.
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Huang, Chia-Yi, and 黃嘉怡. "K+ channel Kv3.4 is essential for axon growth by limiting the influx of Ca2+ into growth cones." Thesis, 2017. http://ndltd.ncl.edu.tw/handle/4mrg66.
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博士國立陽明大學
神經科學研究所
105
Membrane excitability in the axonal growth cones of embryonic neurons influences axon growth. Voltage-gated K+ (Kv) channels are key factors in controlling membrane excitability, but whether they regulate axon growth remains unclear. Here, we report that Kv3.4 is expressed in the axonal growth cones of embryonic spinal commissural neurons, motoneurons, dorsal root ganglion neurons, retinal ganglion cells and callosal projection neurons during axon growth. Our in vitro (cultured dorsal spinal neurons of chick embryos) and in vivo (developing chick spinal commissural axons and rat callosal axons) findings demonstrate that knockdown of Kv3.4 by a specific shRNA impedes axon initiation, elongation, pathfinding, and fasciculation. In cultured dorsal spinal neurons, blockade of Kv3.4 by blood depressing substance II (BDSII) suppresses axon growth via an increase in the amplitude and frequency of Ca2+ influx through T-type and L-type Ca2+ channels. Electrophysiological results show that Kv3.4, the major Kv channel in the axonal growth cones of embryonic dorsal spinal neurons, is activated at more hyperpolarized potentials and inactivated more slowly than it is in postnatal and adult neurons. The opening of Kv3.4 channels effectively reduces growth cone membrane excitability, thereby limiting excessive Ca2+ influx at subthreshold potentials or during Ca2+-dependent action potentials. Furthermore, excessive Ca2+ influx induced by an optogenetic approach also inhibits axon growth. Interestingly, knockdown of Wnt3a reduces Kv3.4 expression in developing spinal commissural axons. Our findings suggest that Kv3.4 reduces growth cone membrane excitability and maintains [Ca2+]i at an optimal concentration for normal axon growth.
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Vennekamp, Julia [Verfasser]. "Synthese und elektrophysiologische Testung hochwirksamer Psoralenderivate als nicht-peptidische Blocker des lymphozytären Kaliumkanals Kv1.3 / vorgelegt von Julia Vennekamp." 2002. http://d-nb.info/972280251/34.
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Yang, Jung-Hui, and 楊榮慧. "Induction of Mechanical Pain by Interdependent Downregulation between K+ Channel Kv4.3 and Accessory KChIP1 in Pain-Sensing Neurons." Thesis, 2012. http://ndltd.ncl.edu.tw/handle/90509963481417683197.
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碩士國立陽明大學
神經科學研究所
100
Kv4 channels evoke A-type K+ currents which play a critical role in regulating neuronal excitability. Native Kv4 channels function in complex comprising Kv4 α-subunits and accessory β-subunits, such as cytosolic K+ channel interacting proteins (KChIPs) and transmembrane dipeptidyl peptidase like proteins (DPPLs). Compared with Kv4 α-subunits alone, A-type K+ currents are robustly increased when they are co-expressed with accessory β-subunits in heterologous systems. The protein expression of Kv4 α- or β- subunits affect protein levels of the other. However, the related physiological significance has not been explored. Kv4.3, one of the Kv4 α-subunits, is expressed selectively in the cell bodies of a subset of pain-sensing neurons and its down-regulation induces mechanical pain. In this study, we found that KChIP1 and Kv4.3 were co-expressed in a subset of pain-sensing neurons. In a neuropathic pain model induced by lumbar spinal nerve ligation in the rat, the protein level of KChIP1 was reduced in pain-sensing neurons, same as that of Kv4.3. After knockdown either KChIP1 or Kv4.3 expression by intrathecal injection of gene-specific antisense oligonucleotide, KChIP1 and Kv4.3 protein levels were simultaneously decreased in pain-sensing neurons and mechanical hypersensitivity was induced. We also examined that knockdown effect of another Kv4 β-subunit DPP10, whose mRNA has been detected in the DRG. Our data showed that mechanical hypersensitivity was induced although Kv4.3 protein level was not affected. These data reveal that after decreasing either KChIP1 or DPP10 β-subunit in the DRG, mechanical pain develops. Kv4.3 and KChIP1 protein levels are co-dependent, whereas DPP10 and Kv4.3 protein levels are not.
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Wernekenschnieder, Anja [Verfasser]. "Untersuchungen zu den inhibitorischen Wirkungen von Curcumin- und Psoralen-Derivaten auf den lymphozytären Kaliumkanal Kv1.3 / vorgelegt von Anja Wernekenschnieder." 2003. http://d-nb.info/972286160/34.
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Beck, Sascha Daniel [Verfasser]. "Modulation des epithelialen Natriumkanals (ENaC) und des Shaker-Kaliumkanals Kv1.3 durch die Aldosteron-induzierte Serin-Threonin-Kinase SGK / vorgelegt von Sascha Daniel Beck." 2003. http://d-nb.info/96907915X/34.
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Henne, Jutta. "Untersuchung zur Veränderung der Aktionspotentialmuster während der Reifung von Forellen Retina Ganglienzellen (Oncorhynchus mykiss) unter besonderer Berücksichtigung Kv3.1 und B k verwandter Kaliumkanäle." Doctoral thesis, 2005. https://repositorium.ub.uni-osnabrueck.de/handle/urn:nbn:de:gbv:700-2005051113.
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Im Rahmen der vorliegenden Arbeit wurde die Entwicklung von Forellen Retina Ganglienzellen untersucht. Dabei wurde die Fähigkeit der Zellen Aktionspotentiale zu generieren betrachtet. Es konnte festgestellt werden, dass die Anzahl der Aktionspotentiale im Rahmen der Reifung stieg und gleichzeitig ihre Dauer sank. Bei der Ermittlung der passiven elektrischen Membraneigenschaften wurde keine signifikante Erhöhung der Zellgröße mit steigendem Entwicklungsstadium festgestellt. Jedoch zeigte sich eine altersabhängige Steigerung des Membranpotentials. Im nächsten Schritt wurden zugrunde liegenden Summenströme der RGZ charakterisiert. Dabei konnte keine Veränderung des Natriumeinstroms festgestellt werden. Beim Summenausstrom wurde eine signifikante Veränderung des Strommusters ab dem Zeitpunkt des Schlüpfens festgestellt. Durch den Einsatz von spezifischen Blockern konnten Kaliumkanäle aus der Bk und Shaw Familie erstmals zum Zeitpunkt des Schlüpfens nachgewiesen werden, die in adulten RGZ den größten Anteil des Summenausstromes tragen. Die Zuordnung der Summenausströme der frühen Entwicklungsstadien zu einem bestimmten Kanal konnte bis zum Ende dieser Arbeit nicht erreicht werden.Im Rahmen der heterologen Expression eines Forellen Kv3.1 Kanals in Sf21 Zellen konnte eine hohe Sensitivität gegenüber dem Blocker Chinin festgestellt werden. Neben der Blockierung von Kaliumkanälen Blocker, wurde eine weitere Methode untersucht. Dabei zeigte sich, das spezifische Antikörper eine vergleichbare Hemmung des Stromes erreichen wie klassische Blocker.Neben den elektrophysiologischen Methoden zum Nachweis von spezifischen Kaliumkanälen wurde in einem weiterführenden Schritt die Expression von 4 Shaker und 2 Shaw Kanälen mit Hilfe der Einzelzell RT-PCR Technik nachgewiesen. Dabei stimmten die Ergebnisse mit denen der elektrophysiologischen Experimente überein.Für weiterführende Untersuchungen wurde schließlich eine Methode zur Zellkultivierung von Forellen RGZ entwickelt.
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Grabert, Jochen [Verfasser]. "Regulation of interneuronal voltage-gated potassium channels Kv3.1b and Kv3.2 and the calcium-binding protein parvalbumin in the rat visual cortex / submitted by Jochen Grabert." 2005. http://d-nb.info/975799088/34.
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Albers, Florian [Verfasser]. "Identifikation charakteristischer Bindungsstrukturen zwischen den T-lymphozytären Kaliumkanälen Kv1.1, Kv1.3 und SKCa2 und Kanalliganden anhand von Chimären des prokaryotischen Kaliumkanals KcsA / vorgelegt von Florian Albers." 2005. http://d-nb.info/974849731/34.
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