acase@tulane.edu / The sodium-dicarboxylate co-transporter NaDC1/SLC13A2, located at the apical membrane of the proximal tubule, reabsorbs Krebs cycle intermediates from the glomerular filtrate and is thought to be responsible for the bulk of citrate transport in the nephron. Previous studies in our lab have shown that NaDC1 is not calcium-sensitive and that transport of citrate and succinate in opossum kidney (OK) proximal tubule cells is calcium-sensitive. When apical extracellular calcium is lowered apical citrate transport increases significantly in OK cells. In this study we demonstrate that stimulating the Calcium-Sensing Receptor (CaSR) by addition of spermine in normal and low extracellular calcium results in inhibition of succinate transport indicating that the CaSR plays a role in calcium-sensitive dicarboxylate transport regulation. Thapsigargin, commonly used to increase intracellular calcium, also inhibited succinate transport in normal and low extracellular calcium. This indicates that the CaSR signals through the guanine nucleotide binding protein Gq. In addition to increased intracellular calcium, Gq signaling also activates Protein Kinase C (PKC). The PKC activator, Phorbol 12-Myristate 13-Acetate (PMA), inhibited dicarboxylate transport in low extracellular calcium only indicating that PKC regulates calcium-sensitive transport specifically. Also investigated were the potential roles of the Gi and Gs pathways. Gi and Gs inhibit and activate adenylate cyclase respectively. Inhibiting Gi with Pertussis Toxin and treating cells with 8-Br-cAMP had no effect on transport indicating that neither Gi nor Gs regulate dicarboxylate transport. Inhibiting adenylate cyclase with MDL 12,330A decreased dicarboxylate transport in normal and low extracellular calcium. However, 8-Br-cAMP did not reverse these effects indicating that MDL 12,330A is inhibiting transport in some way other than Gi signaling. To determine that in OK cells if ligand biased signaling of the CaSR favors Gq at the expense of Gi and Gs, ELISA assays were used to measure intracellular cAMP concentration. We found that calcium and spermine do not change intracellular levels of cAMP. Thus, our studies on Gq, Gi and Gs signaling reveal that there is ligand biased signaling of the CaSR in favor of the Gq pathway and that dicarboxylate transport is regulated by the CaSR → Gq → PKC pathway. / 1 / Ryan Walker

No description available.

Os complexos [TR2(L)3⋅x(H2O)]y(H2O) (Eu3+, Gd3+ e Tb3+) com os ligantes dicarboxilatos alifáticos OXA, MAL, SUC, GLU, ADP, PIM, SUB, AZL, SEB, UND e DOD foram preparados pelo método de precipitação. Estes compostos de coordenação foram sintetizados em solução aquosa e com aquecimento (~ 80 ºC) e apresentaram-se na forma de pós brancos, cristalinos, não higroscópicos e insolúveis em solventes polares e apolares. A análise elementar (CHN) indicou a proporção molar M:L de 2:3 e o número de moléculas de H2O dos complexos, que foi confi rmado pelos dados de análise térmica (TG/DTG). A temperatura final de saída das moléculas de H2O dos complexos apresentou um padrão em ziguezague em função do tamanho da cadeia carbônica dos ligantes, levando ao chamado efeito odd-even. As análises de espectroscopia de absorção no infravermelho (FTIR) confirmaram a efetiva coordenação dos ligantes já desprotonados aos íons TR3+ via modo misto de coordenação ponte-quelato, exceto no caso dos complexos [TR2(OXA) 3⋅6(H2O)]4(H2O)4(H2O) que ocorre via ponte bidentada. Os difratogramas de raios-X pelo método do pó (XPD) indicam que os complexos apresentam elevada cristalinidade, pertencendo ao sistema cristalino monoclínico e que os complexos com o mesmo ligante e diferentes íons TR3+ são isomórficos. As imagens de microscopia eletrônica de varredura (MEV) mostram que os compostos apresentam diferentes morfologias tais como bastão, placas ou um misto de placas e cubos, como no caso dos complexos de Eu3+ com os ligantes OXA, SUC e DOD respectivamente. A investigação por espectroscopia de absorção dos sais sódicos dos ligantes (Na2L) e a reflectância difusa, bem como o estudo fotoluminescente (espectros de excitação e emissão) dos complexos de Eu3+, Gd3+ e Tb3+ foi realizada e discutida. O comportamento fotoluminescente dos complexos baseados nos tempos de vida (t) do nível emissor 5D0 do íon Eu3+, rendimento quântico intrínseco (QLnLn), taxas de decaimento radiativo (Arad) e não-radiativo (Anrad) foram determinadas. Ademais, foi realizado o estudo sistemático teórico e experimental para calcular os parâmetros de intensidade Ω2 e Ω4. Os espectros de fosforescência resolvidos no tempo dos complexos de Gd3+ apresentaram bandas largas oriundas dos níveis tripleto (T1) dos ligantes ~ 22950 cm-1, mais próximos do nível emissor 5D4 (Tb3+) do que do nível 5D0 (Eu3+), sugerindo que a alta intensidade luminescente exibida pelos complexos de Tb3+ comparados com os complexos análogos de Eu3+ é devida à transferência de energia intramolecular mais eficiente. Os espectros de reflectância difusa confirmam a presença de bandas 4f8→4f75d1 e LMCT nos complexos de Tb3+ e Eu3+, respectivamente. Os espectros de emissão dos íons Tb3+ e Eu3+ apresentaram bandas finas referentes a transições intraconfiguracionais 4f, sendo que as transições 5D4→7F5 (~ 545 nm) e 5D0→7F2 (~ 611 nm) foram as mais intensas, respectivamente. Os valores de rendimento quântico intrínseco QLnLn dos complexos variaram entre 13 e 28%, dentro dos quais o composto [Eu2 (SUC) 3⋅2(H2O)]H2O apresentou o maior valor. Este comportamento espectroscópico mostra que as moléculas de H2O atuam como um eficiente canal de supressão de luminescência. Os valores dos parâmetros de intensidade experimentais e teóricos (Ω2 e Ω4) apresentaram excelente concordância e mostraram o comportamento em ziguezague. Isto sugere que o íon Eu3+ atua como uma poderosa sonda espectroscópica para o efeito odd-even. Os complexos de Gd3+, Eu3+ e Tb3+ apresentaram cores de emissão azul, vermelha e verde, respectivamente, sugerindo que podem ser utilizados como dispositivos moleculares conversores de luz (DMCLs). / The [RE2(L)3⋅x(H2O)]y(H2O) complexes (RE3+: Eu3+, Gd3+ and Tb3+) with the aliphatic dicarboxylates ligands OXA, MAL, SUC, GLU, ADP, PIM, SUB, AZL, SEB, UND e DOD have been prepared by the precipitation method. These coordination compounds were synthesized in aqueous solution and heating (~ 80 °C) and presented as white crystalline powder, non-hygroscopic and insoluble in both polar and nonpolar solvents. The elemental analysis (CHN) indicated the M:L molar ratio of 2:3 and the number of water molecules of the complexes, which were confirmed by thermal analysis (TG/DTG) data. The final evaporating temperature of the H2O molecules of the complexes presented a zigzag pattern as a function of the carbon chain size of the ligands, leading to the so-called odd-even effect. The infrared absorption spectroscopy (FTIR) confirmed the effective coordination of the already deprotonated ligands to the RE3+ ions via the mixed mode of bridge-chelate coordination, except for the [RE2 (OXA)3⋅6(H2O)]4(H2O) complexes that occur via bidentate bridge mode. The X-ray powder diffraction (XPD) patterns indicate that the complexes present high crystallinity and the compounds with the same ligand and different RE3+ ions present isomorphic character. Scanning electron microscopy (SEM) images showed that the Eu3+ complexes with OXA, SUC and DOD ligands exhibited different morphologies such as rods, sheets or a mixture of sheets and cubes, respectively. The absorption spectroscopy investigation of the ligand sodium salts (Na2L) and the diffuse reflectance as well as the luminescence study (excitation and emission spectra) for the Eu3+, Gd3+ and Tb3+ complexes have been performed and discussed. The photoluminescent behavior of the complexes based on the lifetime (t) of the 5D0 emitting level of the Eu3+ ion, intrinsic quantum yield (QLnLn), radiative (Arad) and nonradiative (Anrad) were determined. In addition, the theoretical and experimental systematic study was carried out to calculate the intensity parameters Ω2 and Ω4. The time resolved phosphorescence spectra of the Gd3+ complexes showed broad emission bands assigned to the triplet (T1) states of the ligands at ~ 22950 cm-1, closer to the 5D4 emitting level (Tb3+) than to the 5D0 level (Eu3+), suggesting that the higher luminescent intensity exhibited by the Tb3+ complexes compared to the Eu3+ analog complexes are due to a more efficient L—RE3+ intramolecular energy transfer. The diffuse reflectance data confirmed the presence of 4f8→4f75d1 and LMCT absorption bands in the Tb3+ and Eu3+ complexes, respectively. The emission spectra of the Tb3+ and Eu3+ ions showed narrow bands due to the intraconfigurational 4f transitions, among them the 5D4→7F5 (~ 545 nm) and 5D0→7F2 (~ 611 nm) transitions were the most intense, respectively. The values of intrinsic quantum yield QLnLn of the complexes ranged from 13 to 28%, in which the [Eu2 (SUC)3⋅2(H2O)]H2O complex presented the highest value due to its lower number of H2O molecules. This optical behavior shows that the H2O molecules act as an efficient luminescence quenching channel. The values of experimental and theoretical intensity parameters (Ω2 and Ω4) presented excellent agreement which showed the zigzag behavior. These indicate that the Eu3+ ion acts as a powerful spectroscopic probe for the odd-even effect. The Gd3+, Eu3+ and Tb3+ complexes showed blue, red and green emission colors, respectively, suggesting that can be applied as light-converting molecular devices.

Os complexos [TR2(L)3⋅x(H2O)]y(H2O) (Eu3+, Gd3+ e Tb3+) com os ligantes dicarboxilatos alifáticos OXA, MAL, SUC, GLU, ADP, PIM, SUB, AZL, SEB, UND e DOD foram preparados pelo método de precipitação. Estes compostos de coordenação foram sintetizados em solução aquosa e com aquecimento (~ 80 ºC) e apresentaram-se na forma de pós brancos, cristalinos, não higroscópicos e insolúveis em solventes polares e apolares. A análise elementar (CHN) indicou a proporção molar M:L de 2:3 e o número de moléculas de H2O dos complexos, que foi confi rmado pelos dados de análise térmica (TG/DTG). A temperatura final de saída das moléculas de H2O dos complexos apresentou um padrão em ziguezague em função do tamanho da cadeia carbônica dos ligantes, levando ao chamado efeito odd-even. As análises de espectroscopia de absorção no infravermelho (FTIR) confirmaram a efetiva coordenação dos ligantes já desprotonados aos íons TR3+ via modo misto de coordenação ponte-quelato, exceto no caso dos complexos [TR2(OXA) 3⋅6(H2O)]4(H2O)4(H2O) que ocorre via ponte bidentada. Os difratogramas de raios-X pelo método do pó (XPD) indicam que os complexos apresentam elevada cristalinidade, pertencendo ao sistema cristalino monoclínico e que os complexos com o mesmo ligante e diferentes íons TR3+ são isomórficos. As imagens de microscopia eletrônica de varredura (MEV) mostram que os compostos apresentam diferentes morfologias tais como bastão, placas ou um misto de placas e cubos, como no caso dos complexos de Eu3+ com os ligantes OXA, SUC e DOD respectivamente. A investigação por espectroscopia de absorção dos sais sódicos dos ligantes (Na2L) e a reflectância difusa, bem como o estudo fotoluminescente (espectros de excitação e emissão) dos complexos de Eu3+, Gd3+ e Tb3+ foi realizada e discutida. O comportamento fotoluminescente dos complexos baseados nos tempos de vida (t) do nível emissor 5D0 do íon Eu3+, rendimento quântico intrínseco (QLnLn), taxas de decaimento radiativo (Arad) e não-radiativo (Anrad) foram determinadas. Ademais, foi realizado o estudo sistemático teórico e experimental para calcular os parâmetros de intensidade Ω2 e Ω4. Os espectros de fosforescência resolvidos no tempo dos complexos de Gd3+ apresentaram bandas largas oriundas dos níveis tripleto (T1) dos ligantes ~ 22950 cm-1, mais próximos do nível emissor 5D4 (Tb3+) do que do nível 5D0 (Eu3+), sugerindo que a alta intensidade luminescente exibida pelos complexos de Tb3+ comparados com os complexos análogos de Eu3+ é devida à transferência de energia intramolecular mais eficiente. Os espectros de reflectância difusa confirmam a presença de bandas 4f8→4f75d1 e LMCT nos complexos de Tb3+ e Eu3+, respectivamente. Os espectros de emissão dos íons Tb3+ e Eu3+ apresentaram bandas finas referentes a transições intraconfiguracionais 4f, sendo que as transições 5D4→7F5 (~ 545 nm) e 5D0→7F2 (~ 611 nm) foram as mais intensas, respectivamente. Os valores de rendimento quântico intrínseco QLnLn dos complexos variaram entre 13 e 28%, dentro dos quais o composto [Eu2 (SUC) 3⋅2(H2O)]H2O apresentou o maior valor. Este comportamento espectroscópico mostra que as moléculas de H2O atuam como um eficiente canal de supressão de luminescência. Os valores dos parâmetros de intensidade experimentais e teóricos (Ω2 e Ω4) apresentaram excelente concordância e mostraram o comportamento em ziguezague. Isto sugere que o íon Eu3+ atua como uma poderosa sonda espectroscópica para o efeito odd-even. Os complexos de Gd3+, Eu3+ e Tb3+ apresentaram cores de emissão azul, vermelha e verde, respectivamente, sugerindo que podem ser utilizados como dispositivos moleculares conversores de luz (DMCLs). / The [RE2(L)3⋅x(H2O)]y(H2O) complexes (RE3+: Eu3+, Gd3+ and Tb3+) with the aliphatic dicarboxylates ligands OXA, MAL, SUC, GLU, ADP, PIM, SUB, AZL, SEB, UND e DOD have been prepared by the precipitation method. These coordination compounds were synthesized in aqueous solution and heating (~ 80 °C) and presented as white crystalline powder, non-hygroscopic and insoluble in both polar and nonpolar solvents. The elemental analysis (CHN) indicated the M:L molar ratio of 2:3 and the number of water molecules of the complexes, which were confirmed by thermal analysis (TG/DTG) data. The final evaporating temperature of the H2O molecules of the complexes presented a zigzag pattern as a function of the carbon chain size of the ligands, leading to the so-called odd-even effect. The infrared absorption spectroscopy (FTIR) confirmed the effective coordination of the already deprotonated ligands to the RE3+ ions via the mixed mode of bridge-chelate coordination, except for the [RE2 (OXA)3⋅6(H2O)]4(H2O) complexes that occur via bidentate bridge mode. The X-ray powder diffraction (XPD) patterns indicate that the complexes present high crystallinity and the compounds with the same ligand and different RE3+ ions present isomorphic character. Scanning electron microscopy (SEM) images showed that the Eu3+ complexes with OXA, SUC and DOD ligands exhibited different morphologies such as rods, sheets or a mixture of sheets and cubes, respectively. The absorption spectroscopy investigation of the ligand sodium salts (Na2L) and the diffuse reflectance as well as the luminescence study (excitation and emission spectra) for the Eu3+, Gd3+ and Tb3+ complexes have been performed and discussed. The photoluminescent behavior of the complexes based on the lifetime (t) of the 5D0 emitting level of the Eu3+ ion, intrinsic quantum yield (QLnLn), radiative (Arad) and nonradiative (Anrad) were determined. In addition, the theoretical and experimental systematic study was carried out to calculate the intensity parameters Ω2 and Ω4. The time resolved phosphorescence spectra of the Gd3+ complexes showed broad emission bands assigned to the triplet (T1) states of the ligands at ~ 22950 cm-1, closer to the 5D4 emitting level (Tb3+) than to the 5D0 level (Eu3+), suggesting that the higher luminescent intensity exhibited by the Tb3+ complexes compared to the Eu3+ analog complexes are due to a more efficient L—RE3+ intramolecular energy transfer. The diffuse reflectance data confirmed the presence of 4f8→4f75d1 and LMCT absorption bands in the Tb3+ and Eu3+ complexes, respectively. The emission spectra of the Tb3+ and Eu3+ ions showed narrow bands due to the intraconfigurational 4f transitions, among them the 5D4→7F5 (~ 545 nm) and 5D0→7F2 (~ 611 nm) transitions were the most intense, respectively. The values of intrinsic quantum yield QLnLn of the complexes ranged from 13 to 28%, in which the [Eu2 (SUC)3⋅2(H2O)]H2O complex presented the highest value due to its lower number of H2O molecules. This optical behavior shows that the H2O molecules act as an efficient luminescence quenching channel. The values of experimental and theoretical intensity parameters (Ω2 and Ω4) presented excellent agreement which showed the zigzag behavior. These indicate that the Eu3+ ion acts as a powerful spectroscopic probe for the odd-even effect. The Gd3+, Eu3+ and Tb3+ complexes showed blue, red and green emission colors, respectively, suggesting that can be applied as light-converting molecular devices.

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

La base phosphazène ButP4 associée au thiophénol ou au bis (2-mercaptoéthyl) éther a été utilisée avec succès pour amorcer quantitativement la polymérisation anionique par ouverture de cycle des monomères cyclopropane-1,1-dicarboxylates de dialkyle. Pour des températures comprises entre 30 et 60°C dans le THF ou entre 30 et 100°C dans le toluéne, le mécanisme observé est celui d'une polymérisation anionique vivante qui conduit à des polymères présentant des indices de polymolécularité faibles et dont les Mn expérimentaux (mesurés par SEC et RMN 1H) sont en accord avec les valeurs théoriques. D'autres systèmes déamorçage comme le carbazole ou des composés possédant un proton acide associés à ButP4 conduisent également à des polymères bien définis. Une étude cinétique montre que l'ordre interne en monomère est égal à 1 sur l'ensemble de la gamme de conversion. Le système déamorçage thiophénol / ButP4 dans le THF présente une réactivité bien supérieure à celle du thiophénolate de sodium dans le DMSO qui est le système classique d'amorçage pour ce type de polymérisation. Différents agents de terminaison, comme l'acide chlorhydrique, le bromure d'allyle ou le bromure de propargyle, ont été utilisés pour terminer les réactions et ont conduit à l'obtention de polyméres hétérotéléchéliques. D'autres dérivés de cyclopropanes présentant des substituants variés ont également été examinés. Ces résultats ouvrent de très intéressantes perspectives dans la préparation d'architectures complexes comme des copolyméres à blocs, greffés ou en étoile. Les premières expériences de copolymérisation ont d'ailleurs été couronnées de succès. Afin d'obtenir de nouveaux canaux ioniques artificiels, différents monomères cyclopropane-1,1- dicarboxylates porteurs d'éthers-couronne ont été synthétisés. La polymérisation anionique par ouverture de cycle de ceux-ci a été étudiée en utilisant soit le thiophénolate de sodium soit le système thiophénol / ButP4 comme amorceur. Ces travaux ont également permis l'obtention d'un nouveau type de poly(éther-ester) qui s'est révélé intéressant comme perméabilisant membranaire. Les interactions des oligo(éther-ester)s avec des membranes modèles planes, des vésicules unilamellaires et des cellules ont été étudiées en collaboration avec des physiciens et des biologistes. Des résultats prometteurs en termes de transport d'ions ont été obtenus et sont présentés dans ce mémoire / The tetrameric phosphazene base ButP4 in association with thiophenol or bis(2-mercaptoethyl) ether has been successfully used in order to initiate the anionic ring-opening polymerization of di-n-alkyl cyclopropane-1,1-dicarboxylates. Well-defined monofunctional or difunctional polymers with a very narrow molecular weight distribution were obtained through a living process at temperatures between 30 and 60°C in THF or between 30 and 100°C in toluene. An excellent agreement is observed between theoretical and experimental Mn values (measured by SEC and by NMR). Other initiating systems such as carbazole or compounds with an acidic proton in association with ButP4 lead also to welldefined polymers. A kinetic study shows a first order with respect to the monomer concentration over the entire conversion range. The initiating system thiophenol / ButP4 in THF shows a much higher reactivity compared to the alkali metal thiophenolate which is the classical one. The living ends were reacted with different terminating agents such as hydrochloric acid, allyl and propargyl bromide thus leading to telechelic polymers. Other cyclopropane derivatives with various substituents have been also examined. These results open very exciting perspectives for the preparation of new architectures such as block and graft copolymers, star polymers. The first copolymer attempts were very successful. With the aim of designing new ion channel biomimics, cyclopropane-1,1-dicarboxylate monomers with crown-ethers substituents were synthesized. The anionic ring-opening polymerization of these monomers has been investigated using either sodium thiophenolate or thiophenol activated by ButP4. Moreover a new alternating poly(ether-ester) was obtained which is an interesting membrane permeabilizer. Its interaction with unilamellar vesicles, planar phospholipidic membranes and cells was studied in collaboration with biophysicists and biologists. Very promising results have been obtained

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