18 results on '"Dooley, Ruth"'
Search Results
2. Isomerisation of palladium π-allyl complexes
- Author
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Dooley, Ruth Elizabeth, Lloyd-Jones, Guy, and Lusby, Paul
- Subjects
541 ,asymmetric allylic alkylation ,enantioselective synthesis ,palladium p-allyl ,stereochemistry - Abstract
The palladium-catalysed asymmetric allylic alkylation is a mild and versatile bond forming reaction between a nucleophile and allylic electrophile. The wide scope of nucleophiles used, and the high regio- and stereoselectivity obtainable renders this transformation an important technique in enantioselective synthesis. The mechanism is known to go via a key palladium π-allyl intermediate, followed by nucleophilic addition occurring at the terminal allylic carbon. Both the formation of the palladium π-allyl, and the nucleophilic addition to generate the alkylated product and palladium(0) proceed with high levels of inversion of stereochemistry, and both provide an opportunity for the induction of stereochemistry. However in the case of ligand controlled nucleophilic addition memory effects have been observed. The epimerisation of the palladium π-allyl before nucleophilic attack is key to achieving high levels of selectivity when racemic starting materials and chiral ligands are employed. Previous work in the Lloyd-Jones group has determined that prolonging the lifetime of the palladium π-allyl species, either by the use of weakly coordinating counter ions or slow addition of the nucleophile reduces this memory effect, however increasing the rate of epimerisation would have a result in a similar effect. One of the mechanisms resulting in the epimerisation of the palladium π-allyl species is mediated by palladium(0), however the details of the mechanism are not well understood. We describe the synthesis of a diastereotopic palladium cyclohexenyl ester and labelled the complex with 108palladium and d3 at the cyclohexenyl ester. Using simultaneous 31P NMR and mass spectrometry, we have acquired strong evidence against mechanisms involving a single electron transfer, as proposed by Stille, of formation of a dinuclear palladium(I) species followed by an inversion event, and we have gained evidence supporting the direct nucleophilic addition of the palladium(0), resulting in inversion of stereochemistry. The differences in rates of nucleophilic attack involving monodentate and bidentate phosphine ligands on both the palladium I-cyclohexenyl ester have also been explored. Throughout the mechanistic investigation, it was noted that the 31P NMR spectroscopy experiment used gave non-quantitative results, and in fact the differences in quantification of the species varied with the spectrometer used. We also describe our investigations into where these differences arise from and an optimum set of parameters for quantitative 31P NMR spectroscopy. The conclusions are also applicable to other heternuclear NMR spectroscopic experiments.
- Published
- 2016
3. Aldosterone as a renal growth factor
- Author
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Thomas, Warren, Dooley, Ruth, and Harvey, Brian J.
- Published
- 2010
- Full Text
- View/download PDF
4. Olfactory receptor signaling is regulated by the post-synaptic density 95, Drosophila discs large, zona-occludens 1 (PDZ) scaffold multi-PDZ domain protein 1
- Author
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Dooley, Ruth, Baumgart, Sabrina, Rasche, Sebastian, Hatt, Hanns, and Neuhaus, Eva M.
- Published
- 2009
- Full Text
- View/download PDF
5. Purinergic receptor antagonists inhibit odorant-mediated CREB phosphorylation in sustentacular cells of mouse olfactory epithelium
- Author
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Hatt Hanns, Toetter Bastian, Mashukova Anastasia, Dooley Ruth, and Neuhaus Eva M
- Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 ,Neurophysiology and neuropsychology ,QP351-495 - Abstract
Abstract Background Extracellular nucleotides have long been known to play neuromodulatory roles and to be involved in intercellular signalling. In the olfactory system, ATP is released by olfactory neurons, and exogenous ATP can evoke an increase in intracellular calcium concentration in sustentacular cells, the nonneuronal supporting cells of the olfactory epithelium. Here we investigate the hypothesis that olfactory neurons communicate with sustentacular cells via extracellular ATP and purinergic receptor activation. Results Here we show that exposure of mice to a mixture of odorants induced a significant increase in the levels of the transcription factor CREB phosphorylated at Ser-133 in the nuclei of both olfactory sensory neurons and sustentacular cells. This activation was dependent on adenylyl cyclase III-mediated olfactory signaling and on activation of P2Y purinergic receptors on sustentacular cells. Purinergic receptor antagonists inhibited odorant-dependent CREB phosphorylation specifically in the nuclei of the sustentacular cells. Conclusion Our results point to a possible role for extracellular nucleotides in mediating intercellular communication between the neurons and sustentacular cells of the olfactory epithelium in response to odorant exposure. Maintenance of extracellular ionic gradients and metabolism of noxious chemicals by sustentacular cells may therefore be regulated in an odorant-dependent manner by olfactory sensory neurons.
- Published
- 2011
- Full Text
- View/download PDF
6. Anion-Initiated Trifluoromethylation by TMSCF3: Deconvolution of the Siliconate–Carbanion Dichotomy by Stopped-Flow NMR/IR.
- Author
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Johnston, Craig P., West, Thomas H., Dooley, Ruth E., Reid, Marc, Jones, Ariana B., King, Edward J., Leach, Andrew G., and Lloyd-Jones, Guy C.
- Published
- 2018
- Full Text
- View/download PDF
7. Multi-PDZ Domain Protein 1 (MUPP1) as a novel interaction partner of olfactory receptors
- Author
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Dooley, Ruth Catherine (B. Sc.) and Neuroscience
- Subjects
Geruchssinn ,Rezeptor ,ddc:570 ,Olfaktorische Analyse ,Anti-Phopholipid-Antikörper - Abstract
Olfaktorische Rezeptoren sind G-Protein gekoppelte Rezeptoren mit sieben Transmembrandomänen. Die im Rahmen dieser Arbeit durchgeführte Analyse olfaktorischer Rezeptoren ergab, dass am Ende der C-terminalen Region klassische Bindungsmotive existieren, welche durch PDZ Proteine spezifisch erkannt werden können. Da solchen Protein-Protein Interaktionen eine zentrale Rolle in der Organisation diverser Zellsignalwege zugesprochen wird, stellt die mögliche Interaktion eines olfaktorischen Rezeptors mit einem PDZ Protein einen Mechanismus für die Regulation der olfaktorischen Signaltransduktionskaskade dar. In dieser Arbeit konnte eine direkte Interaktion zwischen den PDZ-Domänen 1+2 von MUPP1 mit dem C-Terminus eines olfaktorischen Rezeptors nachgewiesen werden. Eine RNAi induzierte Reduktion von MUPP1 in Hana3A-Zellen zeigte eine verzögerte Abfallszeitkonstante der Kalziumantwort des Riechrezeptors nach Ligandengabe. The unique ability of mammals to detect and discriminate between thousands of different odorant molecules is governed by the diverse array of olfactory receptors (ORs) found on the dendrites of olfactory sensory neurons (OSNs). ORs are 7-transmembrane-domain GPCRs. Interestingly, certain ORs possess a classical PDZ domain binding motif in their C-terminal regions. It has previously been shown that PDZ proteins (PSD-95, Discs large, ZO-1) specifically recognize short peptide motifs in the C-terminus of their target proteins. Multi-PDZ Domain Protein 1 (MUPP1) is expressed in OSNs, in the signal transduction compartments. Here we show a direct interaction between PDZ domains 1+2 of MUPP1 and the C-terminus of olfactory receptor OR2AG1. Knockdown of MUPP1 in Hana3A cells leads to an impaired decay of response of OR to odorant.
- Published
- 2008
8. The scaffold protein MUPP1 regulates odorant-mediated signaling in olfactory sensory neurons.
- Author
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Baumgart, Sabrina, Jansen, Fabian, Bintig, Willem, Kalbe, Benjamin, Herrmann, Christian, Klumpers, Fabian, Köster, S. David, Scholz, Paul, Rasche, Sebastian, Dooley, Ruth, Metzler-Nolte, Nils, Spehr, Marc, Hatt, Hanns, and Neuhaus, Eva M.
- Subjects
SCAFFOLD proteins ,OLFACTORY receptors ,GENETIC transduction ,MICROBIAL genetics ,SENSORY neurons ,RECEPTIVE fields (Neurology) ,PHYSIOLOGY - Abstract
The olfactory signal transduction cascade transforms odor information into electrical signals by a cAMP-based amplification mechanism. The mechanisms underlying the very precise temporal and spatial organization of the relevant signaling components remains poorly understood. Here, we identify, using co-immunoprecipitation experiments, a macromolecular assembly of signal transduction components in mouse olfactory neurons, organized through MUPP1. Disruption of the PDZ signaling complex, through use of an inhibitory peptide, strongly impaired odor responses and changed the activation kinetics of olfactory sensory neurons. In addition, our experiments demonstrate that termination of the response is dependent on PDZ-based scaffolding. These findings provide new insights into the functional organization, and regulation, of olfactory signal transduction. [ABSTRACT FROM AUTHOR]
- Published
- 2014
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9. Using Machine Learning to Optimize Appropriate Advance Care Planning Documents in Electronic Health Records.
- Author
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Bharadwaj, Parag, Dooley, Ruth, Dabagh, Sarah, Chan, Verena, Galli, David, Hyman, Katy, Randhawa, Manjit S., and Solomon, Adam
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- *
NATURAL language processing , *MACHINE learning , *ADVANCE directives (Medical care) , *ELECTRONIC health records , *INFORMATION technology - Abstract
The article discusses use of Machine Learning to Optimize Appropriate Advance Care Planning Documents in Electronic Health Records. It mentions use in minimizing errors of scanned documents related to advance care planning; and also mentions information that assists in directing the course of care is the advance health directive and physician orders for life sustaining treatment.
- Published
- 2021
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10. Aldosterone-induced ENaC and basal Na+/K+-ATPase trafficking via protein kinase D1-phosphatidylinositol 4-kinaseIIIβ trans Golgi signalling in M1 cortical collecting duct cells.
- Author
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Dooley, Ruth, Angibaud, Emmanuelle, Yusef, Yamil R., Thomas, Warren, and Harvey, Brian J.
- Subjects
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ALDOSTERONE , *SODIUM/POTASSIUM ATPase , *PROTEIN kinases , *PHOSPHATIDYLINOSITOL 3-kinases , *CELLULAR signal transduction , *MINERALOCORTICOID receptors - Abstract
Highlights: [•] Aldosterone induces rapid PKD1-dependent ENaCγ membrane trafficking in M1 cells. [•] Na+/K+-ATPase activity and localization is impaired in shRNA-PKD1 knockdown cells. [•] Aldosterone induces an interaction between PKD1 and PI4KIIIβ at the TGN. [Copyright &y& Elsevier]
- Published
- 2013
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11. Non-genomic actions of aldosterone: From receptors and signals to membrane targets
- Author
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Dooley, Ruth, Harvey, Brian J., and Thomas, Warren
- Subjects
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RENIN-angiotensin system , *GENOMICS , *MITOGEN-activated protein kinases , *MINERALOCORTICOID receptors , *ALDOSTERONE regulation , *KIDNEY tubules , *GENE expression - Abstract
Abstract: In tissues which express the mineralocorticoid receptor (MR), aldosterone modulates the expression of membrane targets such as the subunits of the epithelial Na+ channel, in combination with important signalling intermediates such as serum and glucocorticoid-regulated kinase-1. In addition, the rapid ‘non-genomic’ activation of protein kinases and secondary messenger signalling cascades has also been detected in aldosterone-sensitive tissues of the nephron, distal colon and cardiovascular system. These rapid actions are variously described as being coupled to MR or to an as yet unidentified, membrane-associated aldosterone receptor. The rapidly activated signalling cascades add a level of fine-tuning to the activity of aldosterone-responsive membrane transporters and also modulate the aldosterone-induced changes in gene expression through receptor and transcription factor phosphorylation. [Copyright &y& Elsevier]
- Published
- 2012
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12. Protein kinase D1 modulates aldosterone-induced ENaC activity in a renal cortical collecting duct cell line
- Author
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McEneaney, Victoria, Dooley, Ruth, Yusef, Yamil R., Keating, Niamh, Quinn, Ursula, Harvey, Brian J., and Thomas, Warren
- Subjects
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PROTEIN kinases , *ALDOSTERONE , *SODIUM channels , *EPITHELIAL cells , *RENAL hypertension , *GENE expression , *CELL lines , *CELL membranes - Abstract
Abstract: Aldosterone treatment of M1-CCD cells stimulated an increase in epithelial Na+ channel (ENaC) α-subunit expression that was mainly localized to the apical membrane. PKD1-suppressed cells constitutively expressed ENaCα at low abundance, with no increase after aldosterone treatment. In the PKD1-suppressed cells, ENaCα was mainly localized proximal to the basolateral surface of the epithelium both before and after aldosterone treatment. Apical membrane insertion of ENaCβ in response to aldosterone treatment was also sensitive to PKD1 suppression as was the aldosterone-induced rise in the amiloride-sensitive, trans-epithelial current (I TE ). The interaction of the mineralocorticoid receptor (MR) with specific elements in the promoters of aldosterone responsive genes is stabilized by ligand interaction and phosphorylation. PKD1 suppression inhibited aldosterone-induced SGK-1 expression. The nuclear localization of MR was also blocked by PKD1 suppression and MEK antagonism implicating both these kinases in MR nuclear stabilization. PKD1 thus modulates aldosterone-induced ENaC activity through the modulation of sub-cellular trafficking and the stabilization of MR nuclear localization. [Copyright &y& Elsevier]
- Published
- 2010
- Full Text
- View/download PDF
13. Protein kinase D stabilizes aldosterone-induced ERK1/2 MAP kinase activation in M1 renal cortical collecting duct cells to promote cell proliferation
- Author
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McEneaney, Victoria, Dooley, Ruth, Harvey, Brian J., and Thomas, Warren
- Subjects
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MITOGEN-activated protein kinases , *ALDOSTERONE , *CELL proliferation , *GENETIC transcription , *CELLULAR signal transduction , *PROTEIN synthesis , *CELL lines , *MINERALOCORTICOIDS - Abstract
Abstract: Aldosterone elicits transcriptional responses in target tissues and also rapidly stimulates the activation of protein kinase signalling cascades independently of de novo protein synthesis. Here we investigated aldosterone-induced cell proliferation and extra-cellular regulated kinase 1 and 2 (ERK1/2) mitogen activated protein (MAP) kinase signalling in the M1 cortical collecting duct cell line (M1-CCD). Aldosterone promoted the proliferative growth of M1-CCD cells, an effect that was protein kinase D1 (PKD1), PKCδ and ERK1/2-dependent. Aldosterone induced the rapid activation of ERK1/2 with peaks of activation at 2 and 10 to 30min after hormone treatment followed by sustained activation lasting beyond 120min. M1-CCD cells suppressed in PKD1 expression exhibited only the early, transient peaks in ERK1/2 activation without the sustained phase. Aldosterone stimulated the physical association of PKD1 with ERK1/2 within 2min of treatment. The mineralocorticoid receptor (MR) antagonist RU28318 inhibited the early and late phases of aldosterone-induced ERK1/2 activation, and also aldosterone-induced proliferative cell growth. Aldosterone induced the sub-cellular redistribution of ERK1/2 to the nuclei at 2min and to cytoplasmic sites, proximal to the nuclei after 30min. This sub-cellular distribution of ERK1/2 was inhibited in cells suppressed in the expression of PKD1. [Copyright &y& Elsevier]
- Published
- 2010
- Full Text
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14. Protein kinase D2 regulates epithelial sodium channel activity and aldosterone non-genomic responses in renal cortical collecting duct cells.
- Author
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Thomas, Warren, Dooley, Ruth, Quinn, Sinead, Robles, Manuel Yusef, and Harvey, Brian J.
- Subjects
- *
PROTEIN kinases , *SODIUM channels , *SERINE/THREONINE kinases , *ALDOSTERONE antagonists , *CELLS , *CELL lines , *GENE expression - Abstract
Protein kinase D2 (PKD2) is a serine/threonine protein kinase which plays an important role in vesicle fission at the trans-Golgi network (TGN) to coordinate subcellular trafficking with gene expression. We found that in the rat kidney, PKD2 is specifically expressed in collecting duct principal cells predominantly at the apical membrane and with lower basal expression in cytosolic compartments. When rats were maintained on a Na+ depleted diet (<0.87 mmol Na+/kg) to increase plasma aldosterone levels, PKD2 became internalized to a cytoplasmic compartment. Treatment of murine M1 cortical collecting duct (M1-CCD) cells with aldosterone (10 nM) promoted PKD2 co-localization with the trans-Golgi network within 30 min. PKD2 underwent autophosphorylation at Ser876 within 10 min of aldosterone treatment and remained phosphorylated (active) for at least 24 h. A stable PKD2 shRNA knock-down (PKD2 KD) M1-CCD cell line was developed to study the role of PKD2 in epithelial Na+ channel (ENaC) trafficking and transepithelial Na+ transport (SCC) in epithelial monolayers grown in Ussing chambers. The PKD2 KD cells developed transepithelial resistance with kinetics equivalent to wild-type cells, however the transepithelial voltage and Na+ current were significantly elevated in PKD2 knock-down CCD epithelia. The higher basal SCC was due to increased ENaC activity. Aldosterone treatment for 24 h resulted in a decline in ENaC activity in the PKD2 KD cells as opposed to the increase observed in the wild-type cells. The paradoxical inhibition of SCC by aldosterone in PKD2 KD epithelium was attributed to a reduction in ENaC current and lower membrane abundance of ENaC, demonstrating that PKD2 plays a critical tonic role in ENaC trafficking and channel subunit stability. The rapid activation of PKD2 by aldosterone is synergistic with the transcriptional activity of MR and contributes to increased ENaC activity. [ABSTRACT FROM AUTHOR]
- Published
- 2020
- Full Text
- View/download PDF
15. Odorant receptor heterodimerization in the olfactory system of Drosophila melanogaster.
- Author
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Neuhaus, Eva M, Gisselmann, G&aouml;nter, Zhang, Weiyi, Dooley, Ruth, Stärtkuhl, Klemens, and Hatt, Hanns
- Subjects
DROSOPHILA melanogaster ,NERVOUS system ,NEURONS ,CELLS ,DROSOPHILIDAE ,PROTEINS - Abstract
Despite increasing knowledge about dimerization of G-protein-coupled receptors, nothing is known about dimerization in the largest subfamily, odorant receptors. Using a combination of biochemical and electrophysiological approaches, we demonstrate here that odorant receptors can dimerize. DOR83b, an odorant receptor that is ubiquitously expressed in olfactory neurons from Drosophila melanogaster and highly conserved among insect species, forms heterodimeric complexes with other odorant-receptor proteins, which strongly increases their functionality. [ABSTRACT FROM AUTHOR]
- Published
- 2005
- Full Text
- View/download PDF
16. Anion-Initiated Trifluoromethylation by TMSCF 3 : Deconvolution of the Siliconate-Carbanion Dichotomy by Stopped-Flow NMR/IR.
- Author
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Johnston CP, West TH, Dooley RE, Reid M, Jones AB, King EJ, Leach AG, and Lloyd-Jones GC
- Abstract
The mechanism of CF
3 transfer from R3 SiCF3 (R = Me, Et, iPr) to ketones and aldehydes, initiated by M+ X- (<0.004 to 10 mol %), has been investigated by analysis of kinetics (variable-ratio stopped-flow NMR and IR),13 C/2 H KIEs, LFER, addition of ligands (18-c-6, crypt-222), and density functional theory calculations. The kinetics, reaction orders, and selectivity vary substantially with reagent (R3 SiCF3 ) and initiator (M+ X- ). Traces of exogenous inhibitors present in the R3 SiCF3 reagents, which vary substantially in proportion and identity between batches and suppliers, also affect the kinetics. Some reactions are complete in milliseconds, others take hours, and others stall before completion. Despite these differences, a general mechanism has been elucidated in which the product alkoxide and CF3 - anion act as chain carriers in an anionic chain reaction. Silyl enol ether generation competes with 1,2-addition and involves protonation of CF3 - by the α-C-H of the ketone and the OH of the enol. The overarching mechanism for trifluoromethylation by R3 SiCF3 , in which pentacoordinate siliconate intermediates are unable to directly transfer CF3 - as a nucleophile or base, rationalizes why the turnover rate (per M+ X- initiator) depends on the initial concentration (but not identity) of X- , the identity (but not concentration) of M+ , the identity of the R3 SiCF3 reagent, and the carbonyl/R3 SiCF3 ratio. It also rationalizes which R3 SiCF3 reagent effects the most rapid trifluoromethylation, for a specific M+ X- initiator.- Published
- 2018
- Full Text
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17. Purinergic receptor antagonists inhibit odorant-mediated CREB phosphorylation in sustentacular cells of mouse olfactory epithelium.
- Author
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Dooley R, Mashukova A, Toetter B, Hatt H, and Neuhaus EM
- Subjects
- Animals, Cells, Cultured, Mice, Olfactory Mucosa cytology, Olfactory Mucosa drug effects, Olfactory Receptor Neurons drug effects, Phosphorylation, Smell drug effects, CREB-Binding Protein metabolism, Odorants, Olfactory Mucosa physiology, Olfactory Receptor Neurons physiology, Purinergic Antagonists pharmacology, Receptors, Odorant metabolism, Smell physiology
- Abstract
Background: Extracellular nucleotides have long been known to play neuromodulatory roles and to be involved in intercellular signalling. In the olfactory system, ATP is released by olfactory neurons, and exogenous ATP can evoke an increase in intracellular calcium concentration in sustentacular cells, the nonneuronal supporting cells of the olfactory epithelium. Here we investigate the hypothesis that olfactory neurons communicate with sustentacular cells via extracellular ATP and purinergic receptor activation., Results: Here we show that exposure of mice to a mixture of odorants induced a significant increase in the levels of the transcription factor CREB phosphorylated at Ser-133 in the nuclei of both olfactory sensory neurons and sustentacular cells. This activation was dependent on adenylyl cyclase III-mediated olfactory signaling and on activation of P2Y purinergic receptors on sustentacular cells. Purinergic receptor antagonists inhibited odorant-dependent CREB phosphorylation specifically in the nuclei of the sustentacular cells., Conclusion: Our results point to a possible role for extracellular nucleotides in mediating intercellular communication between the neurons and sustentacular cells of the olfactory epithelium in response to odorant exposure. Maintenance of extracellular ionic gradients and metabolism of noxious chemicals by sustentacular cells may therefore be regulated in an odorant-dependent manner by olfactory sensory neurons.
- Published
- 2011
- Full Text
- View/download PDF
18. The regulation of cell growth and survival by aldosterone.
- Author
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Dooley R, Harvey BJ, and Thomas W
- Subjects
- 11-beta-Hydroxysteroid Dehydrogenase Type 2, Animals, Blood Vessels physiology, Brain drug effects, Brain physiopathology, Cardiovascular Diseases physiopathology, Cell Differentiation drug effects, Cell Proliferation drug effects, Cell Survival drug effects, Humans, Kidney drug effects, Kidney physiopathology, Kidney Diseases physiopathology, MAP Kinase Signaling System physiology, Myocytes, Cardiac physiology, Nephrons drug effects, Nephrons growth & development, Receptors, Glucocorticoid physiology, Receptors, Mineralocorticoid drug effects, Renin-Angiotensin System physiology, Aldosterone physiology, Receptors, Mineralocorticoid physiology
- Abstract
The steroid hormone aldosterone is synthesized from cholesterol, mainly in the zona glomerulosa of the adrenal cortex. Aldosterone exerts its effects in the epithelial tissues of the kidney and colon and in non-epithelial tissues such as the brain and cardiovasculature. The genomic response to aldosterone involves dimerization of the mineralocorticoid receptor (MR), dissociation of heat shock proteins from MR, translocation of the aldosterone-MR complex to the nucleus and the concomitant regulation of gene expression. Rapid responses to aldosterone occur within seconds to minutes, do not involve transcription or translation and can modulate directly or indirectly the later genomic responses. Aside from the well-known effects of aldosterone on the regulation of sodium and water homeostasis, aldosterone can also produce deleterious structural changes in tissues by inducing hypertrophy and the dysregulation of proliferation and apoptosis, leading to fibrosis and tissue remodelling. Here we discuss the involvement of aldosterone-mediated rapid signalling cascades in the development of disease states such as chronic kidney disease and heart failure, and the antagonists that can inhibit these pathophysiological responses.
- Published
- 2011
- Full Text
- View/download PDF
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