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Article ; Online: Gephyrin: a key regulatory protein of inhibitory synapses and beyond.

Groeneweg, Femke L / Trattnig, Christa / Kuhse, Jochen / Nawrotzki, Ralph A / Kirsch, Joachim

2018 Volume 150, Issue 5, Page(s) 489–508

Abstract: Scaffolding proteins underlying postsynaptic membrane specializations are important structural and functional components of both excitatory and inhibitory synapses. At inhibitory synapses, gephyrin was identified as anchoring protein. Gephyrin self- ... ...

Abstract	Scaffolding proteins underlying postsynaptic membrane specializations are important structural and functional components of both excitatory and inhibitory synapses. At inhibitory synapses, gephyrin was identified as anchoring protein. Gephyrin self-assembles into a complex flat submembranous lattice that slows the lateral mobility of glycine and GABA
MeSH term(s)	Animals ; Carrier Proteins/chemistry ; Carrier Proteins/metabolism ; Humans ; Membrane Proteins/chemistry ; Membrane Proteins/metabolism ; Synapses/drug effects ; Synapses/metabolism
Chemical Substances	Carrier Proteins ; Membrane Proteins ; gephyrin
Language	English
Publishing date	2018-09-27
Publishing country	Germany
Document type	Journal Article ; Review
ZDB-ID	1222930-1
ISSN	1432-119X ; 0301-5564 ; 0948-6143
ISSN (online)	1432-119X
ISSN	0301-5564 ; 0948-6143
DOI	10.1007/s00418-018-1725-2
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Article ; Online: Polymorphic differences within HLA-C alleles contribute to alternatively spliced transcripts lacking exon 5.

Ehlers, Femke A I / Olieslagers, Timo I / Groeneweg, Mathijs / Bos, Gerard M J / Tilanus, Marcel G J / Voorter, Christina E M / Wieten, Lotte

HLA

2022 Volume 100, Issue 3, Page(s) 232–243

Abstract: The HLA genes are amongst the most polymorphic in the human genome. Alternative splicing could add an extra layer of complexity, but has not been studied extensively. Here, we applied an RNA based approach to study the influence of allele polymorphism on ...

Abstract	The HLA genes are amongst the most polymorphic in the human genome. Alternative splicing could add an extra layer of complexity, but has not been studied extensively. Here, we applied an RNA based approach to study the influence of allele polymorphism on alternative splicing of HLA-C in peripheral blood. RNA was isolated from these peripheral cells, converted into cDNA and amplified specifically for 12 common HLA-C allele groups. Through subsequent sequencing of HLA-C, we observed alternative splicing variants of HLA-C04 and 16 that resulted in exon 5 skipping and were co-expressed with the mature transcript. Investigation of intron 4 sequences of HLA-C04 and 16 compared with other HLA-C alleles demonstrated no effect on predicted splice sites and branch point. To further investigate if the unique polymorphic positions in exon 5 of HLA-C04 or 16 may facilitate alternative splicing by acting on splicing regulatory elements (SRE), in-silico splicing analysis was performed. While the HLA-C04 specific SNP in exon 5 had no effect on predicted exonic SRE, the HLA-C16 specific exon 5 SNP did alter exonic SRE. Our findings provide experimental and theoretical support for the concept that polymorphisms within the HLA-C alleles influence the alternative splicing of HLA-C.
MeSH term(s)	Alleles ; Alternative Splicing ; Exons/genetics ; HLA-C Antigens/genetics ; Humans ; Introns ; Polymorphism, Genetic ; RNA/genetics
Chemical Substances	HLA-C Antigens ; RNA (63231-63-0)
Language	English
Publishing date	2022-06-27
Publishing country	England
Document type	Journal Article
ZDB-ID	2845111-9
ISSN	2059-2310 ; 2059-2302
ISSN (online)	2059-2310
ISSN	2059-2302
DOI	10.1111/tan.14695
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Article ; Online: Mineralocorticoid and glucocorticoid receptors at the neuronal membrane, regulators of nongenomic corticosteroid signalling.

Groeneweg, Femke L / Karst, Henk / de Kloet, E Ron / Joëls, Marian

Molecular and cellular endocrinology

2012 Volume 350, Issue 2, Page(s) 299–309

Abstract: The balance between corticosteroid actions induced via activation of the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR) determines the brain's response to stress. While both receptors are best known for their delayed genomic role, ... ...

Abstract	The balance between corticosteroid actions induced via activation of the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR) determines the brain's response to stress. While both receptors are best known for their delayed genomic role, it has become increasingly evident that they can also associate with the plasma membrane and act as mediators of rapid, nongenomic signalling. Nongenomic corticosteroid actions in the brain are required for the coordination of a rapid adaptive response to stress; membrane-associated MRs and GRs play a major role herein. However, many questions regarding the underlying mechanism are still unresolved. How do MR and GR translocate to the membrane and what are their downstream signalling partners? In this review we discuss these issues based on insights obtained from related receptors, most notably the estrogen receptor α.
MeSH term(s)	Adrenal Cortex Hormones/metabolism ; Animals ; Cell Membrane/metabolism ; Humans ; Models, Biological ; Neurons/metabolism ; Neurons/ultrastructure ; Receptors, Glucocorticoid/genetics ; Receptors, Glucocorticoid/metabolism ; Receptors, Glucocorticoid/physiology ; Receptors, Mineralocorticoid/genetics ; Receptors, Mineralocorticoid/metabolism ; Receptors, Mineralocorticoid/physiology ; Signal Transduction/genetics ; Signal Transduction/physiology
Chemical Substances	Adrenal Cortex Hormones ; Receptors, Glucocorticoid ; Receptors, Mineralocorticoid
Language	English
Publishing date	2012-03-24
Publishing country	Ireland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	187438-x
ISSN	1872-8057 ; 0303-7207
ISSN (online)	1872-8057
ISSN	0303-7207
DOI	10.1016/j.mce.2011.06.020
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Article ; Online: Rapid non-genomic effects of corticosteroids and their role in the central stress response.

Groeneweg, Femke L / Karst, Henk / de Kloet, E Ron / Joëls, Marian

The Journal of endocrinology

2011 Volume 209, Issue 2, Page(s) 153–167

Abstract: In response to a stressful encounter, the brain activates a comprehensive stress system that engages the organism in an adaptive response to the threatening situation. This stress system acts on multiple peripheral tissues and feeds back to the brain; ... ...

Abstract	In response to a stressful encounter, the brain activates a comprehensive stress system that engages the organism in an adaptive response to the threatening situation. This stress system acts on multiple peripheral tissues and feeds back to the brain; one of its key players is the family of corticosteroid hormones. Corticosteroids affect brain functioning through both delayed, genomic and rapid, non-genomic mechanisms. The latter mode of action has long been known, but it is only in recent years that the physiological basis in the brain is beginning to be unravelled. We now know that corticosteroids exert rapid, non-genomic effects on the excitability and activation of neurons in (amongst others) the hypothalamus, hippocampus, amygdala and prefrontal cortex. In addition, corticosteroids affect cognition, adaptive behaviour and neuroendocrine output within minutes. Knowledge on the identity of the receptors and secondary pathways mediating the non-genomic effects of corticosteroids on a cellular level is accumulating. Interestingly, in many cases, an essential role for the 'classical' mineralocorticoid and glucocorticoid receptors in a novel membrane-associated mechanism is found. Here, we systematically review the recent literature on non-genomic actions of corticosteroids on neuronal activity and functioning in selected limbic brain targets. Further, we discuss the relevance of these permissive effects for cognition and neuroendocrine control, and the integration of this novel mode of action into the complex balanced pattern of stress effects in the brain.
MeSH term(s)	Animals ; Behavior, Animal/physiology ; Brain/physiology ; Cognition/physiology ; Corticosterone/physiology ; Humans ; Neurosecretory Systems/physiology ; Stress, Physiological
Chemical Substances	Corticosterone (W980KJ009P)
Language	English
Publishing date	2011-05
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	3028-4
ISSN	1479-6805 ; 0022-0795
ISSN (online)	1479-6805
ISSN	0022-0795
DOI	10.1530/JOE-10-0472
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Article: Mineralocorticoid and glucocorticoid receptors at the neuronal membrane, regulators of nongenomic corticosteroid signalling

Groeneweg, Femke L / Karst, Henk / de Kloet, E. Ron / Joëls, Marian

Molecular and cellular endocrinology. 2012 Mar. 24, v. 350, no. 2

2012

Abstract: The balance between corticosteroid actions induced via activation of the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR) determines the brain’s response to stress. While both receptors are best known for their delayed genomic role, ... ...

Abstract	The balance between corticosteroid actions induced via activation of the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR) determines the brain’s response to stress. While both receptors are best known for their delayed genomic role, it has become increasingly evident that they can also associate with the plasma membrane and act as mediators of rapid, nongenomic signalling. Nongenomic corticosteroid actions in the brain are required for the coordination of a rapid adaptive response to stress; membrane-associated MRs and GRs play a major role herein. However, many questions regarding the underlying mechanism are still unresolved. How do MR and GR translocate to the membrane and what are their downstream signalling partners? In this review we discuss these issues based on insights obtained from related receptors, most notably the estrogen receptor α.
Keywords	brain ; estrogen receptors ; glucocorticoid receptors ; mineralocorticoid receptors ; plasma membrane ; stress response
Language	English
Dates of publication	2012-0324
Size	p. 299-309.
Publishing place	Elsevier Ireland Ltd
Document type	Article
ZDB-ID	187438-x
ISSN	1872-8057 ; 0303-7207
ISSN (online)	1872-8057
ISSN	0303-7207
DOI	10.1016/j.mce.2011.06.020
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Quantitation of glucocorticoid receptor DNA-binding dynamics by single-molecule microscopy and FRAP.

Groeneweg, Femke L / van Royen, Martin E / Fenz, Susanne / Keizer, Veer I P / Geverts, Bart / Prins, Jurrien / de Kloet, E Ron / Houtsmuller, Adriaan B / Schmidt, Thomas S / Schaaf, Marcel J M

PloS one

2014 Volume 9, Issue 3, Page(s) e90532

Abstract: Recent advances in live cell imaging have provided a wealth of data on the dynamics of transcription factors. However, a consistent quantitative description of these dynamics, explaining how transcription factors find their target sequences in the vast ... ...

Abstract	Recent advances in live cell imaging have provided a wealth of data on the dynamics of transcription factors. However, a consistent quantitative description of these dynamics, explaining how transcription factors find their target sequences in the vast amount of DNA inside the nucleus, is still lacking. In the present study, we have combined two quantitative imaging methods, single-molecule microscopy and fluorescence recovery after photobleaching, to determine the mobility pattern of the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR), two ligand-activated transcription factors. For dexamethasone-activated GR, both techniques showed that approximately half of the population is freely diffusing, while the remaining population is bound to DNA. Of this DNA-bound population about half the GRs appeared to be bound for short periods of time (∼ 0.7 s) and the other half for longer time periods (∼ 2.3 s). A similar pattern of mobility was seen for the MR activated by aldosterone. Inactive receptors (mutant or antagonist-bound receptors) show a decreased DNA binding frequency and duration, but also a higher mobility for the diffusing population. Likely, very brief (≤ 1 ms) interactions with DNA induced by the agonists underlie this difference in diffusion behavior. Surprisingly, different agonists also induce different mobilities of both receptors, presumably due to differences in ligand-induced conformational changes and receptor complex formation. In summary, our data provide a consistent quantitative model of the dynamics of GR and MR, indicating three types of interactions with DNA, which fit into a model in which frequent low-affinity DNA binding facilitates the search for high-affinity target sequences.
MeSH term(s)	Animals ; COS Cells ; Cell Line, Tumor ; Chlorocebus aethiops ; DNA/metabolism ; Fluorescence Recovery After Photobleaching/methods ; Humans ; Microscopy/methods ; Models, Theoretical ; Protein Binding ; Receptors, Glucocorticoid/metabolism ; Receptors, Mineralocorticoid/metabolism
Chemical Substances	Receptors, Glucocorticoid ; Receptors, Mineralocorticoid ; DNA (9007-49-2)
Language	English
Publishing date	2014-03-14
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0090532
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Article ; Online: Quantitation of glucocorticoid receptor DNA-binding dynamics by single-molecule microscopy and FRAP.

Femke L Groeneweg / Martin E van Royen / Susanne Fenz / Veer I P Keizer / Bart Geverts / Jurrien Prins / E Ron de Kloet / Adriaan B Houtsmuller / Thomas S Schmidt / Marcel J M Schaaf

PLoS ONE, Vol 9, Iss 3, p e

2014 Volume 90532

Abstract	Recent advances in live cell imaging have provided a wealth of data on the dynamics of transcription factors. However, a consistent quantitative description of these dynamics, explaining how transcription factors find their target sequences in the vast amount of DNA inside the nucleus, is still lacking. In the present study, we have combined two quantitative imaging methods, single-molecule microscopy and fluorescence recovery after photobleaching, to determine the mobility pattern of the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR), two ligand-activated transcription factors. For dexamethasone-activated GR, both techniques showed that approximately half of the population is freely diffusing, while the remaining population is bound to DNA. Of this DNA-bound population about half the GRs appeared to be bound for short periods of time (∼ 0.7 s) and the other half for longer time periods (∼ 2.3 s). A similar pattern of mobility was seen for the MR activated by aldosterone. Inactive receptors (mutant or antagonist-bound receptors) show a decreased DNA binding frequency and duration, but also a higher mobility for the diffusing population. Likely, very brief (≤ 1 ms) interactions with DNA induced by the agonists underlie this difference in diffusion behavior. Surprisingly, different agonists also induce different mobilities of both receptors, presumably due to differences in ligand-induced conformational changes and receptor complex formation. In summary, our data provide a consistent quantitative model of the dynamics of GR and MR, indicating three types of interactions with DNA, which fit into a model in which frequent low-affinity DNA binding facilitates the search for high-affinity target sequences.
Keywords	Medicine ; R ; Science ; Q
Subject code	612
Language	English
Publishing date	2014-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Mitochondrial Dynamics in Visual Cortex Are Limited In Vivo and Not Affected by Axonal Structural Plasticity.

Smit-Rigter, Laura / Rajendran, Rajeev / Silva, Catia A P / Spierenburg, Liselot / Groeneweg, Femke / Ruimschotel, Emma M / van Versendaal, Danielle / van der Togt, Chris / Eysel, Ulf T / Heimel, J Alexander / Lohmann, Christian / Levelt, Christiaan N

Current biology : CB

2016 Volume 26, Issue 19, Page(s) 2609–2616

Abstract: Mitochondria buffer intracellular ... ...

Abstract	Mitochondria buffer intracellular Ca
Language	English
Publishing date	2016-10-10
Publishing country	England
Document type	Journal Article
ZDB-ID	1071731-6
ISSN	1879-0445 ; 0960-9822
ISSN (online)	1879-0445
ISSN	0960-9822
DOI	10.1016/j.cub.2016.07.033
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Article ; Online: Effectiveness and safety of the tri-iodothyronine analogue Triac in children and adults with MCT8 deficiency: an international, single-arm, open-label, phase 2 trial.

Groeneweg, Stefan / Peeters, Robin P / Moran, Carla / Stoupa, Athanasia / Auriol, Françoise / Tonduti, Davide / Dica, Alice / Paone, Laura / Rozenkova, Klara / Malikova, Jana / van der Walt, Adri / de Coo, Irenaeus F M / McGowan, Anne / Lyons, Greta / Aarsen, Femke K / Barca, Diana / van Beynum, Ingrid M / van der Knoop, Marieke M / Jansen, Jurgen /

Manshande, Martien / Lunsing, Roelineke J / Nowak, Stan / den Uil, Corstiaan A / Zillikens, M Carola / Visser, Frank E / Vrijmoeth, Paul / de Wit, Marie Claire Y / Wolf, Nicole I / Zandstra, Angelique / Ambegaonkar, Gautam / Singh, Yogen / de Rijke, Yolanda B / Medici, Marco / Bertini, Enrico S / Depoorter, Sylvia / Lebl, Jan / Cappa, Marco / De Meirleir, Linda / Krude, Heiko / Craiu, Dana / Zibordi, Federica / Oliver Petit, Isabelle / Polak, Michel / Chatterjee, Krishna / Visser, Theo J / Visser, W Edward

The lancet. Diabetes & endocrinology

2019 Volume 7, Issue 9, Page(s) 695–706

Abstract: Background: Deficiency of the thyroid hormone transporter monocarboxylate transporter 8 (MCT8) causes severe intellectual and motor disability and high serum tri-iodothyronine (T: Methods: In this investigator-initiated, multicentre, open-label, ... ...

Abstract	Background: Deficiency of the thyroid hormone transporter monocarboxylate transporter 8 (MCT8) causes severe intellectual and motor disability and high serum tri-iodothyronine (T Methods: In this investigator-initiated, multicentre, open-label, single-arm, phase 2, pragmatic trial, we investigated the effectiveness and safety of oral Triac in male paediatric and adult patients with MCT8 deficiency in eight countries in Europe and one site in South Africa. Triac was administered in a predefined escalating dose schedule-after the initial dose of once-daily 350 μg Triac, the daily dose was increased progressively in 350 μg increments, with the goal of attaining serum total T Findings: Between Oct 15, 2014, and June 1, 2017, we screened 50 patients, all of whom were eligible. Of these patients, four (8%) patients decided not to participate because of travel commitments. 46 (92%) patients were therefore enrolled in the trial to receive Triac (median age 7·1 years [range 0·8-66·8]). 45 (98%) participants received Triac and had at least one follow-up measurement of thyroid function and thus were included in the analyses of the primary endpoints. Of these 45 patients, five did not complete the trial (two patients withdrew [travel burden, severe pre-existing comorbidity], one was lost to follow-up, one developed of Graves disease, and one died of sepsis). Patients required a mean dose of 38.3 μg/kg of bodyweight (range 6·4-84·3) to attain T Interpretation: Key features of peripheral thyrotoxicosis were alleviated in paediatric and adult patients with MCT8 deficiency who were treated with Triac. Triac seems a reasonable treatment strategy to ameliorate the consequences of untreated peripheral thyrotoxicosis in patients with MCT8 deficiency. Funding: Dutch Scientific Organization, Sherman Foundation, NeMO Foundation, Wellcome Trust, UK National Institute for Health Research Cambridge Biomedical Centre, Toulouse University Hospital, and Una Vita Rara ONLUS.
MeSH term(s)	Adolescent ; Child ; Child, Preschool ; Europe ; Follow-Up Studies ; Guidelines as Topic ; Humans ; Infant ; Male ; Membrane Transport Proteins/administration & dosage ; Membrane Transport Proteins/pharmacology ; Mental Retardation, X-Linked/drug therapy ; Mental Retardation, X-Linked/physiopathology ; Muscle Hypotonia/drug therapy ; Muscle Hypotonia/physiopathology ; Muscular Atrophy/drug therapy ; Muscular Atrophy/physiopathology ; Patient Safety ; South Africa ; Triiodothyronine/administration & dosage ; Triiodothyronine/analogs & derivatives ; Triiodothyronine/pharmacology ; Young Adult
Chemical Substances	Membrane Transport Proteins ; Triiodothyronine (06LU7C9H1V) ; 3,3',5-triiodothyroacetic acid (29OQ9EU4R1)
Language	English
Publishing date	2019-07-31
Publishing country	England
Document type	Clinical Trial, Phase II ; Journal Article ; Multicenter Study ; Research Support, Non-U.S. Gov't
ISSN	2213-8595
ISSN (online)	2213-8595
DOI	10.1016/S2213-8587(19)30155-X
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Article: Mineralocorticoid and glucocorticoid receptors at the neuronal membrane, regulators of nongenomic corticosteroid signalling

Groeneweg, Femke L. / Karst, Henk / de Kloet, E. Ron / Joëls, Marian

Molecular and cellular endocrinology

Volume v. 350,, Issue no. 2

Abstract: The balance between corticosteroid actions induced via activation of the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR) determines the brain’s response to stress. While both receptors are best known for their delayed genomic role, ... ...

Abstract	The balance between corticosteroid actions induced via activation of the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR) determines the brain’s response to stress. While both receptors are best known for their delayed genomic role, it has become increasingly evident that they can also associate with the plasma membrane and act as mediators of rapid, nongenomic signalling. Nongenomic corticosteroid actions in the brain are required for the coordination of a rapid adaptive response to stress; membrane-associated MRs and GRs play a major role herein. However, many questions regarding the underlying mechanism are still unresolved. How do MR and GR translocate to the membrane and what are their downstream signalling partners? In this review we discuss these issues based on insights obtained from related receptors, most notably the estrogen receptor α.
Keywords	estrogen receptors ; glucocorticoid receptors ; plasma membrane ; mineralocorticoid receptors ; brain ; stress response
Language	English
Document type	Article
ISSN	0303-7207
Database	AGRIS - International Information System for the Agricultural Sciences and Technology

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