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Article ; Online: Prophylactic Herpes Simplex Virus 2 (HSV-2) Vaccines Adjuvanted with Stable Emulsion and Toll-Like Receptor 9 Agonist Induce a Robust HSV-2-Specific Cell-Mediated Immune Response, Protect against Symptomatic Disease, and Reduce the Latent Viral Reservoir.

Hensel, Michael T / Marshall, Jason D / Dorwart, Michael R / Heeke, Darren S / Rao, Eileen / Tummala, Padmaja / Yu, Li / Cohen, Gary H / Eisenberg, Roselyn J / Sloan, Derek D

Journal of virology

2017 Volume 91, Issue 9

Abstract: Several prophylactic vaccines targeting herpes simplex virus 2 (HSV-2) have failed in the clinic to demonstrate sustained depression of viral shedding or protection from recurrences. Although these vaccines have generated high titers of neutralizing ... ...

Abstract	Several prophylactic vaccines targeting herpes simplex virus 2 (HSV-2) have failed in the clinic to demonstrate sustained depression of viral shedding or protection from recurrences. Although these vaccines have generated high titers of neutralizing antibodies (NAbs), their induction of robust CD8 T cells has largely been unreported, even though evidence for the importance of HSV-2 antigen-specific CD8 T cells is mounting in animal models and in translational studies involving subjects with active HSV-2-specific immune responses. We developed a subunit vaccine composed of the NAb targets gD and gB and the novel T cell antigen and tegument protein UL40, and we compared this vaccine to a whole-inactivated-virus vaccine (formaldehyde-inactivated HSV-2 [FI-HSV-2]). We evaluated different formulations in combination with several Th1-inducing Toll-like receptor (TLR) agonists
MeSH term(s)	Adjuvants, Immunologic/pharmacology ; Animals ; Antibodies, Neutralizing/blood ; Antibodies, Neutralizing/immunology ; Antibodies, Viral/blood ; Antibodies, Viral/immunology ; Antigens, Viral/immunology ; CD8-Positive T-Lymphocytes/immunology ; Disease Models, Animal ; Female ; Glycoproteins/immunology ; Guinea Pigs ; Herpes Simplex/immunology ; Herpes Simplex/prevention & control ; Herpes Simplex/virology ; Herpes Simplex Virus Vaccines/immunology ; Herpesvirus 2, Human/immunology ; Herpesvirus 2, Human/physiology ; Immunity, Cellular/immunology ; Mice ; Mice, Inbred C57BL ; Oligodeoxyribonucleotides/immunology ; Toll-Like Receptor 9/immunology ; Vaccines, Subunit/immunology ; Viral Envelope Proteins/immunology ; Virus Latency/immunology
Chemical Substances	Adjuvants, Immunologic ; Antibodies, Neutralizing ; Antibodies, Viral ; Antigens, Viral ; Glycoproteins ; Herpes Simplex Virus Vaccines ; Oligodeoxyribonucleotides ; Toll-Like Receptor 9 ; Vaccines, Subunit ; Viral Envelope Proteins
Language	English
Publishing date	2017-04-13
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80174-4
ISSN	1098-5514 ; 0022-538X
ISSN (online)	1098-5514
ISSN	0022-538X
DOI	10.1128/JVI.02257-16
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Article: The solute carrier 26 family of proteins in epithelial ion transport.

Dorwart, Michael R / Shcheynikov, Nikolay / Yang, Dongki / Muallem, Shmuel

Physiology (Bethesda, Md.)

2008 Volume 23, Page(s) 104–114

Abstract: Transepithelial Cl(-) and HCO(3)(-) transport is critically important for the function of all epithelia and, when altered or ablated, leads to a number of diseases, including cystic fibrosis, congenital chloride diarrhea, deafness, and hypotension (78, ... ...

Abstract	Transepithelial Cl(-) and HCO(3)(-) transport is critically important for the function of all epithelia and, when altered or ablated, leads to a number of diseases, including cystic fibrosis, congenital chloride diarrhea, deafness, and hypotension (78, 111, 119, 126). HCO(3)(-) is the biological buffer that maintains acid-base balance, thereby preventing metabolic and respiratory acidosis (48). HCO(3)(-) also buffers the pH of the mucosal layers that line all epithelia, protecting them from injury (2). Being a chaotropic ion, HCO(3)(-) is essential for solubilization of ions and macromolecules such as mucins and digestive enzymes in secreted fluids. Most epithelia have a Cl(-)/HCO(3) exchange activity in the luminal membrane. The molecular nature of this activity remained a mystery for many years until the discovery of SLC26A3 and the realization that it is a member of a new family of Cl(-) and HCO(3)(-) transporters, the SLC26 family (73, 78). This review will highlight structural features, the functional diversity, and several regulatory aspects of the SLC26 transporters.
MeSH term(s)	Amino Acid Sequence ; Animals ; Anion Transport Proteins/chemistry ; Anion Transport Proteins/genetics ; Anion Transport Proteins/metabolism ; Antiporters/chemistry ; Antiporters/genetics ; Antiporters/metabolism ; Epithelial Cells/metabolism ; Evolution, Molecular ; Humans ; Molecular Sequence Data ; Multigene Family ; Protein Conformation
Chemical Substances	Anion Transport Proteins ; Antiporters
Language	English
Publishing date	2008-04
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2158667-6
ISSN	1548-9221 ; 1548-9213
ISSN (online)	1548-9221
ISSN	1548-9213
DOI	10.1152/physiol.00037.2007
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Article ; Online: S. aureus MscL is a pentamer in vivo but of variable stoichiometries in vitro: implications for detergent-solubilized membrane proteins.

Dorwart, Michael R / Wray, Robin / Brautigam, Chad A / Jiang, Youxing / Blount, Paul

PLoS biology

2010 Volume 8, Issue 12, Page(s) e1000555

Abstract: While the bacterial mechanosensitive channel of large conductance (MscL) is the best studied biological mechanosensor and serves as a paradigm for how a protein can sense and respond to membrane tension, the simple matter of its oligomeric state has led ... ...

Abstract	While the bacterial mechanosensitive channel of large conductance (MscL) is the best studied biological mechanosensor and serves as a paradigm for how a protein can sense and respond to membrane tension, the simple matter of its oligomeric state has led to debate, with models ranging from tetramers to hexamers. Indeed, two different oligomeric states of the bacterial mechanosensitive channel MscL have been resolved by X-ray crystallography: The M. tuberculosis channel (MtMscL) is a pentamer, while the S. aureus protein (SaMscL) forms a tetramer. Because several studies suggest that, like MtMscL, the E. coli MscL (EcoMscL) is a pentamer, we re-investigated the oligomeric state of SaMscL. To determine the structural organization of MscL in the cell membrane we developed a disulfide-trapping approach. Surprisingly, we found that virtually all SaMscL channels in vivo are pentameric, indicating this as the physiologically relevant and functional oligomeric state. Complementing our in vivo results, we purified SaMscL and assessed its oligomeric state using three independent approaches (sedimentation equilibrium centrifugation, crosslinking, and light scattering) and established that SaMscL is a pentamer when solubilized in Triton X-100 and C(8)E(5) detergents. However, performing similar experiments on SaMscL solubilized in LDAO, the detergent used in the crystallographic study, confirmed the tetrameric oligomerization resolved by X-ray crystallography. We further demonstrate that this stoichiometric shift is reversible by conventional detergent exchange experiments. Our results firmly establish the pentameric organization of SaMscL in vivo. Furthermore they demonstrate that detergents can alter the subunit stoichiometry of membrane protein complexes in vitro; thus, in vivo assays are necessary to firmly establish a membrane protein's true functionally relevant oligomeric state.
MeSH term(s)	Bacterial Proteins/chemistry ; Bacterial Proteins/metabolism ; Crystallography, X-Ray ; Detergents ; Membrane Proteins/chemistry ; Membrane Proteins/metabolism ; Protein Multimerization ; Solubility ; Staphylococcus aureus/chemistry ; Staphylococcus aureus/metabolism
Chemical Substances	Bacterial Proteins ; Detergents ; Membrane Proteins
Language	English
Publishing date	2010-12-07
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2126776-5
ISSN	1545-7885 ; 1544-9173
ISSN (online)	1545-7885
ISSN	1544-9173
DOI	10.1371/journal.pbio.1000555
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Article ; Online: SOAR and the polybasic STIM1 domains gate and regulate Orai channels.

Yuan, Joseph P / Zeng, Weizhong / Dorwart, Michael R / Choi, Young-Jin / Worley, Paul F / Muallem, Shmuel

Nature cell biology

2009 Volume 11, Issue 3, Page(s) 337–343

Abstract: Influx of Ca(2+) through store-operated Ca(2+) channels (SOCs) is a central component of receptor-evoked Ca(2+) signals. Orai channels are SOCs that are gated by STIM1, a Ca(2+) sensor located in the ER but how it gates and regulates the Orai channels is ...

Abstract	Influx of Ca(2+) through store-operated Ca(2+) channels (SOCs) is a central component of receptor-evoked Ca(2+) signals. Orai channels are SOCs that are gated by STIM1, a Ca(2+) sensor located in the ER but how it gates and regulates the Orai channels is unknown. Here, we report the molecular basis for gating of Orais by STIM1. All Orai channels are fully activated by the conserved STIM1 amino acid fragment 344-442, which we termed SOAR (the STIM1 Orai activating region). SOAR acts in combination with STIM1 (450-485) to regulate the strength of interaction with Orai1. Activation of Orai1 by SOAR recapitulates all the kinetic properties of Orai1 activation by STIM1. However, mutations of STIM1 within SOAR prevent activation of Orai1 but not co-clustering of STIM1 and Orai1 in response to Ca(2+) store depletion, indicating that STIM1-Orai1 co-clustering is not sufficient for Orai1 activation. An intact carboxy terminus alpha-helicial region of Orai is required for activation by SOAR. Deleting most of the Orai1 amino terminus impaired Orai1 activation by STIM1, but Orai1(Delta1-73) interacted with and was fully activated by SOAR. Accordingly, the characteristic inward rectification of Orai is mediated by an interaction between the polybasic STIM1 (672-685) and a Pro-rich region in the N terminus of Orai1. Hence, the essential properties of Orai1 function can be rationalized by interactions with discrete regions of STIM1.
MeSH term(s)	Amino Acid Motifs ; Calcium Channels/chemistry ; Calcium Channels/metabolism ; Cell Line ; Humans ; Ion Channel Gating ; Lysine/metabolism ; Membrane Proteins/chemistry ; Membrane Proteins/metabolism ; Mutation/genetics ; Neoplasm Proteins/chemistry ; Neoplasm Proteins/metabolism ; ORAI1 Protein ; Proline/metabolism ; Protein Binding ; Protein Structure, Tertiary ; Stromal Interaction Molecule 1 ; Structure-Activity Relationship
Chemical Substances	Calcium Channels ; Membrane Proteins ; Neoplasm Proteins ; ORAI1 Protein ; ORAI1 protein, human ; STIM1 protein, human ; Stromal Interaction Molecule 1 ; Proline (9DLQ4CIU6V) ; Lysine (K3Z4F929H6)
Language	English
Publishing date	2009-02-01
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1474722-4
ISSN	1476-4679 ; 1465-7392
ISSN (online)	1476-4679
ISSN	1465-7392
DOI	10.1038/ncb1842
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Zs.A 5169: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article: SLC26A9 is a Cl(-) channel regulated by the WNK kinases.

Dorwart, Michael R / Shcheynikov, Nikolay / Wang, Youxue / Stippec, Steve / Muallem, Shmuel

The Journal of physiology

2007 Volume 584, Issue Pt 1, Page(s) 333–345

Abstract: SLC26A9 is a member of the SLC26 family of anion transporters, which is expressed at high levels in airway and gastric surface epithelial cells. The transport properties and regulation of SLC26A9, and thus its physiological function, are not known. Here ... ...

Abstract	SLC26A9 is a member of the SLC26 family of anion transporters, which is expressed at high levels in airway and gastric surface epithelial cells. The transport properties and regulation of SLC26A9, and thus its physiological function, are not known. Here we report that SLC26A9 is a highly selective Cl(-) channel with minimal OH(-)/HCO(3)(-) permeability that is regulated by the WNK kinases. Expression in Xenopus oocytes and simultaneous measurement of membrane potential or current, intracellular pH (pH(i)) and intracellular Cl(-) (Cl(-)(i)) revealed that expression of SLC26A9 resulted in a large Cl(-) current. SLC26A9 displays a selectivity sequence of I(-) > Br(-) > NO(3)(-) > Cl(-) > Glu(-), but it conducts Br(-) > Cl(-) > I(-) > NO(3)(-) > Glu(-), with NO(3)(-) and I(-) inhibiting the Cl(-) conductance. Similarly, expression of SLC26A9 in HEK cells resulted in a large Cl(-) current. Although detectable, OH(-) and HCO(3)(-) fluxes in oocytes expressing SLC26A9 were very small. Moreover, HCO(3)(-) had no discernable effect on the Cl(-) current, the reversal potential in the presence or absence of Cl(-)(o) and, importantly, HCO(3)(-) had no effect on Cl(-) fluxes. These findings indicate that SLC26A9 is a Cl(-) channel with minimal OH(-)/HCO(3)(-) permeability. Co-expression of SLC26A9 with the WNK kinases WNK1, WNK3 or WNK4 inhibited SLC26A9 activity, and the inhibition was independent of WNK kinase activity. Immunolocalization in oocytes and cell surface biotinylation in HEK cells indicated that the WNK-mediated inhibition of SLC26A9 activity is caused by reduced SLC26A9 surface expression. Expression of SLC26A9 in the airway and the response of the WNKs to homeostatic stress raise the possibility that SLC26A9 serves to mediate the response of the airway to stress.
MeSH term(s)	Animals ; Antiporters/metabolism ; Bicarbonates/metabolism ; Cell Line ; Chlorides/metabolism ; Cystic Fibrosis/metabolism ; Epithelial Cells/metabolism ; Female ; Humans ; Protein Serine-Threonine Kinases/metabolism ; Stress, Physiological/metabolism ; Sulfate Transporters ; Xenopus
Chemical Substances	Antiporters ; Bicarbonates ; Chlorides ; SLC26A9 protein, human ; Sulfate Transporters ; Protein Serine-Threonine Kinases (EC 2.7.11.1)
Language	English
Publishing date	2007-08-02
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	3115-x
ISSN	1469-7793 ; 0022-3751
ISSN (online)	1469-7793
ISSN	0022-3751
DOI	10.1113/jphysiol.2007.135855
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Article ; Online: S. aureus MscL is a pentamer in vivo but of variable stoichiometries in vitro

Michael R Dorwart / Robin Wray / Chad A Brautigam / Youxing Jiang / Paul Blount

PLoS Biology, Vol 8, Iss 12, p e

implications for detergent-solubilized membrane proteins.

2010 Volume 1000555

Abstract	While the bacterial mechanosensitive channel of large conductance (MscL) is the best studied biological mechanosensor and serves as a paradigm for how a protein can sense and respond to membrane tension, the simple matter of its oligomeric state has led to debate, with models ranging from tetramers to hexamers. Indeed, two different oligomeric states of the bacterial mechanosensitive channel MscL have been resolved by X-ray crystallography: The M. tuberculosis channel (MtMscL) is a pentamer, while the S. aureus protein (SaMscL) forms a tetramer. Because several studies suggest that, like MtMscL, the E. coli MscL (EcoMscL) is a pentamer, we re-investigated the oligomeric state of SaMscL. To determine the structural organization of MscL in the cell membrane we developed a disulfide-trapping approach. Surprisingly, we found that virtually all SaMscL channels in vivo are pentameric, indicating this as the physiologically relevant and functional oligomeric state. Complementing our in vivo results, we purified SaMscL and assessed its oligomeric state using three independent approaches (sedimentation equilibrium centrifugation, crosslinking, and light scattering) and established that SaMscL is a pentamer when solubilized in Triton X-100 and C(8)E(5) detergents. However, performing similar experiments on SaMscL solubilized in LDAO, the detergent used in the crystallographic study, confirmed the tetrameric oligomerization resolved by X-ray crystallography. We further demonstrate that this stoichiometric shift is reversible by conventional detergent exchange experiments. Our results firmly establish the pentameric organization of SaMscL in vivo. Furthermore they demonstrate that detergents can alter the subunit stoichiometry of membrane protein complexes in vitro; thus, in vivo assays are necessary to firmly establish a membrane protein's true functionally relevant oligomeric state.
Keywords	Biology (General) ; QH301-705.5
Subject code	572
Language	English
Publishing date	2010-12-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
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Article: Congenital Chloride-losing Diarrhea Causing Mutations in the STAS Domain Result in Misfolding and Mistrafficking of SLC26A3

Dorwart, Michael R / Shcheynikov, Nikolay / Baker, Jennifer M.R / Forman-Kay, Julie D / Muallem, Shmuel / Thomas, Philip J

Journal of biological chemistry. 2008 Mar. 28, v. 283, no. 13

2008

Abstract: Congenital chloride-losing diarrhea (CLD) is a genetic disorder causing watery stool and dehydration. Mutations in SLC26A3 (solute carrier 26 family member 3), which functions as a coupled Cl⁻/[Formula: see text] exchanger, cause CLD. SLC26A3 is a ... ...

Abstract	Congenital chloride-losing diarrhea (CLD) is a genetic disorder causing watery stool and dehydration. Mutations in SLC26A3 (solute carrier 26 family member 3), which functions as a coupled Cl⁻/[Formula: see text] exchanger, cause CLD. SLC26A3 is a membrane protein predicted to contain 12 transmembrane-spanning α-helices and a C-terminal STAS (sulfate transporters and anti-sigma-factor) domain homologous to the bacterial anti-sigma-factor antagonists. The STAS domain is required for SLC26A3 Cl⁻/[Formula: see text] exchange function and for the activation of cystic fibrosis transmembrane conductance regulator by SLC26A3. Here we investigate the molecular mechanism(s) by which four CLD-causing mutations (ΔY526/7, I544N, I675/6ins, and G702Tins) in the STAS domain lead to disease. In a heterologous mammalian expression system biochemical, immunohistochemical, and ion transport experiments suggest that the four CLD mutations cause SLC26A3 transporter misfolding and/or mistrafficking. Expression studies with the isolated STAS domain suggest that the I675/6ins and G702Tins mutations disrupt the STAS domain directly, whereas limited proteolysis experiments suggest that the ΔY526/7 and I544N mutations affect a later step in the folding and/or trafficking pathway. The data suggest that these CLD-causing mutations cause disease by at least two distinct molecular mechanisms, both ultimately leading to loss of functional protein at the plasma membrane.
Language	English
Dates of publication	2008-0328
Size	p. 8711-8722.
Publishing place	American Society for Biochemistry and Molecular Biology
Document type	Article
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
Database	NAL-Catalogue (AGRICOLA)

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Article: Congenital chloride-losing diarrhea causing mutations in the STAS domain result in misfolding and mistrafficking of SLC26A3.

Dorwart, Michael R / Shcheynikov, Nikolay / Baker, Jennifer M R / Forman-Kay, Julie D / Muallem, Shmuel / Thomas, Philip J

The Journal of biological chemistry

2008 Volume 283, Issue 13, Page(s) 8711–8722

Abstract: Congenital chloride-losing diarrhea (CLD) is a genetic disorder causing watery stool and dehydration. Mutations in SLC26A3 (solute carrier 26 family member 3), which functions as a coupled Cl(-)/HCO(3)(-) exchanger, cause CLD. SLC26A3 is a membrane ... ...

Abstract	Congenital chloride-losing diarrhea (CLD) is a genetic disorder causing watery stool and dehydration. Mutations in SLC26A3 (solute carrier 26 family member 3), which functions as a coupled Cl(-)/HCO(3)(-) exchanger, cause CLD. SLC26A3 is a membrane protein predicted to contain 12 transmembrane-spanning alpha-helices and a C-terminal STAS (sulfate transporters and anti-sigma-factor) domain homologous to the bacterial anti-sigma-factor antagonists. The STAS domain is required for SLC26A3 Cl(-)/HCO(3)(-) exchange function and for the activation of cystic fibrosis transmembrane conductance regulator by SLC26A3. Here we investigate the molecular mechanism(s) by which four CLD-causing mutations (DeltaY526/7, I544N, I675/6ins, and G702Tins) in the STAS domain lead to disease. In a heterologous mammalian expression system biochemical, immunohistochemical, and ion transport experiments suggest that the four CLD mutations cause SLC26A3 transporter misfolding and/or mistrafficking. Expression studies with the isolated STAS domain suggest that the I675/6ins and G702Tins mutations disrupt the STAS domain directly, whereas limited proteolysis experiments suggest that the DeltaY526/7 and I544N mutations affect a later step in the folding and/or trafficking pathway. The data suggest that these CLD-causing mutations cause disease by at least two distinct molecular mechanisms, both ultimately leading to loss of functional protein at the plasma membrane.
MeSH term(s)	Amino Acid Motifs ; Animals ; Antiporters/chemistry ; Antiporters/genetics ; Antiporters/metabolism ; Cell Line ; Chloride-Bicarbonate Antiporters ; Chlorides/metabolism ; Chlorocebus aethiops ; Circular Dichroism ; Conserved Sequence ; Diarrhea/congenital ; Diarrhea/genetics ; Diarrhea/metabolism ; Humans ; Molecular Sequence Data ; Mutation/genetics ; Protein Transport ; Sequence Alignment ; Sulfate Transporters ; Temperature
Chemical Substances	Antiporters ; Chloride-Bicarbonate Antiporters ; Chlorides ; SLC26A3 protein, human ; Sulfate Transporters
Language	English
Publishing date	2008-01-23
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2997-x
ISSN	1083-351X ; 0021-9258
ISSN (online)	1083-351X
ISSN	0021-9258
DOI	10.1074/jbc.M704328200
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Article: Regulatory interaction between CFTR and the SLC26 transporters.

Shcheynikov, Nikolay / Ko, Shigeru B H / Zeng, Weizhong / Choi, Joo Young / Dorwart, Michael R / Thomas, Philip J / Muallem, Shmuel

Novartis Foundation symposium

2006 Volume 273, Page(s) 177–86; discussion 186–92, 261–4

Abstract: ... of CFTR R domain, the R domain binds to the SLC26 transporter STAS domain. Interaction of the R and STAS ...

Abstract	Most epithelia that express CFTR secrete fluid rich in HCO3- and poor in Cl- that is generated by a CFTR-dependent Cl- absorption and HCO3- secretion process that when aberrant leads to human diseases such as cystic fibrosis and congenital chloride diarrhoea. Epithelial Cl- absorption and HCO3- secretion require expression of CFTR and other Cl- and HCO3- transporters in the luminal membrane of the secreting cells. Recent advances in understanding this critical epithelial function revealed that the luminal Cl- and HCO3- transporters are members of the SLC26 family. Characterization of several members of the family reveals that all characterized thus far are electrogenic with an isoform specific Cl-/HCO3- transport stoichiometry. In vivo these transporters exist in a transporting complex with CFTR. The SLC26 transporters and CFTR are recruited to the complex by binding to scaffolds containing PDZ domains. Upon stimulation and PKA-dependent phosphorylation of CFTR R domain, the R domain binds to the SLC26 transporter STAS domain. Interaction of the R and STAS domains results in a marked and mutual activation of CFTR and the SLC26 transporters. The significance of this mode of regulation to epithelial Cl- absorption and HCO3- secretion is obvious.
MeSH term(s)	Animals ; Anion Transport Proteins/metabolism ; Bicarbonates/metabolism ; Chlorides/metabolism ; Cystic Fibrosis Transmembrane Conductance Regulator/chemistry ; Cystic Fibrosis Transmembrane Conductance Regulator/metabolism ; Humans ; Models, Biological ; Oocytes ; Protein Binding ; Protein Structure, Tertiary ; Xenopus
Chemical Substances	Anion Transport Proteins ; Bicarbonates ; Chlorides ; Cystic Fibrosis Transmembrane Conductance Regulator (126880-72-6)
Language	English
Publishing date	2006
Publishing country	England
Document type	Journal Article
ISSN	1528-2511
ISSN	1528-2511
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Article: Slc26a6 regulates CFTR activity in vivo to determine pancreatic duct HCO3- secretion: relevance to cystic fibrosis.

Wang, Youxue / Soyombo, Abigail A / Shcheynikov, Nikolay / Zeng, Weizhong / Dorwart, Michael / Marino, Christopher R / Thomas, Philip J / Muallem, Shmuel

The EMBO journal

2006 Volume 25, Issue 21, Page(s) 5049–5057

Abstract: Fluid and HCO(3)(-) secretion are vital functions of the pancreatic duct and other secretory epithelia. CFTR and Cl(-)/HCO(3)(-) exchange activity at the luminal membrane are required for these functions. The molecular identity of the Cl(-)/HCO(3)(-) ... ...

Abstract	Fluid and HCO(3)(-) secretion are vital functions of the pancreatic duct and other secretory epithelia. CFTR and Cl(-)/HCO(3)(-) exchange activity at the luminal membrane are required for these functions. The molecular identity of the Cl(-)/HCO(3)(-) exchangers and their relationship with CFTR in determining fluid and HCO(3)(-) secretion are not known. We show here that the Cl(-)/HCO(3)(-) exchanger slc26a6 controls CFTR activity and ductal fluid and HCO(3)(-) secretion. Unexpectedly, deletion of slc26a6 in mice and measurement of fluid and HCO(3)(-) secretion into sealed intralobular pancreatic ducts revealed that deletion of slc26a6 enhanced spontaneous and decreased stimulated secretion. Remarkably, inhibition of CFTR activity with CFTR(inh)-172, knock-down of CFTR by siRNA and measurement of CFTR current in WT and slc26a6(-/-) duct cells revealed that deletion of slc26a6 resulted in dis-regulation of CFTR activity by removal of tonic inhibition of CFTR by slc26a6. These findings reveal the intricate regulation of CFTR activity by slc26a6 in both the resting and stimulated states and the essential role of slc26a6 in pancreatic HCO(3)(-) secretion in vivo.
MeSH term(s)	Animals ; Antiporters/deficiency ; Antiporters/metabolism ; Bicarbonates/metabolism ; Chlorides/metabolism ; Cystic Fibrosis/genetics ; Cystic Fibrosis/metabolism ; Cystic Fibrosis Transmembrane Conductance Regulator/metabolism ; Gene Expression Regulation/genetics ; Humans ; Mice ; Mice, Knockout ; Pancreatic Ducts/secretion ; Pancreatic Juice/metabolism ; RNA, Small Interfering/genetics ; RNA, Small Interfering/metabolism ; RNA, Small Interfering/pharmacology
Chemical Substances	Antiporters ; Bicarbonates ; Chlorides ; RNA, Small Interfering ; Slc26a6 protein, mouse ; Cystic Fibrosis Transmembrane Conductance Regulator (126880-72-6)
Language	English
Publishing date	2006-11-01
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	586044-1
ISSN	1460-2075 ; 0261-4189
ISSN (online)	1460-2075
ISSN	0261-4189
DOI	10.1038/sj.emboj.7601387
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