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1.
Handb Clin Neurol ; 121: 1277-93, 2014.
Article in English | MEDLINE | ID: mdl-24365419

ABSTRACT

In the past decade, substantial improvements in patient and graft survival for pancreas and small bowel transplants have been achieved. Despite this progress, many patients still develop neurologic complications in the course of their illness. Small bowel transplants produce more neurologic complications because of the complex metabolic environment in which the procedure is performed and because of the intense immune suppression necessitated by the greater immunogenicity of the intestinal mucosa. Pancreas transplants stabilize and/or improve the signs and symptoms of diabetic neuropathy over time. Because transplantation of the pancreas is often coupled with a kidney transplant and small intestine with liver, neurologic complications in these patients sometimes reflect problems involving the organ partner or both organs. The spectrum of neurologic complications for pancreas and small bowel transplant recipients is similar to other organ transplants but their frequency varies depending on the type of transplant performed.


Subject(s)
Intestine, Small/transplantation , Nervous System Diseases/etiology , Organ Transplantation/adverse effects , Pancreas Transplantation/adverse effects , Graft Rejection/epidemiology , Humans , Nervous System Diseases/epidemiology , Nervous System Diseases/therapy , Perioperative Period , Postoperative Complications/epidemiology , Postoperative Complications/therapy , Postoperative Period
4.
EMBO J ; 25(21): 5049-57, 2006 Nov 01.
Article in English | MEDLINE | ID: mdl-17053783

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.


Subject(s)
Antiporters/metabolism , Bicarbonates/metabolism , Cystic Fibrosis Transmembrane Conductance Regulator/metabolism , Cystic Fibrosis/metabolism , Pancreatic Ducts/metabolism , Animals , Antiporters/deficiency , Chlorides/metabolism , Cystic Fibrosis/genetics , Gene Expression Regulation/genetics , Humans , Mice , Mice, Knockout , Pancreatic Juice/metabolism , RNA, Small Interfering/genetics , RNA, Small Interfering/metabolism , RNA, Small Interfering/pharmacology , Sulfate Transporters
5.
J Cyst Fibros ; 3 Suppl 2: 73-7, 2004 Aug.
Article in English | MEDLINE | ID: mdl-15463932

ABSTRACT

Detection of cystic fibrosis transmembrane conductance regulator (CFTR) protein is usually a difficult task to accomplish due to the low levels of expression and high turnover that this membrane protein is submitted to in the cell. Common biochemical methods can be used for the detection of CFTR but several critical points must be taken into account. The scope of this article is to outline biochemical methods commonly used to assess CFTR expression, processing and membrane localization.


Subject(s)
Cell Membrane/metabolism , Cystic Fibrosis Transmembrane Conductance Regulator/biosynthesis , Cystic Fibrosis Transmembrane Conductance Regulator/isolation & purification , Genetic Techniques , Immunologic Techniques , Biotinylation , Cell Membrane/immunology , Glycosylation , Humans
6.
J Biol Chem ; 277(32): 28948-58, 2002 Aug 09.
Article in English | MEDLINE | ID: mdl-12039948

ABSTRACT

The cystic fibrosis transmembrane conductance regulator (CFTR) is a cAMP-regulated chloride channel whose phosphorylation regulates both channel gating and its trafficking at the plasma membrane. Cysteine string proteins (Csps) are J-domain-containing, membrane-associated proteins that have been functionally implicated in regulated exocytosis. Therefore, we evaluated the possibility that Csp is involved in regulated CFTR trafficking. We found Csp expressed in mammalian epithelial cell lines, several of which express CFTR. In Calu-3 airway cells, immunofluorescence colocalized Csp with calnexin in the endoplasmic reticulum and with CFTR at the apical membrane domain. CFTR coprecipitated with Csp from Calu-3 cell lysates. Csp associated with both core-glycosylated immature and fully glycosylated mature CFTRs (bands B and C); however, in relation to the endogenous levels of the B and C bands expressed in Calu-3 cells, the Csp interaction with band B predominated. In vitro protein binding assays detected physical interactions of both mammalian Csp isoforms with the CFTR R-domain and the N terminus, having submicromolar affinities. In Xenopus oocytes expressing CFTR, Csp overexpression decreased the chloride current and membrane capacitance increases evoked by cAMP stimulation and decreased the levels of CFTR protein detected by immunoblot. In mammalian cells, the steady-state expression of CFTR band C was eliminated, and pulse-chase studies showed that Csp coexpression blocked the conversion of immature to mature CFTR and stabilized band B. These results demonstrate a primary role for Csp in CFTR protein maturation. The physical interaction of this Hsc70-binding protein with immature CFTR, its localization in the endoplasmic reticulum, and the decrease in production of mature CFTR observed during Csp overexpression reflect a role for Csp in CFTR biogenesis. The documented role of Csp in regulated exocytosis, its interaction with mature CFTR, and its coexpression with CFTR at the apical membrane domain of epithelial cells may reflect also a role for Csp in regulated CFTR trafficking at the plasma membrane.


Subject(s)
Cystic Fibrosis Transmembrane Conductance Regulator/metabolism , Membrane Proteins/metabolism , Animals , Binding, Competitive , Blotting, Western , Cell Line , Cell Membrane/metabolism , Cells, Cultured , Cyclic AMP/metabolism , Dose-Response Relationship, Drug , Endoplasmic Reticulum/metabolism , Exocytosis , Fluorescent Antibody Technique , Glycosylation , HSP40 Heat-Shock Proteins , Humans , Immunoblotting , Microscopy, Fluorescence , Precipitin Tests , Protein Binding , Protein Isoforms , Protein Structure, Tertiary , Reverse Transcriptase Polymerase Chain Reaction , Time Factors , Transfection , Xenopus
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