scholarly journals Cystic Fibrosis Transmembrane Conductance Regulator Facilitates ATP Release by Stimulating a Separate ATP Release Channel for Autocrine Control of Cell Volume Regulation

2000 ◽  
Vol 276 (9) ◽  
pp. 6621-6630 ◽  
Author(s):  
Gavin M. Braunstein ◽  
Richard M. Roman ◽  
John P. Clancy ◽  
Brian A. Kudlow ◽  
Amanda L. Taylor ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Cell Volume ◽  
Volume Regulation ◽  
Cell Volume Regulation ◽  
Atp Release ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Release Channel ◽  
Autocrine Control ◽  
Cystic Fibrosis Transmembrane

Cellular ATP release by the cystic fibrosis transmembrane conductance regulator

1996 ◽  
Vol 270 (2) ◽  
pp. C538-C545 ◽  
Author(s):  
A. G. Prat ◽  
I. L. Reisin ◽  
D. A. Ausiello ◽  
H. F. Cantiello
Keyword(s):  
Cystic Fibrosis ◽  
Atp Release ◽  
Functional Expression ◽  
Transmembrane Conductance Regulator ◽  
O2 Consumption ◽  
Transmembrane Conductance ◽  
Intracellular Atp ◽  
Physiological Relevance ◽  
Before And After ◽  
Cystic Fibrosis Transmembrane

Recent studies from our laboratory indicate that members of the ATP-binding cassette (ABC) family of transporters, including P-glycoprotein and cystic fibrosis transmembrane conductance regulator (CFTR), are ATP-permeable channels. The physiological relevance of this novel transport mechanism is largely unknown. In the present study, intra- and extracellular ATP content, cellular ATP release, and O2 consumption before and after adenosine 3',5'-cyclic monophosphate (cAMP) stimulation were determined to assess the role of CFTR in the transport of ATP under physiological conditions. The functional expression of CFTR by the stable transfection of mouse mammary carcinoma cells, C1271, with human epithelial CFTR cDNA resulted in a stimulated metabolism, since both basal and cAMP-inducible O2 consumption were increased compared with mock-transfected cells. The stimulated (but not basal) O2 consumption was inhibited by diphenyl-2-carboxylic acid (DPC), a known inhibitor of CFTR. CFTR expression was also associated with the cAMP-activated and DPC-inhibitable release of intracellular ATP. The recovery of intracellular ATP from complete depletion after metabolic poisoning was also assessed under basal and cAMP-stimulated conditions. The various maneuvers indicate that CFTR may be an important contributor to the release of cellular ATP, which may help modify signal transduction pathways associated with secretory Cl- movement or other related processes. Changes in the CFTR-mediated delivery of nucleotides to the extracellular compartment may play an important role in the onset and reversal of the cystic fibrosis phenotype.

Modelling Cl − homeostasis and volume regulation of the cardiac cell

2006 ◽  
Vol 364 (1842) ◽  
pp. 1245-1265 ◽  
Author(s):  
K Terashima ◽  
A Takeuchi ◽  
N Sarai ◽  
S Matsuoka ◽  
E.B Shim ◽  
...  
Keyword(s):  
Volume Regulation ◽  
Cell Model ◽  
Cell Volume Regulation ◽  
Transmembrane Conductance Regulator ◽  
Adrenergic Stimulation ◽  
Transmembrane Conductance ◽  
Model Study ◽  
Negative Membrane Potential ◽  
A Cell ◽  
Cystic Fibrosis Transmembrane

We aim at introducing a Cl − homeostasis to the cardiac ventricular cell model (Kyoto model), which includes the sarcomere shortening and the mitochondria oxidative phosphorylation. First, we examined mechanisms underlying the cell volume regulation in a simple model consisting of Na + /K + pump, Na + –K + –2Cl − cotransporter 1 (NKCC1), cystic fibrosis transmembrane conductance regulator, volume-regulated Cl − channel and background Na + , K + and Cl − currents. The high intracellular Cl − concentration of approximately 30 mM was achieved by the balance between the secondary active transport via NKCC1 and passive currents. Simulating responses to Na + /K + pump inhibition revealed the essential role of Na + /K + pump in maintaining the cellular osmolarity through creating the negative membrane potential, which extrudes Cl − from a cell, confirming the previous model study in the skeletal muscle. In addition, this model well reproduced the experimental data such as the responses to hypotonic shock in the presence or absence of β-adrenergic stimulation. Finally, the volume regulation via Cl − homeostasis was successfully incorporated to the Kyoto model. The steady state was well established in the comprehensive cell model in respect to both the intracellular ion concentrations and the shape of the action potential, which are all in the physiological range. The source code of the model, which can reproduce every result, is available from http://www.sim-bio.org/ .

scholarly journals Cystic Fibrosis Transmembrane Conductance Regulator–associated ATP Release Is Controlled by a Chloride Sensor

1998 ◽  
Vol 143 (3) ◽  
pp. 645-657 ◽  
Author(s):  
Qinshi Jiang ◽  
Daniel Mak ◽  
Sreenivas Devidas ◽  
Erik M. Schwiebert ◽  
Alvina Bragin ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Molecular Mechanisms ◽  
Atp Release ◽  
Chloride Concentration ◽  
Transmembrane Conductance Regulator ◽  
Transmembrane Conductance ◽  
Channel Pore ◽  
Cystic Fibrosis Transmembrane ◽  
Atp Efflux ◽  
Cl Conductance

The cystic fibrosis transmembrane conductance regulator (CFTR) is a chloride channel that is defective in cystic fibrosis, and has also been closely associated with ATP permeability in cells. Using a Xenopus oocyte cRNA expression system, we have evaluated the molecular mechanisms that control CFTR-modulated ATP release. CFTR-modulated ATP release was dependent on both cAMP activation and a gradient change in the extracellular chloride concentration. Activation of ATP release occurred within a narrow concentration range of external Cl− that was similar to that reported in airway surface fluid. Mutagenesis of CFTR demonstrated that Cl− conductance and ATP release regulatory properties could be dissociated to different regions of the CFTR protein. Despite the lack of a need for Cl− conductance through CFTR to modulate ATP release, alterations in channel pore residues R347 and R334 caused changes in the relative ability of different halides to activate ATP efflux (wtCFTR, Cl >> Br; R347P, Cl >> Br; R347E, Br >> Cl; R334W, Cl = Br). We hypothesize that residues R347 and R334 may contribute a Cl− binding site within the CFTR channel pore that is necessary for activation of ATP efflux in response to increases of extracellular Cl−. In summary, these findings suggest a novel chloride sensor mechanism by which CFTR is capable of responding to changes in the extracellular chloride concentration by modulating the activity of an unidentified ATP efflux pathway. This pathway may play an important role in maintaining fluid and electrolyte balance in the airway through purinergic regulation of epithelial cells. Insight into these molecular mechanisms enhances our understanding of pathogenesis in the cystic fibrosis lung.

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