cftr channel voltage gated

 

Voltage-gated chloride channels display a variety of important physiological and cellular roles that include regulation of pH, volume homeostasis, organic solute transport, cell migration, cell proliferation and differentiation. The deeper part of a river or harbor, especially a deep navigable passage. 295, No. CFTR functions as a phosphorylation and ATP-gated anion channel, increasing the conductance for certain anions (e.g. Schematic view of the CFTR permeation pathway. COVID-19 is an emerging, rapidly evolving situation. We discuss these special properties of CFTR in the context of its evolutionary history as an ABC transporter. 885, 30 September 2020 | Frontiers in Pharmacology, Vol. In fact, NPPB also slows hydrolytic channel closing rate by slowing the ATP hydrolysis step [FIGURE 2E, step O1→O2 (59)]. These results could indeed reflect some intrinsic AK activity for CFTR, but they could also be explained by the activity of an endogenous AK associated with HeLa cell membranes; reduced labeling of the CFTR mutants could then reflect impaired binding to CFTR’s site 2 of the labeled β-32P-2-N3-ADP produced by the associated AK. Although GLPG1837 was found to be more effective on G551D and G1349D CFTR than VX-770, the mechanisms of action of the two drugs seem similar; indeed, GLPG1837 also potentiates both WT CFTR and nonhydrolytic mutants and acts by speeding channel opening and by slowing both hydrolytic and nonhydrolytic pore closure (265). Such an arrangement is sterically incompatible both with a transition to an outward-facing TMD conformation and with NBD dimerization, explaining the inhibitory effect of the unphosphorylated R domain on channel gating. Second, CFTR is the only ligand … The gene that encodes the CFTR protein, which is also called CFTR, is located on chromosome 7. Finally, because phosphorylation little affected [α32P]8-azido-ATP labeling of NBD1, or of NBD2, in the presence of Vi, phosphorylation was suggested to modulate coupling between ATP hydrolysis cycles and gating movements, similar to an automobile clutch (14). See this image and copyright information in PMC. Consistent with its extremely hydrophobic nature (logP, ~6.3) the binding site for VX-770 is believed to be located in the membrane-spanning region of CFTR (112). CFTR channel is driven by binding of ATP to its cytosolic NBDs (9). A … School University of Guelph; Course Title CHEM 1040; Type. Because membrane-associated endogenous phosphatase activity is independent of the amount of applied kinase, at steady state the R domain is expected to become phosphorylated to a higher stoichiometry when the applied PKA concentration is higher. In the lungs, this open channel transports ciº out of the epithelial cells and into the airways. Interestingly, CFTR was found to mediate efflux of large organic anions, such as gluconate or lactobionate (142), or of reduced and oxidized glutathione (143) from the cytosolic solution but not influx of the same anions from the extracellular solution; this asymmetry was disrupted when ATP hydrolysis was prevented, using PPi or AMPPNP. Of note, the position corresponding to R352 in human CFTR, mutations at which appear to differentially affect conductance in the O1 and O2 state (113), is positioned at a constriction of the permeation pathway in Sav1866-based homology models (52, 163), but in the wider intracellular vestibule in the outward-facing zebrafish CFTR structure (274) and in models based on McjD (52). 2020 Jul 29;21(1):200. doi: 10.1186/s12931-020-01442-9. 12, Copyright © 2021 the American Physiological Society, Ai T, Bompadre SG, Sohma Y, Wang X, Li M, Hwang TC, Direct effects of 9-anthracene compounds on cystic fibrosis transmembrane conductance regulator gating, Ai T, Bompadre SG, Wang X, Hu S, Li M, Hwang TC, Capsaicin potentiates wild-type and mutant cystic fibrosis transmembrane conductance regulator chloride-channel currents, Aleksandrov AA, Aleksandrov L, Riordan JR, Nucleoside triphosphate pentose ring impact on CFTR gating and hydrolysis, Aleksandrov AA, Chang X, Aleksandrov L, Riordan JR, The non-hydrolytic pathway of cystic fibrosis transmembrane conductance regulator ion channel gating, Relationship between nucleotide binding and ion channel gating in cystic fibrosis transmembrane conductance regulator, Regulation of CFTR ion channel gating by MgATP, Aleksandrov L, Aleksandrov AA, Chang XB, Riordan JR, The First Nucleotide Binding Domain of Cystic Fibrosis Transmembrane Conductance Regulator Is a Site of Stable Nucleotide Interaction, whereas the Second Is a Site of Rapid Turnover, Aller SG, Yu J, Ward A, Weng Y, Chittaboina S, Zhuo R, Harrell PM, Trinh YT, Zhang Q, Urbatsch IL, Chang G, Structure of P-glycoprotein reveals a molecular basis for poly-specific drug binding, Anderson MP, Berger HA, Rich DP, Gregory RJ, Smith AE, Welsh MJ, Nucleoside triphosphates are required to open the CFTR chloride channel, How to turn the reaction coordinate into time, Dual roles of the sixth transmembrane segment of the CFTR chloride channel in gating and permeation, Structural basis for the channel function of a degraded ABC transporter, CFTR (ABCC7), Bársony O, Szalóki G, Türk D, Tarapcsák S, Gutay-Tóth Z, Bacsó Z, Holb IJ, Székvölgyi L, Szabó G, Csanády L, Szakács G, Goda K, A single active catalytic site is sufficient to promote transport in P-glycoprotein, Prolonged nonhydrolytic interaction of nucleotide with CFTR’s NH2-terminal nucleotide binding domain and its role in channel gating, Baukrowitz T, Hwang TC, Nairn AC, Gadsby DC, Coupling of CFTR Cl- channel gating to an ATP hydrolysis cycle, Bear CE, Li CH, Kartner N, Bridges RJ, Jensen TJ, Ramjeesingh M, Riordan JR, Purification and functional reconstitution of the cystic fibrosis transmembrane conductance regulator (CFTR), Conformational changes in a pore-lining helix coupled to cystic fibrosis transmembrane conductance regulator channel gating, Becq F, Verrier B, Chang XB, Riordan JR, Hanrahan JW, cAMP- and Ca2+-independent activation of cystic fibrosis transmembrane conductance regulator channels by phenylimidazothiazole drugs, Berger AL, Randak CO, Ostedgaard LS, Karp PH, Vermeer DW, Welsh MJ, Curcumin stimulates cystic fibrosis transmembrane conductance regulator Cl- channel activity, Berger HA, Anderson MP, Gregory RJ, Thompson S, Howard PW, Maurer RA, Mulligan R, Smith AE, Welsh MJ, Identification and regulation of the cystic fibrosis transmembrane conductance regulator-generated chloride channel, Regulation of the cystic fibrosis transmembrane conductance regulator Cl- channel by specific protein kinases and protein phosphatases, Billet A, Jia Y, Jensen T, Riordan JR, Hanrahan JW, Regulation of the cystic fibrosis transmembrane conductance regulator anion channel by tyrosine phosphorylation, Billet A, Jia Y, Jensen TJ, Hou YX, Chang XB, Riordan JR, Hanrahan JW, Potential sites of CFTR activation by tyrosine kinases, Bompadre SG, Ai T, Cho JH, Wang X, Sohma Y, Li M, Hwang TC, CFTR gating I: Characterization of the ATP-dependent gating of a phosphorylation-independent CFTR channel (DeltaR-CFTR), Bompadre SG, Cho JH, Wang X, Zou X, Sohma Y, Li M, Hwang TC, CFTR gating II: Effects of nucleotide binding on the stability of open states, G551D and G1349D, two CF-associated mutations in the signature sequences of CFTR, exhibit distinct gating defects, Regulation of airway surface liquid volume by human airway epithelia, Boucher RC, Stutts MJ, Knowles MR, Cantley L, Gatzy JT, Na+ transport in cystic fibrosis respiratory epithelia. 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