2,3-butanedione monoxime affects cystic fibrosis transmembrane conductance regulator channel function through phosphorylation-dependent and phosphorylation-independent mechanisms: the role of bilayer material properties.

2,3-butanedione monoxime affects cystic fibrosis transmembrane conductance regulator channel function through phosphorylation-dependent and phosphorylation-independent mechanisms: the role of bilayer material properties. Research Abstract Details 

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2,3-butanedione monoxime affects cystic fibrosis transmembrane conductance regulator channel function through phosphorylation-dependent and phosphorylation-independent mechanisms: the role of bilayer material properties. Abstract Text:

Pablo Artigas,Subhi J Al'aref,E Ashley Hobart, ,Masayuki Sakaguchi,Samuel Straw,Olaf S Andersen,

2,3-Butanedione monoxime (BDM) is widely believed to act as a chemical phosphatase. We therefore examined the effects of BDM on the cystic fibrosis transmembrane regulator (CFTR) Cl(-) channel, which is regulated by phosphorylation in a complex manner. In guinea pig ventricular myocytes, forskolin-activated whole-cell CFTR currents responded biphasically to external 20 mM BDM: a rapid approximately 2-fold current activation was followed by a slower (tau approximately 20 s) inhibition (to approximately 20% of control). The inhibitory response was abolished by intracellular dialysis with the phosphatase inhibitor microcystin, suggesting involvement of endogenous phosphatases. The BDM-induced activation was studied further in Xenopus laevis oocytes expressing human epithelial CFTR. The concentration for half-maximal BDM activation (K(0.5)) was state-dependent, approximately 2 mM for highly and approximately 20 mM for partially phosphorylated channels, suggesting a modulated receptor mechanism. Because BDM modulates many different membrane proteins with similar K(0.5) values, we tested whether BDM could alter protein function by altering lipid bilayer properties rather than by direct BDM-protein interactions. Using gramicidin channels of different lengths (different channel-bilayer hydrophobic mismatch) as reporters of bilayer stiffness, we found that BDM increases channel appearance rates and lifetimes (reduces bilayer stiffness). At 20 mM BDM, the appearance rates increase approximately 4-fold (for the longer, 15 residues/monomer, channels) to approximately 10-fold (for the shorter, 13 residues/monomer channels); the lifetimes increase approximately 50% independently of channel length. BDM thus reduces the energetic cost of bilayer deformation, an effect that may underlie the effects of BDM on CFTR and other membrane proteins; the state-dependent changes in K(0.5) are consistent with such a bilayer-mediated mechanism.

2,3-butanedione monoxime affects cystic fibrosis transmembrane conductance regulator channel function through phosphorylation-dependent and phosphorylation-independent mechanisms: the role of bilayer material properties. Publishing Authors By Initials

P Artigas,SJ Al'aref,EA Hobart,LF ,M Sakaguchi,S Straw,OS Andersen,

For similar animals: chordata: vertebrates: amphibia: anura: pipidae: xenopus: xenopus laevis research abstracts see: animals: chordata: vertebrates: amphibia: anura: pipidae: xenopus: xenopus laevis research

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2,3-butanedione monoxime affects cystic fibrosis transmembrane conductance regulator channel function through phosphorylation-dependent and phosphorylation-independent mechanisms: the role of bilayer material properties. Journal Published:

PUBLICATION TYPE: Research Support, Non-U.S. Gov

Journal: Molecular pharmacology

VOLUME: 70

Page Numbers: 2015-26

Journal Abbreviation: Mol. Pharmacol.

ISSN: 0026-895X

DAY: 11

MONTH: 09

YEAR: 2006

2,3-butanedione monoxime affects cystic fibrosis transmembrane conductance regulator channel function through phosphorylation-dependent and phosphorylation-independent mechanisms: the role of bilayer material properties. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 35623

2,3-butanedione monoxime affects cystic fibrosis transmembrane conductance regulator channel function through phosphorylation-dependent and phosphorylation-independent mechanisms: the role of bilayer material properties. Keywords Mesh Terms:

KEYWORDS: Xenopus laevis

MESH TERMS: metabolism

Chemical & Substance for Abstract: 2,3-butanedione monoxime affects cystic fibrosis transmembrane conductance regulator channel function through phosphorylation-dependent and phosphorylation-independent mechanisms: the role of bilayer material properties. Information

Substance Name: diacetylmonoxime

Registry Number: 57-71-6

Grant and Affiliation Information for 2,3-butanedione monoxime affects cystic fibrosis transmembrane conductance regulator channel function through phosphorylation-dependent and phosphorylation-independent mechanisms: the role of bilayer material properties.

AFFILIATION: Laboratory of Cardiac/Membrane Physiology, The Rockefeller University, 1230 York Ave., New York, NY 10021, USA. artigas@rockefeller.edu

Country: United States

AGENCY: United States NHLBI

GRANT: HL36783

ACRONYM: HL

MEDLINETA: Mol Pharmacol

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