Regulation of CFTR chloride channel macroscopic conductance by extracellular bicarbonate

Man Song Li, Ryan G. Holstead, Wuyang Wang, Paul Linsdell

Research output: Contribution to journalArticlepeer-review

15 Citations (Scopus)

Abstract

The CFTR contributes to Cl- and HCO3- transport across epithelial cell apical membranes. The extracellular face of CFTR is exposed to varying concentrations of Cl- and HCO 3- in epithelial tissues, and there is evidence that CFTR is sensitive to changes in extracellular anion concentrations. Here we present functional evidence that extracellular Cl- and HCO3 - regulate anion conduction in open CFTR channels. Using cell-attached and inside-out patch-clamp recordings from constitutively active mutant E1371Q-CFTR channels, we show that voltage-dependent inhibition of CFTR currents in intact cells is significantly stronger when the extracellular solution contains HCO3- than when it contains Cl -. This difference appears to reflect differences in the ability of extracellular HCO3- and Cl- to interact with and repel intracellular blocking anions from the pore. Strong block by endogenous cytosolic anions leading to reduced CFTR channel currents in intact cells occurs at physiologically relevant HCO3- concentrations and membrane potentials and can result in up to ∼50% inhibition of current amplitude. We propose that channel block by cytosolic anions is a previously unrecognized, physiologically relevant mechanism of channel regulation that confers on CFTR channels sensitivity to different anions in the extracellular fluid. We further suggest that this anion sensitivity represents a feedback mechanism by which CFTR-dependent anion secretion could be regulated by the composition of the secretions themselves. Implications for the mechanism and regulation of CFTR-dependent secretion in epithelial tissues are discussed.

Original languageEnglish
Pages (from-to)C65-C74
JournalAmerican Journal of Physiology - Cell Physiology
Volume300
Issue number1
DOIs
Publication statusPublished - Jan 2011

ASJC Scopus Subject Areas

  • Physiology
  • Cell Biology

PubMed: MeSH publication types

  • Journal Article
  • Research Support, Non-U.S. Gov't

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