title: Direct block of the cystic fibrosis transmembrane conductance regulator Cl(-) channel by butyrate and phenylbutyrate.
abstract: Chloride permeation through the cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channel is inhibited by a broad range of intracellular organic anions. Here it is shown, using patch clamp recording from CFTR-transfected mammalian cell lines, that the fatty acids butyrate and 4-phenylbutyrate cause a voltage-dependent block of CFTR Cl(-) currents when applied to the cytoplasmic face of membrane patches, with apparent K(d)s (at 0 mV) of 29.6 mM for butyrate and 6.6 mM for 4-phenylbutyrate. At the single channel level, both these fatty acids caused an apparent reduction in CFTR current amplitude, suggesting a kinetically fast blocking mechanism. The concentration-dependence of block suggests that CFTR-mediated Cl(-) currents in vivo may be affected by both 4-phenylbutyrate used in the treatment of various diseases, including cystic fibrosis, and by butyrate produced endogenously within the colonic lumen.
authors.affiliation: Department of Physiology and Biophysics, Dalhousie University, Sir Charles Tupper Medical Building, Halifax, Nova Scotia, B3H 4H7, Canada. paul.linsdell@dal.ca
authors.forename: P
authors.initials: P
authors.lastname: Linsdell
mesh_terms: D000818:Animals; D002087:Butyrates / Q000494:pharmacology*; D016466:CHO Cells; D018118:Chloride Channels / Q000037:antagonists & inhibitors; D006224:Cricetinae; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000037:antagonists & inhibitors*; D004594:Electrophysiology; D007668:Kidney / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010654:Phenylbutyrates / Q000494:pharmacology*
chemical_list: D002087:Butyrates; D018118:Chloride Channels; D010654:Phenylbutyrates; D019005:Cystic Fibrosis Transmembrane Conductance Regulator