Direct block of the cystic fibrosis transmembrane conductance regulator Cl- channel by butyrate and phenylbutyrate

Chloride permeation through the cystic fibrosis transmembrane conductance r egulator (CFTR) Cl- channel is inhibited by a broad range of intracellular organic anions. Here it is shown, using patch clamp recording from CFTR-tra nsfected mammalian cell lines, that the fatty acids butyrate and 4-phenylbu tyrate 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 channe l level. both these fatty acids caused an apparent reduction in CFTR curren t amplitude. suggesting a kinetically fast blocking mechanism. The concentr ation-dependence of block suggests that CFTR-mediated Cl- currents in vivo may be affected by both 4-phenylbutyrate used in the treatment of various d iseases, including cystic fibrosis, and by butyrate produced endogenously w ithin the colonic lumen. (C) 2001 Elsevier Science B.V. All rights reserved .