A synthetic channel-forming peptide induces Cl(-) secretion: modulation by Ca(2+)-dependent K(+) channels.

Wallace DP, Tomich JM, Eppler JW, Iwamoto T, Grantham JJ, Sullivan LP Biochim Biophys Acta2000 00, 1464: 1, 69-82

Abstract: A synthetic Cl(-) channel-forming peptide, C-K4-M2GlyR, applied to the apical membrane of human epithelial cell monolayers induces transepithelial Cl(-) and fluid secretion. The sequence of the core peptide, M2GlyR, corresponds to the second membrane-spanning region of the glycine receptor, a domain thought to line the pore of the ligand-gated Cl(-) channel. Using a pharmacological approach, we show that the flux of Cl(-) through the artificial Cl(-) channel can be regulated by modulating basolateral K(+) efflux through Ca(2+)-dependent K(+) channels. Application of C-K4-M2GlyR to the apical surface of monolayers composed of human colonic cells of the T84 cell line generated a sustained increase in short-circuit current (I(SC)) and caused net fluid secretion. The current was inhibited by the application of clotrimazole, a non-specific inhibitor of K(+) channels, and charybdotoxin, a potent inhibitor of Ca(2+)-dependent K(+) channels. Direct activation of these channels with 1-ethyl-2-benzimidazolinone (1-EBIO) greatly amplified the Cl(-) secretory current induced by C-K4-M2GlyR. The effect of the combination of C-K4-M2GlyR and 1-EBIO on I(SC) was significantly greater than the sum of the individual effects of the two compounds and was independent of cAMP. Treatment with 1-EBIO also increased the magnitude of fluid secretion induced by the peptide. The cooperative action of C-K4-M2GlyR and 1-EBIO on I(SC) was attenuated by Cl(-) transport inhibitors, by removing Cl(-) from the bathing solution and by basolateral treatment with K(+) channel blockers. These results indicate that apical membrane insertion of Cl(-) channel-forming peptides such as C-K4-M2GlyR and direct activation of basolateral K(+) channels with benzimidazolones may coordinate the apical Cl(-) conductance and the basolateral K(+) conductance, thereby providing a pharmacological approach to modulating Cl(-) and fluid secretion by human epithelia deficient in cystic fibrosis transmembrane conductance regulator Cl(-) channels.

SOTO | USA > SOT Literature > Cystic Fibrosis > A synthetic channel-forming peptide induces Cl(-) secretion: modulation by Ca(2+)-dependent K(+) channels.

Editor Recommends
Most Read Articles

Editor Recommends

This SOT Literature Page and all its contents herein are published by SOTO-USA solely for the purpose of education. All rights reserved by SOTO-USA to accept, reject or modify any submission for publication. The opinions stated in the electronically printed material herein are those of the authors and do not necessarily represent the opinions of SOTO-USA or other individuals associated with SOTO-USA. SOTO-USA does not guarantee or make any representation that the printed material contained herein is valid, reliable or accurate. SOTO-USA does not assume any responsibility for injury arising from any use or misuse of the printed material herein. The printed material contained herein is assumed to be from reliable sources and there is no implication that the printed material herein present the only, or the best methodologies or procedures for the care or treatment of conditions discussed. It is incumbent upon the reader to verify the accuracy of any diagnosis and treatment information contained herein, and to make modifications as new information and/or research arises.