Details

Autor(en) / Beteiligte

• Roth, Eva K
• Hirtz, Stephanie
• Duerr, Julia
• Wenning, Daniel
• Eichler, Irmgard
• Seydewitz, Hans H
• Amaral, Margarida D
• Mall, Marcus A

Titel

The K.sup.+ Channel Opener 1-EBIO Potentiates Residual Function of Mutant CFTR in Rectal Biopsies from Cystic Fibrosis Patients

Ist Teil von

• PloS one, 2011-08, Vol.6 (8), p.e24445

Ort / Verlag

Public Library of Science

Erscheinungsjahr

2011

Link zum Volltext

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• Background The identification of strategies to improve mutant CFTR function remains a key priority in the development of new treatments for cystic fibrosis (CF). Previous studies demonstrated that the K.sup.+ channel opener 1-ethyl-2-benzimidazolone (1-EBIO) potentiates CFTR-mediated Cl.sup.- secretion in cultured cells and mouse colon. However, the effects of 1-EBIO on wild-type and mutant CFTR function in native human colonic tissues remain unknown. Methods We studied the effects of 1-EBIO on CFTR-mediated Cl.sup.- secretion in rectal biopsies from 47 CF patients carrying a wide spectrum of CFTR mutations and 57 age-matched controls. Rectal tissues were mounted in perfused micro-Ussing chambers and the effects of 1-EBIO were compared in control tissues, CF tissues expressing residual CFTR function and CF tissues with no detectable Cl.sup.- secretion. Results Studies in control tissues demonstrate that 1-EBIO activated CFTR-mediated Cl.sup.- secretion in the absence of cAMP-mediated stimulation and potentiated cAMP-induced Cl.sup.- secretion by 39.2#177;6.7% (P0.001) via activation of basolateral Ca.sup.2+ -activated and clotrimazole-sensitive KCNN4 K.sup.+ channels. In CF specimens, 1-EBIO potentiated cAMP-induced Cl.sup.- secretion in tissues with residual CFTR function by 44.4#177;11.5% (P0.001), but had no effect on tissues lacking CFTR-mediated Cl.sup.- conductance. Conclusions We conclude that 1-EBIO potentiates Cl.sup.- secretion in native CF tissues expressing CFTR mutants with residual Cl.sup.- channel function by activation of basolateral KCNN4 K.sup.+ channels that increase the driving force for luminal Cl.sup.- exit. This mechanism may augment effects of CFTR correctors and potentiators that increase the number and/or activity of mutant CFTR channels at the cell surface and suggests KCNN4 as a therapeutic target for CF.