title: The K+ channel opener 1-EBIO potentiates residual function of mutant CFTR in rectal biopsies from cystic fibrosis patients.
abstract: 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⁺ channel opener 1-ethyl-2-benzimidazolone (1-EBIO) potentiates CFTR-mediated Cl⁻ 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⁻ 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⁻ secretion.
  
  
  RESULTS
  Studies in control tissues demonstrate that 1-EBIO activated CFTR-mediated Cl⁻ secretion in the absence of cAMP-mediated stimulation and potentiated cAMP-induced Cl⁻ secretion by 39.2±6.7% (P<0.001) via activation of basolateral Ca²⁺-activated and clotrimazole-sensitive KCNN4 K⁺ channels. In CF specimens, 1-EBIO potentiated cAMP-induced Cl⁻ secretion in tissues with residual CFTR function by 44.4±11.5% (P<0.001), but had no effect on tissues lacking CFTR-mediated Cl⁻ conductance.
  
  
  CONCLUSIONS
  We conclude that 1-EBIO potentiates Cl⁻secretion in native CF tissues expressing CFTR mutants with residual Cl⁻ channel function by activation of basolateral KCNN4 K⁺ channels that increase the driving force for luminal Cl⁻ 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.
authors: Division of Pediatric Pulmonology and Allergy and Cystic Fibrosis Center, Department of Pediatrics III, University of Heidelberg, Heidelberg, Germany.
authors: Eva K
authors: EK
authors: Roth
authors: Stephanie
authors: S
authors: Hirtz
authors: Julia
authors: J
authors: Duerr
authors: Daniel
authors: D
authors: Wenning
authors: Irmgard
authors: I
authors: Eichler
authors: Hans H
authors: HH
authors: Seydewitz
authors: Margarida D
authors: MD
authors: Amaral
authors: Marcus A
authors: MA
authors: Mall
mesh_terms: D000293:Adolescent; D000328:Adult; D001562:Benzimidazoles / Q000494:pharmacology*; D001706:Biopsy; D002118:Calcium / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D002712:Chlorides / Q000378:metabolism; D002794:Choline / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D003550:Cystic Fibrosis / Q000473:pathology*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000378:metabolism*; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005838:Genotype; D006801:Humans; D066298:In Vitro Techniques; D015640:Ion Channel Gating / Q000187:drug effects*; D008875:Middle Aged; D050505:Mutant Proteins / Q000378:metabolism*; D015221:Potassium Channels / Q000378:metabolism*; D012007:Rectum / Q000187:drug effects / Q000473:pathology*; D055815:Young Adult
chemical_list: D001562:Benzimidazoles; D002712:Chlorides; D050505:Mutant Proteins; D015221:Potassium Channels; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D000242:Cyclic AMP; C102635:1-ethyl-2-benzimidazolinone; D002794:Choline; D002118:Calcium