Importance of basolateral K+conductance in maintaining Cl−secretion in murine nasal and colonic epithelia

Autor: Alan W. Cuthbert, Dina A. H. Mufti, Hannah J. Durrington, M. E. Hickman, L J MacVinish
Rok vydání: 1998
Předmět:
Zdroj: The Journal of Physiology. 510:237-247
ISSN: 0022-3751
DOI: 10.1111/j.1469-7793.1998.237bz.x
Popis: The hyperpolarization of the apical membrane which results from the activation of basolateral K+ channels increases the driving force for the exit of Cl− ions in electrogenic secretory epithelia, as first proposed by Smith & Frizzel in 1984. In situations where Cl− secretion is inadequate, activation of K+ channels may provide a strategy for increasing Cl− secretion. Cystic fibrosis (CF) is an example of a disease condition where, as a result of various genetic mutations, the cystic fibrosis transmembrane conductance regulator, CFTR, is absent from the apical membrane or is present but functionally impaired, and Cl− secretion fails (Riordan et al. 1989; Cheng et al. 1990). Abnormalities in the transporting characteristics of epithelia lining the airways, alimentary canal, hepatobiliary tree and exocrine pancreas are responsible for the morbidity and mortality associated with the disease (Boat, Welsh & Beaudet, 1989). In the airways, calcium-activated chloride channel (CAC) responses are upregulated (Grubb, Vick & Boucher, 1994b), and activation of these channels via apically located purinoceptors has been the basis of a clinical trial to treat the disease (Olivier et al. 1996), but no alternative Cl− channels are found in the gut. Most human CF patients have lost a triplet codon at position 508, resulting in CFTR with a phenylalanine missing in the first nucleotide-binding fold. This aberrant protein fails to be trafficked to the apical membrane and is degraded in the cells (Cheng et al. 1990). Efforts have been made to alter cellular processes so that some ΔF508 CFTR can be diverted to an apical location where it shows reduced Cl− channel activity (Rubenstein, Egan & Zeitlen, 1997). In such situations more effective Cl− secretion might be achieved if basolateral K+ channels were activated simultaneously. Mice carrying the CF mutation lack lung pathology, attributed to a major increase in CACs, and die at an early age from gut pathology leading to peritonitis (Clarke, Grubb, Yankaskas, Cotton, McKenzie & Boucher, 1994). We have shown previously that when murine nasal or tracheal epithelia are pretreated with 2,5-di-(tert-butyl)-1,4-benzohydroquinone (TBHQ)-ionomycin the CAC system becomes desensitized, so that wild-type and CF tissues are easily differentiated (MacVinish et al. 1997a; MacVinish, Goddard, Colledge, Higgins, Evans & Cuthbert, 1997b). Here the nasal and colonic epithelia of wild-type and CF mice have been investigated without this pretreatment. The role played by basolateral K+ channels in supporting and maintaining electrogenic Cl− secretion has been investigated.
Databáze: OpenAIRE
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