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

摘要

class="enumerated" style="list-style-type:decimal">Epithelia lining the nasal passages and descending colon of wild-type and cystic fibrosis (CF) mice were examined by the short-circuit current technique. Additionally, intracellular Ca²⁺ ion determinations were made in nasal epithelial cells. Forskolin produced anion secretory currents in wild-type and CF nasal epithelia. It produced similar effects in wild-type colonic epithelia, but not in colonic epithelia from CF mice.After electrogenic Na⁺ transport was blocked with amiloride and electrogenic Cl⁻ secretion was stimulated with forskolin, the ability of K⁺ channel blockers to inhibit the forskolin-induced Cl⁻ current was determined. The order of efficiency for nasal epithelium was: Ba²⁺ > clofilium ⋙ TEA = azimilide ⋙ trans-6-cyano-4-(N-ethylsulphonyl-N-methylamino)-3-hydroxy-2,2-dimethyl-chromane (293B) = charybdotoxin, whereas for the colonic epithelium the order was: Ba²⁺ = 293B ⋙ azimilide = TEA ⋙ clofilium = charybdotoxin.1-Ethyl-2-benzimdazolinone (1-EBIO) was able to generate large Cl⁻-secretory currents in colonic epithelia which were partially sensitive to charybdotoxin, with the remaining current being inhibited by 293B. In nasal epithelia 1-EBIO produced only a small transient effect on current.Forskolin released intracellular Ca²⁺ in nasal epithelial cells; this activity was attenuated when more powerful Ca²⁺-releasing agents were applied first.It is concluded that an action on basolateral cAMP-sensitive K⁺ channels is an important determinant of the maintained responses to forskolin in nasal and colonic epithelia, in addition to the effects on the cystic fibrosis transmembrane conductance regulator (CFTR) in the apical membrane. In CF nasal epithelia the activation of calcium-activated chloride channels (CACs) substitutes for the effect on CFTR. On the basis of the different orders of potency of the blocking agents and the differential response to 1-EBIO it is concluded that the cAMP-sensitive K⁺ channels are different in the airways and the gut.