The role of K+ channels in colonic Cl(-)secretion

Cl- secretion in the rat colonic crypt base cell (be) requires the coordinated (a) opening of Cl- channels in the luminal membrane; (b) activation of the Na(+)2Cl(-)K(+) cotransporter; (c) enhanced conductive K+ exit from the cell; and (d) increased pumping by the (Na+ + K+)-ATPase. In this study we focus on the importance of conductive K+ exit. After stimulation with the cholinergic agonist carbachol (CCH, 0.1-10 mu mol/l) be respond with a marked increase in whole cell (we) conductance and a hyperpolarization of the membrane voltage (V-m). This is paralleled by a marked increase in the (Cl- secretory) shore-circuit current (I-sc) in Ussing chamber studies of the intact distal colon. Current evidence favors the view that CCH, via IP3, enhances cytosolic Ca2+ activity, and that Ca2+ increases the open probability of Cl- channels indirectly and that of K+ channels directly. After stimulation with PGE(2) be also enhance the we conductance, but this is paralleled by a marked depolarization of V-m. Again these effects correspond to a marked increase in (Cl- secretory) I-sc. The depolarization and enhanced we conductance is partly due to the activation of Cl- channels. However, current evidence suggests that these effects on Cl- channels are paralleled by an activation of K+ channels. The chromanol 293B, by inhibiting these K+ channels specifically, abolishes PGE(2)-induced Cl- secretion completely, but has no effect on basal K+ conductance or on CCH-induced Cl- secretion. CCH apparently activates a Ca2+-dependent K+ channel with a conductance of 10-20 pS, whilst PGE(2) (or cAMP) activate a much smaller K+ channel. Only the latter K+ channel can be inhibited by 293B in excised patches. Noise analysis suggests that this K+ channel has a conductance of <3 pS and fast kinetics. The complete 293B induced inhibition of Cl- secretion caused by PGE(2) can be explained by the fact that PGE(2) induces a marked depolarization and that this depolarization reduces the basal K+ conductance. Current evidence suggests that this inhibition of the basal K+ conductance is caused by a depolarization induced inhibition of Ca2+ entry.