Specific blockade of slowly activating I_sK channels by chromanols — impact on the role of I_sK channels in epithelia

Abstract

Chromanols, which were recently shown to inhibit cAMP-mediated CI secretion in colon crypts via a blockade of a cAMP-activated K + conductance, were analyzed for their effects on distinct cloned K + channels expressed in Xenopus oocytes. The lead chromanol 293B specifically inhibited I~K channels with an ICs0 of 7 pmol/1 without affecting the delayed rectifier Kvl.1 or the inward rectifier Kir2.1. Moreover, several other chromanols displayed the same rank order of potency for Isx inhibition as demonstrated in colon crypts. Finally, we tested the effects of the previously described I~K blocker azimilide on cAMP mediated CI secretion in rat colon crypts. Similar to 293B azimilide inhibited the forskolin induced CI-secretion. These data suggest that Isx protein induced K + conductances are the targets for the chromanol 293B and its analogues, and azimilide.

KvLQT1 Potassium Channel but Not IsK Is the Molecular Target fortrans-6-Cyano-4-(N-ethylsulfonyl-N-methylamino)-3-hydroxy-2,2-dimethyl-chromane

“…The chromanol compound 293B was a good candidate because it was previously found to block the K ϩ current induced by expression of IsK in X. laevis oocytes (12). Here, we demonstrate that 293B is a potent blocker of human KvLQT1 K ϩ channels and that it binds to the channel protein itself but not to the IsK regulator.…”

P2Y6 receptor mediates colonic NaCl secretion via differential activation of cAMP-mediated transport

“…An important difference between the "secretory" response of the two nucleotides is obvious when comparing Figure 1, b and c. Whereas the effect of ATP was transient, that of UDP showed a persistent activation of secretion. Furthermore, the effect of UDP was completely inhibited by 293B, a specific inhibitor of the KCNQ1/KCNE3 K + channels (25), whereas the ATP-mediated response was insensitive to 293B (data not shown; n = 5). In rat colonic mucosa this K + channel is activated by cAMP and provides the driving force for CFTR-mediated Clextrusion across the apical membrane (14,19).…”

Disruption of the K+ Channel β-Subunit KCNE3 Reveals an Important Role in Intestinal and Tracheal Cl− Transport

“…Before KCNQ1/KCNE3 channels were identified (22), KCNQ1/ KCNE1 heteromers were implicated in transport across colonic epithelia (54). However, expression levels of KCNE1 are low or even below detection limit in colon and trachea (39), and forskolin-stimulated intestinal Cl Ϫ secretion was normal in kcne1 Ϫ/Ϫ mice (55, 56).…”