Abstract

The cognitive enhancer XE991 interacts with K⁺ channels consisting of KCNQ2 and KCNQ3 heteromultimers to block the M-current. XE991 can also block KCNQ1 K⁺ channels expressed in oocytes, but sensitivity is reduced when the channels are coexpressed with minK (KCNE1). The purpose of the study was to examine the interaction of XE991 with other types of K⁺ channel, especially those in the basolateral membranes of murine epithelia. K⁺ channel blockade was measured by the inhibition of chloride secretion resulting from depolarization. XE991 inhibited the chloride secretory current in colonic epithelia by an interaction with basolateral K⁺ channels when forskolin was used as the stimulus. However, when 1-ethyl-2-benzimidazolinone (EBIO) was used to stimulate chloride secretion, XE991 was ineffective unless charybdotoxin was also present. Because EBIO also activates Ca²⁺-sensitive K⁺ channels, whereas forskolin activates only cAMP-sensitive K⁺ channels, it is concluded that the latter are the targets for XE991. XE991 had effects similar to those of 293B on epithelial chloride transport, for which the target is known to be KCNQ1/KCNE3 multimers. mRNA for both these components of the cAMP-sensitive K⁺ channels were found in high abundance in the colon, whereas KCNE1 was barely detectable. Furthermore, both XE991 and 293B were active in colonic epithelia from KCNE1 knockout mice. By contrast, in nasal epithelium, the forskolin sensitive chloride secretory current was barely sensitive to XE991 but was sensitive to clofilium. Xenopus laevis oocytes in which both KCNQ1 and KCNE3 had been expressed were significantly more sensitive to XE991 than oocytes expressing only KCNQ1.