XE991 reveals differences in K+ channels regulating chloride secretion in murine airway and colonic epithelium

The cognitive enhancer XE991 interacts with K+ channels consisting of KCNQ2 and KCNQ3 heteromultimers to block the M-current. XE991 can also block KCN Q1 K+ channels expressed in oocytes, but sensitivity is reduced when the ch annels are coexpressed with minK (KCNE1). The purpose of the study was to e xamine 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 depola rization. XE991 inhibited the chloride secretory current in colonic epithel ia by an interaction with basolateral K+ channels when forskolin was used a s the stimulus. However, when 1-ethyl-2-benzimidazolinone (EBIO) was used t o stimulate chloride secretion, XE991 was ineffective unless charybdotoxin was also present. Because EBIO also activates Ca2+-sensitive K+ channels, w hereas forskolin activates only cAMP-sensitive K+ channels, it is concluded that the latter are the targets for XE991. XE991 had effects similar to th ose of 293B on epithelia[ chloride transport, for which the target is known to be KCNQ1/KCNE3 multimers. mRNA for both these components of the CAMP-se nsitive K+ channels were found in high abundance in the colon, whereas KCNE 1 was barely detectable. Furthermore, both XE991 and 293B were active in co lonic 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 XE 991 than oocytes expressing only KCNQ1.