K+ Channel KVLQT1 Located in the Basolateral Membrane of Distal Colonic Epithelium is Not Essential for Activating Cl- Secretion

The cellular mechanism for Cl ⁻ and K ⁺ secretion in the colonic epithelium requires K ⁺ channels in the basolateral and apical membranes. Colonic mucosa from guinea pig and rat were fixed, sectioned, and then probed with antibodies to the K ⁺ channel proteins K _V LQT1 ( Kcnq1 ) and minK-related peptide 2 (MiRP2, Kcne3 ). Immunofluorescence labeling for Kcnq1 was most prominent in the lateral membrane of crypt cells in rat colon. The guinea pig distal colon had distinct lateral membrane immunoreactivity for Kcnq1 in crypt and surface cells. In addition, Kcne3 , an auxiliary subunit for Kcnq1 , was detected in the lateral membrane of crypt and surface cells in guinea pig distal colon. Transepithelial short-circuit current ( I _sc ) and transepithelial conductance ( G _t ) were measured for colonic mucosa during secretory activation by epinephrine (EPI), prostaglandin E ₂ (PGE ₂ ), and carbachol (CCh). HMR1556 (10 μM), an inhibitor of Kcnq1 channels (Gerlach U, Brendel J, Lang HJ, Paulus EF, Weidmann K, Brüggemann A, Busch A, Suessbrich H, Bleich M, and Greger R. J Med Chem 44: 3831–3837, 2001), partially (∼50%) inhibited Cl ⁻ secretory I _sc and G _t activated by PGE ₂ and CCh in rat colon with an IC ₅₀ of 55 nM, but in guinea pig distal colon Cl ⁻ secretory I _sc and G _t were unaltered. EPI-activated K ⁺ -secretory I _sc and G _t also were essentially unaltered by HMR1556 in both rat and guinea pig colon. Although immunofluorescence labeling with a Kcnq1 antibody supported the basolateral membrane presence in colonic epithelium of the guinea pig as well as the rat, the Kcnq1 K ⁺ channel is not an essential component for producing Cl ⁻ secretion. Other K ⁺ channels present in the basolateral membrane presumably must also contribute directly to the K ⁺ conductance necessary for K ⁺ exit during activation of Cl ⁻ secretion in the colonic mucosa.