Upregulation of basolateral small conductance potassium channels (KCNQ1/KCNE3) in ulcerative colitis

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Background Basolateral K+ channels hyperpolarize colonocytes to ensure Na+ (and thus water) absorption. Small conductance basolateral (KCNQ1/KCNE3) K+ channels have never been evaluated in human colon. We therefore evaluated KCNQ1/KCNE3 channels in distal colonic crypts obtained from normal and active ulcerative colitis (UC) patients. Methods KCNQ1 and KCNE3 mRNA levels were determined by qPCR, and KCNQ1/KCNE3 channel activity in normal and UC crypts, and the effects of forskolin (activator of adenylate cyclase) and UC-related proinflammatory cytokines on normal crypts, studied by patch clamp recording. Results Whereas KCNQ1 and KCNE3 mRNA expression was similar in normal and UC crypts, single 6.8 pS channels were seen in 36% of basolateral patches in normal crypts, and to an even greater extent (74% of patches, P < 0.001) in UC crypts, with two or more channels per patch. Channel activity was 10-fold higher (P < 0.001) in UC crypts, with a greater contribution to basolateral conductance (5.85 ± 0.62 mS cm-2) than in controls (0.28 ± 0.04 mS cm-2, P < 0.001). In control crypts, forskolin and thromboxane A2 stimulated channel activity 30-fold and 10-fold respectively, while PGE2, IL-1β, and LTD4 had no effect. Conclusions KCNQ1/KCNE3 channels make only a small contribution to basolateral conductance in normal colonic crypts, with increased channel activity in UC appearing insufficient to prevent colonic cell depolarization in this disease. This supports the proposal that defective Na+ absorption rather than enhanced Cl- secretion, is the dominant pathophysiological mechanism of diarrhea in UC.




Al-Hazza, A., Linley, J., Aziz, Q., Hunter, M., & Sandle, G. (2016). Upregulation of basolateral small conductance potassium channels (KCNQ1/KCNE3) in ulcerative colitis. Biochemical and Biophysical Research Communications, 470(2), 473–478. https://doi.org/10.1016/j.bbrc.2015.12.086

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