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

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• 作者：Adel Al-Hazza^a ; John Linley^a ; Qadeer Aziz^a ; Malcolm Hunter^a ; Geoffrey Sandle^b ; ^{g.i.sandle@leeds.ac.uk" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Human colonic crypts ; Ulcerative colitis ; KCNQ1/KCNE3 channels ; Patch clamp
• 刊名：Biochemical and Biophysical Research Communications
• 出版年：2016
• 出版时间：5 February 2016
• 年：2016
• 卷：470
• 期：2
• 页码：473-478
• 全文大小：894 K

文摘

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.