Goblet cells (GCs) are specialized cells of the intestinal epithelium contributing critically to mucosal homeostasis. One of the functions of GCs is to produce and secrete MUC2, the mucin that forms the scaffold of the intestinal mucus layer coating the epithelium and separates the luminal pathogens and commensal microbiota from the host tissues. Although a variety of ion channels and transporters are thought to impact on MUC2 secretion, the specific cellular mechanisms that regulate GC function remain incompletely understood. Previously, we demonstrated that leucine-rich repeat-containing protein 26 (LRRC26), a known regulatory subunit of the Ca²⁺-and voltage-activated K⁺ channel (BK channel), localizes specifically to secretory cells within the intestinal tract. Here, utilizing a mouse model in which MUC2 is fluorescently tagged, thereby allowing visualization of single GCs in intact colonic crypts, we show that murine colonic GCs have functional LRRC26-associated BK channels. In the absence of LRRC26, BK channels are present in GCs, but are not activated at physiological conditions. In contrast, all tested MUC2⁻ cells completely lacked BK channels. Moreover, LRRC26-associated BK channels underlie the BK channel contribution to the resting transepithelial current across mouse distal colonic mucosa. Genetic ablation of either LRRC26 or BK pore-forming α-subunit in mice results in a dramatically enhanced susceptibility to colitis induced by dextran sodium sulfate. These results demonstrate that normal potassium flux through LRRC26-associated BK channels in GCs has protective effects against colitis in mice.

杯状细胞 (GCs) 是肠上皮的特化细胞，对黏膜稳态具有重要作用。GCs 的功能之一是产生和分泌 MUC2，MUC2 是一种粘蛋白，形成覆盖上皮的肠粘液层支架，并将管腔病原体和共生微生物群与宿主组织分离。尽管多种离子通道和转运蛋白被认为会影响 MUC2 的分泌，但调节 GC 功能的特定细胞机制仍未完全了解。以前，我们证明了富含亮氨酸的重复蛋白 26 (LRRC26)，一种已知的 Ca ²⁺调节亚基- 和电压激活的 K ⁺通道（BK 通道），特异性定位于肠道内的分泌细胞。在这里，利用其中 MUC2 被荧光标记的小鼠模型，从而允许在完整的结肠隐窝中可视化单个 GC，我们表明鼠结肠 GC 具有功能性 LRRC26 相关的 BK 通道。在没有 LRRC26 的情况下，BK 通道存在于 GCs 中，但在生理条件下不被激活。相比之下，所有测试的 MUC2 ^-细胞完全缺乏 BK 通道。此外，LRRC26 相关的 BK 通道是 BK 通道对穿过小鼠远端结肠粘膜的静息跨上皮电流的贡献的基础。小鼠中 LRRC26 或 BK 成孔 α 亚基的基因消融导致葡聚糖硫酸钠诱导的结肠炎易感性显着增强。这些结果表明，通过 GC 中 LRRC26 相关 BK 通道的正常钾通量对小鼠结肠炎具有保护作用。