Goblet cells (GCs) are specialized epithelial cells essential for maintaining mucosal homeostasis. GCs secrete mucin2 (MUC2), a protein that forms the scaffold of the intestinal mucus covering the intestinal epithelium. The mucus acts as a barrier, serving as a first line of defense against luminal pathogens and commensal microbiota. MUC2 secretion is regulated by intracellular Ca 2+ levels and other ionic gradients. However, the precise mechanisms controlling GCs’ physiology remain incompletely understood. We have demonstrated that leucine-rich-repeat-containing protein 26 (LRRC26), a key regulatory subunit of the Ca 2+ -and voltage-activated K + channel (BK channel) in colonic GCs. LRRC26-BK channel complexes represent the primary K + efflux from colonic GCs, where LRRC26 is essential for the complex function at physiological resting conditions. Furthermore, the genetic deletion of LRRC26 in mice increases susceptibility to chemically induced colitis, indicating a protective role of the channel complex against inflammation. Here, we explore the impact of LRRC26-BK channel activity on GC physiology by combining the use of KO mouse models of LRRC26 or the BK pore-forming subunit with a mouse model in which MUC2 is fluorescently tagged, thereby allowing identification of GCs in primary colonic epithelial cell preparations. By using patch-clamp electrophysiology and cell calcium signaling, we found that LRRC26-BK channels critically contribute to establishing the GC membrane potential and sustaining the calcium entry into GCs. Moreover, genetic deletion of either subunit forming LRRC26-BK complexes results in a significantly thinner mucus layer. These findings establish LRRC26-associated BK channels as key regulators of goblet cell function, linking potassium flux to calcium signaling and mucus secretion, with significant implications for colonic homeostasis and disease susceptibility. Supported by WashU-Anesthesiology startup and WashU-CIMED-25-02 to VGP, and NIH GM-118114 to Christopher Lingle.
Delíz et al. (Sun,) studied this question.