Goblet cell LRRC26 regulates BK channel activation and protects against colitis in mice.
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.
['Gonzalez-Perez|Vivian|V|0000-0002-5093-6769', 'Martinez-Espinosa|Pedro L|PL|0000-0003-4274-1010', 'Sala-Rabanal|Monica|M|', 'Bharadwaj|Nikhil|N|', 'Xia|Xiao-Ming|XM|', 'Chen|Albert C|AC|0000-0002-4745-0354', 'Alvarado|David|D|0000-0001-8748-0761', 'Gustafsson|Jenny K|JK|0000-0001-7213-4065', 'Hu|Hongzhen|H|', 'Ciorba|Matthew A|MA|0000-0002-7656-0982', 'Lingle|Christopher J|CJ|0000-0002-9916-3795']
D000818:Animals D003092:Colitis D003106:Colon D004195:Disease Models, Animal D020397:Goblet Cells D006801:Humans D007413:Intestinal Mucosa D051036:Large-Conductance Calcium-Activated Potassium Channels D008564:Membrane Potentials D051379:Mice D055262:Mucin-2 D018408:Patch-Clamp Techniques
LRRC26 Ca2+-activated K+ channels DSS-induced colitis epithelial cells inflammatory bowel disease