13 DEFICIENT ACTIVITY OF A GOBLET CELL-SPECIFIC BK-TYPE POTASSIUM CHANNEL ENHANCES SUSCEPTIBILITY TO DSS-INDUCED COLITIS IN MICE

Abstract

Goblet cells (GC) contribute critically to intestinal barrier function and mucosal immune homeostasis. GC dysfunction is linked to human inflammatory bowel disease (IBD). However, the cellular mechanisms that regulate GC function are incompletely understood. Using a novel mouse model generated in our lab, we have recently identified that an important regulatory subunit of the BK-type potassium channel, called LRRC26 (leucine-rich-repeat containing protein 26), specifically localizes to intestinal GCs. BK channels are membrane proteins enabling K+-efflux from cells in response to an increase in intracellular calcium concentration and/or membrane depolarization. The presence of LRRC26 in GC-BK channels is remarkable since this subunit drastically shifts the activation range such that LRRC26-associated BK channels can contribute to K+ efflux near normal physiological resting conditions. Although upregulation of the gene encoding for the BK channel (the pore-forming subunit) has been associated with increased K+ losses in Ulcerative Colitis patients, the specific role played by BK channels in the IBD pathophysiology is unknown. In this study, we have found that the genetic ablation of LRRC26 or BK-pore forming subunit in mice results in a dramatically enhanced susceptibility to DSS-induced colitis. By using a fluorescence-tagged GC mouse, we have confirmed that murine colonic GCs have functional LRRC26-associated BK channels which become inoperant in the absence of LRRC26. These results suggest that a normal potassium flux though LRRC26-associated BK channels in GCs has protective effects against colitis and perhaps reveals a new potential therapeutic target for IBD. (Supported by LC Pakula IBD Education & Innovation Fund IA-2018-10-IBD-2 to VGP and GM118114 to CJL)