Goblet cell LRRC26 regulates BK channel activation and protects against colitis in mice

Abstract

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 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-negative 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 alpha-subunit in mice results in a dramatically enhanced susceptibility to colitis induced by dextran sodium sulfate (DSS). These results demonstrate that normal potassium flux through LRRC26-associated BK channels in GCs has protective effects against colitis in mice.

The leucine-rich repeat domains of BK channel auxiliary γ subunits regulate their expression, trafficking, and channel-modulation functions

“…The large-conductance, voltage- and calcium-activated potassium (BK, or K Ca1.1 ) channels are ubiquitously expressed and critically involved in various cellular and physiological processes, such as regulation of neuron firing and transmission ( 1 , 2 ), motor coordination ( 3 ), learning and memory ( 4 , 5 ), circadian rhythmicity ( 6 , 7 ), the contractile tone of almost all types of smooth muscle cells ( 8 , 9 ), and resting K + efflux in secretory epithelial cells ( 10 , 11 ). BK channel function is regulated by various auxiliary β and γ subunits and LINGO1 that confer tissue-specific gating and pharmacological properties ( 12 , 13 , 14 , 15 ).…”

“…The γ1 subunit is highly expressed in the salivary glands, prostate, and trachea and is moderately present in thyroid gland, thymus, colon, aorta, and fetal brain; γ2 is predominantly expressed in the testes; and γ3 is primarily expressed in the nervous system ( 17 ). The γ1 subunit confers an unusual capability to the BK channel, making it active in the absence of calcium under the cells’ resting state ( 16 , 17 ), and is thus able to play an important role in resting K + efflux and fluid secretion in nonexcitable secretory cells ( 10 , 11 ). The γ2 subunit potently regulates BK channel function in cochlear inner hair cells ( 18 ).…”

Multi-context genetic modeling of transcriptional regulation resolves novel disease loci

“…Within Alzheimer’s disease, these genes included CBLC[51, 52], MS4A4A [53], and MADD [54] with the GTEx weights, as well as VASP[55, 56], RELB[51], TRAPPC6A[57, 58] with CLUES weights. Additionally, in Crohn’s disease, CONTENT implicated the following genes, whereas previous methods did not: LRRC26[59] and RASSF1A[60] with GTEx weights, as well as CARD6 (an inhibitor of NOD)[61, 62] using CLUES weights. For major depression disorder (MDD), CONTENT implicated CAMP[63] using GTEx weights, and FLOT1 [64, 65] using CLUES weights.…”

“…Within Alzheimer's disease, these genes included CBLC [51,52], MS4A4A [53], and MADD [54] with the GTEx weights, as well as VASP [55,56], RELB [51], TRAPPC6A [57,58] with CLUES weights. Additionally, in Crohn's disease, CONTENT implicated the following genes, whereas previous methods did not: LRRC26 [59] and RASSF1A [60] with GTEx weights, as well as CARD6…”

The LRRC family of BK channel regulatory subunits: potential roles in health and disease

“…Although BK channels have been known to be present in colonic epithelium and BK channels are thought to be associated with colonic K + loss during secretory diarrhoea (Sandle & Hunter, 2010), the precise cellular membranes, the cellular loci and circumstances of activation of BK channels in colonic epithelium have remained incompletely resolved. Somewhat surprisingly, genetic deletion of LRRC26 renders mice sensitive to colitis induced by dextran sodium sulfate (DSS) (Gonzalez-Perez et al 2021), a standard model of colitis primarily involving the distal colon. In response to DSS, LRRC26 KO mice exhibited irreversible loss of body weight and high disease severity indices, and examination of distal colon revealed loss of crypts and GCs.…”