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

• Published in: The Journal of physiology 2022-03, Vol.600 (6), p.1357-1371
• Main Authors: Gonzalez‐Perez, Vivian, Zhou, Yu, Ciorba, Matthew A., Lingle, Christopher J.
• Format: Article
• Language: English
• Subjects: Animal models; Animals; BK channels; Calcium (intracellular); Calcium channels (voltage-gated); Cochlea; Colitis; Colon - metabolism; Epithelial cells; Female; Gene regulation; Goblet cells; Hair cells; Hair Cells, Auditory, Inner - metabolism; intestinal epithelium; Large-Conductance Calcium-Activated Potassium Channel alpha Subunits - metabolism; Large-Conductance Calcium-Activated Potassium Channels - genetics; Large-Conductance Calcium-Activated Potassium Channels - metabolism; leucine‐rich‐repeat proteins (LRR protein); Mammary gland; Membrane Proteins - metabolism; Mice; Mice, Knockout; Potassium; Potassium channels (calcium-gated); Potassium conductance; potassium ion channels; Protein Domains; Regulatory subunits; Reproductive system; Salivary gland; Tumor suppressor genes; Tumors; ulcerative colitis
• ISSN: 0022-3751; 1469-7793
• DOI: 10.1113/JP281952

Large conductance K+ channels, termed BK channels, regulate a variety of cellular and physiological functions. Although universally activated by changes in voltage or [Ca2+]i, the threshold for BK channel activation varies among loci of expression, often arising from cell‐specific regulatory subunits including a family of leucine rich repeat‐containing (LRRC) γ subunits (LRRC26, LRRC52, LRRC55 and LRRC38). The ‘founding’ member of this family, LRRC26, was originally identified as a tumour suppressor in various cancers. An LRRC26 knockout (KO) mouse model recently revealed that LRRC26 is also highly expressed in secretory epithelial cells and partners with BK channels in the salivary gland and colonic goblet cells to promote sustained K+ fluxes likely essential for normal secretory function. To accomplish this, LRRC26 negatively shifts the range of BK channel activation such that channels contribute to K+ flux near typical epithelial cell resting conditions. In colon, the absence of LRRC26 increases vulnerability to colitis. LRRC26‐containing BK channels are also likely important regulators of epithelial function in other loci, including airways, female reproductive tract and mammary gland. Based on an LRRC52 KO mouse model, LRRC52 regulation of large conductance K+ channels plays a role both in sperm function and in cochlear inner hair cells. Although our understanding of LRRC‐containing BK channels remains rudimentary, KO mouse models may help define other organs in which LRRC‐containing channels support normal function. A key topic for future work concerns identification of endogenous mechanisms, whether post‐translational or via gene regulation, that may impact LRRC‐dependent pathologies. figure legend A major function of colonic crypts is the generation of a protective mucus layer separating gut contents from epithelial cells. Two major colonic epithelial cells are mucus‐secreting goblet cells (GCs) and absorptive enterocytes. GCs specifically express BK channels containing the LRRC26 regulatory subunit, which shifts BK channel activation so that, at 0 cytosolic Ca2+, BK channels are activated at membrane potentials (Vm) as negative as −40 mV. In mice lacking LRRC26, GCs also express BK currents, but they not activated with 0 Ca2+ until Vm positive to +50 mV. Such LRRC26 knockout mice exhibit enhanced sensitivity to colitis induced by dextran sodium sulphate. LRRC26 is expected to regulate BK‐mediated K+ fluxes in a variety of secretory epithelial cell