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

Abstract

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.

The Role of Sperm Membrane Potential and Ion Channels in Regulating Sperm Function

“…They are the most diverse class of ion channels and show a great structural diversity ( Table 2 ). Different types of K + channels, including Ca 2+ -activated K + channels of the SLO subfamilies [ 84 , 85 ], voltage-gated K + channels (Kv channels) [ 86 ], inwardly rectifying K + channels (Kir channels) [ 82 , 87 ] and two-pore domain K + channels (K2P) [ 88 , 89 ] have been detected in human sperm.…”

“…SLO channels, also known as KSper, have a major role in regulating capacitation- induced hyperpolarization in the sperm cells [ 23 , 24 , 83 , 84 , 91 ]. SLO channels belong to the family of Ca 2+ -activated K + channels (KCa) and are composed of a pore-forming α subunit, and three types of auxiliary subunits [ 25 , 85 , 112 , 113 , 114 ] ( Table 2 ). The four known α subunits are named SLO1, SLO2.1, SLO2.2 and SLO3, and among them, SLO1 and SLO3 are abundantly expressed in mammalian spermatozoa [ 15 , 83 , 84 , 85 , 90 ].…”

Ca2+-Activated K+ Channels and the Regulation of the Uteroplacental Circulation

“…A group of leucine-rich repeat-containing (LRRC) proteins (~35 kDa) are identified as auxiliary γ subunits of the BK Ca channel [ 48 ]. The expression of LRRC proteins is also tissue-dependent [ 49 ].…”

BK Channel in the Physiology and in the Cancer of Pancreatic Duct: Impact and Reliability of BK Openers

“…It has been reported for other types of cancers that the neoplastic tissue can differ from the normal one in terms of BK splice variants and regulatory subunits expression. For example, Egland et al observed in pancreatic cancer tissues samples the expression of the γ1 protein LRRC26 (also known as CAPC), which left-shifts the voltage-dependence of the channel activation to more hyperpolarized voltages ( Egland et al, 2006 ; Gonzalez-Perez et al, 2022 ). For the parotid BK channel V 1/2 values of 50 mV have been measured when the channel was co-expressed in CHO cells with the LRRC26 protein and of 189 mV for the α subunit expressed alone ( Almassy and Begenisich, 2012 ).…”