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Roles of LRRC26 as an auxiliary ?1-subunit of large-conductance Ca²⁺-activated K⁺ channels in bronchial smooth muscle cells.

ABSTRACT: In visceral smooth muscle cells (SMCs), the large-conductance Ca²⁺-activated K⁺ (BK) channel is one of the key elements underlying a negative feedback mechanism that is essential for the regulation of intracellular Ca²⁺ concentration. Although leucine-rich repeat-containing (LRRC) proteins have been identified as novel auxiliary ?-subunits of the BK channel (BK?) in several cell types, its physiological roles in SMCs are unclear. The BK? expression patterns in selected SM tissues were examined using real-time PCR analyses and Western blotting. The functional contribution of BK?1 to BK channel activity was examined by whole cell patch-clamp in SMCs and heterologous expression systems. BK?1 expression in mouse bronchial SMCs (mBSMCs) was higher than in other several SMC types. Coimmunoprecipitation and total internal reflection fluorescence imaging analyses revealed molecular interaction between BK? and BK?1 in mBSMCs. Under voltage-clamp, steady-state activation of BK channel currents at pCa 8.0 in mBSMCs occurred in a voltage range comparable to that of reconstituted BK?/BK?1 complex. However, this range was much more negative than in mouse aortic SMCs (mASMCs) or in HEK293 cells expressing BK? alone and ?-subunit (BK?1). Mallotoxin, a selective activator of BK channel that lacks BK?1, dose-dependently activated BK currents in mASMCs but not in mBSMCs. The abundant expression of BK?1 in mBSMCs extensively facilitates BK channel activity to keep the resting membrane potential at negative values and prevents contraction under physiological conditions.

SUBMITTER: Noda S

PROVIDER: S-EPMC7052682 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Roles of LRRC26 as an auxiliary γ1-subunit of large-conductance Ca2+-activated K+ channels in bronchial smooth muscle cells.

Noda Sayuri S Suzuki Yoshiaki Y Yamamura Hisao H Giles Wayne R WR Imaizumi Yuji Y

American journal of physiology. Lung cellular and molecular physiology 20191204 2

In visceral smooth muscle cells (SMCs), the large-conductance Ca2+-activated K+ (BK) channel is one of the key elements underlying a negative feedback mechanism that is essential for the regulation of intracellular Ca2+ concentration. Although leucine-rich repeat-containing (LRRC) proteins have been identified as novel auxiliary γ-subunits of the BK channel (BKγ) in several cell types, its physiological roles in SMCs are unclear. The BKγ expression patterns in se ...[more]

PMID: 31800260

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Project description:BackgroundTransmembrane protein 16A (TMEM16A) Ca2+-activated Cl- channels have diverse physiological functions, such as epithelial secretion of Cl- and fluid and sensation of pain. Recent studies have demonstrated that TMEM16A contributes to the pathogenesis of infectious and non-infectious inflammatory diseases. However, the role of TMEM16A in inflammation has not been clearly elucidated.Aim of reviewIn this review, we aimed to provide comprehensive information regarding the roles of TMEM16A in inflammation by summarizing the mechanisms underlying TMEM16A expression and activation under inflammatory conditions, in addition to exploring the diverse inflammatory signaling pathways activated by TMEM16A. This review attempts to develop the idea that TMEM16A plays a diverse role in inflammatory processes and contributes to inflammatory diseases in a cellular environment-dependent manner.Key scientific concepts of reviewMultiple inflammatory mediators, including cytokines (e.g., interleukin (IL)-4, IL-13, IL-6), histamine, bradykinin, and ATP/UTP, as well as bacterial and viral infections, promote TMEM16A expression and/or activity under inflammatory conditions. In addition, TMEM16A activates diverse inflammatory signaling pathways, including the IP3R-mediated Ca2+ signaling pathway, the NF-κB signaling pathway, and the ERK signaling pathway, and contributes to the pathogenesis of many inflammatory diseases. These diseases include airway inflammatory diseases, lipopolysaccharide-induced intestinal epithelial barrier dysfunction, acute pancreatitis, and steatohepatitis. TMEM16A also plays multiple roles in inflammatory processes by increasing vascular permeability and leukocyte adhesion, promoting inflammatory cytokine release, and sensing inflammation-induced pain. Furthermore, TMEM16A plays its diverse pathological roles in different inflammatory diseases depending on the disease severity, proliferating status of the cells, and its interacting partners. We herein propose cellular environment-dependent mechanisms that explain the diverse roles of TMEM16A in inflammation.

Project description:1. Nine bis-quinolinyl and bis-quinolinium compounds related to dequalinium, and previously shown to block apamin-sensitive small conductance Ca(2+)-activated K(+) channels (SK(Ca)), have been tested for their inhibitory effects on actions mediated by intermediate conductance Ca(2+)-activated K(+) channels (IK(Ca)) in rabbit blood cells. 2. In most experiments, a K(+)-sensitive electrode was employed to monitor the IK(Ca)-mediated net loss of cell K(+) that followed the addition of the Ca(2+) ionophore A23187 (2 microM) to red cells suspended at an haematocrit of 1% in a low K(+) (0.12 - 0.17 mM) solution. The remainder used an optical method based on measuring the reduction in light transmission that occurred on applying A23187 (0.4 or 2 microM) to a very dilute suspension of red cells (haematocrit 0.02%). 3. Of the compounds tested, the most potent IK(Ca) blocker was 1,12 bis[(2-methylquinolin-4-yl)amino]dodecane (UCL 1407) which had an IC(50) of 0.85+/-0.06 microM (mean+/-s.d. mean). 4. The inhibitory action of UCL 1407 and its three most active congeners was characterized by (i) a Hill slope greater than unity, (ii) sensitivity to an increase in external [K(+)], and (iii) a time course of onset that suggested use-dependence. Also, the potency of the nonquaternary compounds tested increased with their predicted lipophilicity. These findings suggested that the IK(Ca) blocking action resembles that of cetiedil rather than of clotrimazole. 5. Some quaternized members of the series were also active. The most potent was the monoquaternary UCL 1440 ((1-[N-[1-(3, 5-dimethoxybenzyl)-2-methylquinolinium-4-yl]amino]-10-[N'-(2-me thylqu inolinium-4yl)amino] decane (trifluoroacetate) which had an IC(50) of 1.8+/-0.1 microM. The corresponding bisquaternary UCL 1438 (1, 10-bis[N-[1-(3,5-dimethoxybenzyl)-2-methylquinolinium-4-yl]amino] decane bis(trifluoroacetate) was almost as active (IC(50) 2.7+/-0.3 microM). 6. A bis-aminoquinolium cyclophane (UCL 1684) had little IK(Ca) blocking action despite its great potency at SK(Ca) channels (IC(50) 4.1+/-0.2 nM). 7. The main outcome is the identification of new intermediate-conductance Ca(2+)-activated K(+) channel blockers with a wide range of IK(Ca)/SK(Ca) selectivities.

Dataset Information

Roles of LRRC26 as an auxiliary ?1-subunit of large-conductance Ca²⁺-activated K⁺ channels in bronchial smooth muscle cells.

Publications

Roles of LRRC26 as an auxiliary γ1-subunit of large-conductance Ca<sup>2+</sup>-activated K<sup>+</sup> channels in bronchial smooth muscle cells.

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Dataset Information

Roles of LRRC26 as an auxiliary ?1-subunit of large-conductance Ca2+-activated K+ channels in bronchial smooth muscle cells.

Publications

Roles of LRRC26 as an auxiliary γ1-subunit of large-conductance Ca<sup>2+</sup>-activated K<sup>+</sup> channels in bronchial smooth muscle cells.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Roles of LRRC26 as an auxiliary ?1-subunit of large-conductance Ca²⁺-activated K⁺ channels in bronchial smooth muscle cells.