Targeted Inhibition of KCa3.1 Channel Attenuates Airway Inflammation and Remodeling in Allergic Asthma

Abstract

KCa3.1 has been suggested to be involved in regulating cell activation, proliferation, and migration in multiple cell types, including airway inflammatory and structural cells. However, the contributions of KCa3.1 to airway inflammation and remodeling and subsequent airway hyperresponsiveness (AHR) in allergic asthma remain to be explored. The main purpose of this study was to elucidate the roles of KCa3.1 and the potential therapeutic value of KCa3.1 blockers in chronic allergic asthma. Using real-time PCR, Western blotting, or immunohistochemical analyses, we explored the precise role of KCa3.1 in the bronchi of allergic mice and asthmatic human bronchial smooth muscle cells (BSMCs). We found that KCa3.1 mRNA and protein expression were elevated in the bronchi of allergic mice, and double labeling revealed that up-regulation occurred primarily in airway smooth muscle cells. Triarylmethane (TRAM)-34, a KCa3.1 blocker, dose-dependently inhibited the generation and maintenance of the ovalbumin-induced airway inflammation associated with increased Th2-type cytokines and decreased Th1-type cytokine, as well as subepithelial extracellular matrix deposition, goblet-cell hyperplasia, and AHR in a murine model of asthma. Moreover, the pharmacological blockade and gene silencing of KCa3.1, which was evidently elevated after mitogen stimulation, suppressed asthmatic human BSMC proliferation and migration, and arrested the cell cycle at the G0/G1 phase. In addition, the KCa3.1 activator 1-ethylbenzimidazolinone-induced membrane hyperpolarization and intracellular calcium increase in asthmatic human BSMCs were attenuated by TRAM-34. We demonstrate for the first time an important role for KCa3.1 in the pathogenesis of airway inflammation and remodeling in allergic asthma, and we suggest that KCa3.1 blockers may represent a promising therapeutic strategy for asthma.

Anti-steatotic and anti-fibrotic effects of the KCa3.1 channel inhibitor, Senicapoc, in non-alcoholic liver disease

“…Furthermore, associated with this reduction in hepatic steatosis by Senicapoc was a reduction in markers of hepatic inflammation - the inflammatory component of NAS, 4-HNE and F4/80. While the present study did not seek to determine whether this anti-inflammatory effect derived from the upstream anti-steatotic effect or was a direct effect of KCa3.1 inhibition on Kupffer cells as reported previously, our results with Senicapoc are in line with that of TRAM-34 in a model of murine airway inflammation and remodeling[26]. In that study, TRAM-34 inhibited the generation and maintenance of inflammation and subepithelial extracellular matrix deposition.…”

SK4 channels modulate Ca2+ signalling and cell cycle progression in murine breast cancer

“…Current knowledge suggests that BK (Lallet‐Daher et al ., 2009; Parihar et al ., 2003; Stegen et al ., 2015) and SK4 (Ouadid‐Ahidouch et al ., 2004; Parihar et al ., 2003; Steinle et al ., 2011) activities are required for malignant growth of several tumour‐derived cell lines and of xenografts in immunocompromised mice, highlighting a general role of K Ca channels for cell cycle‐specific functions (Huang and Jan, 2014; Pardo and Stuhmer, 2014). Expression of SK4 and BK in cancer cells follows a cell cycle‐dependent mode (Ouadid‐Ahidouch et al ., 2004; Pardo et al ., 1998) and the mitogen‐dependent regulation of K Ca activity supports a role for both channels in malignant (Faouzi et al ., 2010; Lallet‐Daher et al ., 2009; Wang et al ., 2007a) and nonmalignant cell proliferation (Grgic et al ., 2005; Khanna et al ., 1999; Toyama et al ., 2008; Yu et al ., 2013). By inducing a more negative membrane voltage, activation of K + channels provides a driving force for Ca 2+ influx into the nonexcitable tumour cell.…”

The Role of the Cytoskeleton and Myosin-Vc in the Targeting of KCa3.1 to the Basolateral Membrane of Polarized Epithelial Cells

“…Interestingly, in therapeutic development, many steps have been taken to regulate the K + channel activity of KCa3.1 via pharmacological agonists or inhibitors (Wulff et al, 2001; Bradding and Wulff, 2009; Köhler et al, 2010; Yu et al, 2013), however, little research has been conducted to examine the mechanism of how KCa3.1 is targeted to the plasma membrane. Increased or decreased KCa3.1 activity can result in altered pathophysiological states (Albaqumi et al, 2008; Al-Hazza et al, 2012).…”