Canonical transient receptor potential 3 channels activate NF‐κB to mediate allergic airway disease via PKC‐α/IκB‐α and calcineurin/IκB‐β pathways

Abstract

The purpose of this study was to determine the role of canonical transient receptor potential 3 (TRPC3) channel in allergen-induced airway disease (AIAD) and its underlying signaling mechanisms. The procedures included (1) intravenous injection of lentiviral TRPC3 channel or nonsilencing short hairpin ribonucleic acid (shRNA) to make the channel knockdown (KD) or control mice, (2) allergen sensitization/challenge to induce AIAD, (3) patch-clamp recording and Ca(2+) imaging to examine the channel activity, and (4) gene manipulations and other methods to determine the underlying signaling mechanisms. The findings are that (1) intravenous or intranasal delivery of TRPC3 channel lentiviral shRNAs or blocker 1-[4-[(2,3,3-trichloro-1-oxo-2-propen-1-yl)amino]phenyl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid prevents AIAD in mice, (2) TRPC3 channel KD and overexpression, respectively, blocks and augments protein kinase C-α/nuclear factor of κ light polypeptide gene enhancer in B-cell inhibitor-α (PKC-α/IκB-α)-mediated or calcineurin/IκB-β-dependent, NF-κB-dependent allergen-induced airway smooth muscle cell (ASMC) hyperproliferation and cyclin D1 (an important cell proliferation molecule) induction, and (3) the changes of the major molecules of the PKC-α/IκBα- and calcineurin/IκB-β-dependent NF-κB signaling pathways are also observed in asthmatic human ASMCs. The conclusions are that TRPC3 channels plays an essential role in AIAD via the PKC-α/IκB-α- and calcineurin/IκB-β-dependent NF-κB signaling pathways, and lentiviral shRNA or inhibitor of TRPC3 channels may become novel and effective treatments for AIAD.

TRPC3 overexpression and intervention in airway smooth muscle of ovalbumin‐induced hyperresponsiveness and remodeling

“…We found that 5, 10 µM GdCl 3 attenuated contractile force of ASM, and the contractile force reduced to 81.6 and 61.3%, respectively. Our data in asthmatic Kunming mice were consistent with previous reports in asthmatic Swiss Webster and BALB/c mice (Song et al, ; Wang et al, ).…”

“…Expression level of TRPC3 may affect ASM cell membrane potential. Expression and activity of TRPC3 significantly up‐regulated in OVA‐sensitized/challenged ASM cells, contributing to membrane depolarization and airway hyperresponsiveness (Xiao et al, ; Song et al, ; Wang et al, ). In our study, TRPC3 protein increased in ASM from asthmatic Kunming mice, suggesting that the airway hyperresponsiveness and remodeling induced by OVA may be associated with TRPC3 protein overexpression in ASM.…”

TRPC3‐mediated Ca2+ signals as a promising strategy to boost therapeutic angiogenesis in failing hearts: The role of autologous endothelial colony forming cells

“…In other words, TRPC3 may serve as a platform for signal transduction processes at the PM (Lichtenegger & Groschner, ). Furthermore, TRPC3‐mediated Ca 2+ entry could engage PKCα, thereby promoting IκB‐α phosphorylation and the nuclear translocation of NF‐κB in mouse airway smooth muscle cells (Song et al, ). The same study further showed that TRPC3 stimulates the nuclear relocation of NF‐κB by recruiting the calcineurin/IκB‐β pathway (Song et al, ).…”

Direct Activation of TRPC3 Channels by the Antimalarial Agent Artemisinin

“…Thus, the functional expression of TRPC3 in healthy tissues other than brain may be more restricted than frequently assumed. This property seems to change in diseased conditions, where aberrant TRPC3 expression or function can contribute to the pathophysiology of ataxia [5,37], cardiac arrhythmias [7,38], cardiac hypertrophy [39][40][41], cardiac and renal fibrosis [42,43], to allergic airway disease [44,45], or to inflammatory hyperalgesia [46]. Here, artemisinin may immediately become helpful to differentiate between the functional significance of TRPC3 and TRPC6, which are frequently co-expressed, and to further validate TRPC3 as a potential pharmacological target.…”