Essential role of TRPC3 channel as both NF‐κB upstream and downstream signaling molecule in asthmatic airway hyperresponsiveness and remodeling

Abstract

Canonical transient receptor potential (TRPC) channels are known to be crucial for numerous cellular responses in a variety of cells; however, their functional importance is unknown in airway smooth muscle cells (ASMCs). We recently demonstrate among all identified 7 members, TRPC3 channel predominantly shows a constitutively functional activity in ASMCs, and its expression and activity are significantly augmented in asthmatic ASMCs. Our more recent works reveal that intravenous injection of lentivirus encoding TRPC3 shRNAs into mice via a hydrodynamic delivery technique can effectively silence TRPC3 channel expression and activity in ASMCs. More excitingly, asthmatic airway hyper‐responsiveness, determined by the increased respiratory resistance and enhanced airway muscle contraction, is fully blocked in TRPC3 gene silencing mice. In support of its imperative role, TRPC3 channel shows the remarkably increased activity in response to the intracellular second messengers inositol 1,4,5‐trisphosphate, diacylglycerol and calcium, and all these responses are completely blocked in TRPC3 channel silencing mouse cells. The asthmatic airway remodeling, gauged by the augmented ASMCs proliferation rate revealed by Ki67 and increased ASMCs layer assessed by α‐smooth muscle actin, is abolished as well in TRPC3 silencing mice. We have further found that TRPC3 silencing inhibits the asthmatic increase in NF‐κB activity and cyclin D1 expression, the two vital molecules involved in asthmatic airway remodeling. Equally fascinatingly, inhibition of NF‐κB by silencing its indispensable component p65 prevents the asthmatic increase in TRPC3 expression and activity in ASMCs. Collectively, we conclude that TRPC3 channel may function as both the NF‐κB upstream and downstream signaling molecule to play an essential role in asthmatic airway hyper‐responsiveness and remodeling.