A novel role for TRPM3 in Airway Smooth Muscle Contraction

Bronchoconstriction is a key feature of asthma but the disease drivers and signalling mechanisms involved are not fully understood. TRPM3, a member of the Transient Receptor family of ion channels, has recently been shown to activate airway sensory nerves in both animal and human tissue (Bonvini et al 2018, AJRCCM:197:A7411). However, its role in direct bronchoconstriction is currently untested. We therefore aimed to investigate the role of TRPM3 in contraction of airway smooth muscle. The TRPM3 agonist CIM0216 was shown to cause bronchospasm in vivo in the anaesthetised guinea pig (GP), independent of sensory nerve activation. Tissue bath assays indicated that CIM0216 caused a concentration dependent contraction of GP trachea, which was inhibited by the TRPM3 antagonist Primidone. Further investigation revealed that both removal of the epithelium and addition of the selective NK2 antagonist MEN10376 significantly inhibited the contraction induced by CIM0216. RTPCR studies revealed that the TRPM3 gene was expressed on GP epithelial cells, and the TACR2 gene, which is the receptor for NK2, was expressed on GP ASM. These data suggest that activation of TRPM3 on epithelial cells leads to the release of tachykinins which activate the NK2 receptor on airway smooth muscle to cause bronchoconstriction. Tachykinins such as NKA have been well documented to cause contraction in the asthmatic airway. Although further work is required, this implicates the TRPM3 receptor on epithelial cells as a potential non-neuronal source of tachykinin release and subsequent bronchoconstriction, and also highlights it as a possible novel therapeutic target.