Abstract
In chronic lung diseases, activation of airway sensory nerves initiate respiratory reflexes including cough for which there is currently no safe and effective treatment. Ion channels on sensory afferents can activate these reflexes and as such are attractive therapeutic targets. The ion channel TRPM3 is a sensor of noxious heat (Vriens J.et al.Neuron.2011:70.482-494), is activated by hypoosmolarity and is expressed in somatosensory neurons from dorsal root and trigeminal ganglia. We aimed to characterise the role of TRPM3 in airway sensory nerve activation and the cough reflex.
Single cell PCR demonstrated that TRPM3 was expressed in airway specific neurons from guinea pig (GP) nodose and jugular ganglia. Functional experiments using selective pharmacological tools indicated that the TRPM3 agonist CIM0216 evoked [Ca2+]i flux in isolated airway neurons, and also depolarisation of mouse, GP and human vagus nerves in an in vitro preparation. Depolarisation by CIM0216 and hypoosmolar solution was inhibited by two selective TRPM3 antagonists and in Trpm3-/-mice. Preliminary results demonstrate action potential firing by CIM0216 of C-fibres in the anaesthetised GP.
These data suggest that TRPM3 is expressed in airway sensory neurons and that activators of TRPM3 cause functionally relevant activation of airway nerves. Recent data using preclinical models and clinical challenge studies has demonstrated differing profiles of cough responses across diseases, supporting the concept of disease-specific neurophenotypes and underlining the need to understand airway neurobiology (Belvisi MG.et al.AJRCCM.2016). The discovery of TRPM3 as a regulator of airway reflexes suggests it may be a novel target for antitussive therapy.
- Copyright ©the authors 2016
