Years of tenacious work revealed important changes in T2R signaling that occur with airway epithelial squamous de-differentiation. This paper is a tour-de-force of live cell imaging of indicator dyes and genetically encoded targeted probes for subcellular calcium imaging. We're very proud of this work, and it may reveal novel pathogenic mechanisms in disease where airway de-differentiation occurs, such as COPD, asthma, or chronic rhinosinusitis.
Rather than activating calcium in cilia to increase NO production and ciliary beating, T2R activation in non-ciliated airway cells induces strong nuclear calcium responses that propagate to the mitochondria. This results in mitochondrial depolarization, caspase activation, and apoptotic cell death. This may be a last-resort defense against bacterial infection. However, it may also increase susceptibility of de-differentiated or remodeled epithelia to damage by bacterial metabolites. Moreover, the T2R-activated apoptosis pathway occurs in airway cancer cells. T2Rs may thus contribute to microbiome-tumor cell crosstalk in airway cancers. Targeting T2Rs may be useful for activating cancer cell apoptosis while sparing surrounding tissue.