Taste and smell GPCRs in the lung: Evidence for a previously unrecognized widespread chemosensory system

Taste and smell receptor expression has been traditionally limited to the tongue and nose. We have identified bitter taste receptors (TAS2Rs) and olfactory receptors (ORs) on human airway smooth muscle (HASM) cells. TAS2Rs signal to PLCβ evoking an increase in [Ca²⁺]_i causing membrane hyperpolarization and marked HASM relaxation ascertained by single cell, ex vivo, and in vivo methods. The presence of TAS2Rs in the lung was unexpected, as was the bronchodilatory function which has been shown to be due to signaling within specific microdomains of the cell. Unlike β₂-adrenergic receptor-mediated bronchodilation, TAS2R function is not impaired in asthma and shows little tachyphylaxis. HASM ORs do not bronchodilate, but rather modulate cytoskeletal remodeling and hyperplasia, two cardinal features of asthma. We have shown that short chain fatty acids, byproducts of fermentation of polysaccharides by the gut microbiome, activate HASM ORs. This establishes a non-immune gut-lung mechanism that ties observations on gut microbial communities to asthma phenotypes. Subsequent studies by multiple investigators have revealed expression and specialized functions of TAS2Rs and ORs in multiple cell-types and organs throughout the body. Collectively, the data point towards a previously unrecognized chemosensory system which recognizes endogenous and exogenous agonists. These receptors and their ligands play roles in normal homeostatic functions, predisposition or adaptation to disease, and represent drug targets for novel therapeutics.