Regulation of Intracellular Calcium by Bitter Taste Receptors on Airway Smooth Muscle

Abstract

Recent studies have demonstrated the expression of bitter taste receptors (BTRs) on airway smooth muscle (ASM) using human, mouse, and guinea-pig airways. BTRs, belonging to the Tas2R family, are activated by a wide range of synthetic and natural compounds. However, these receptors are evolved with low, but broad-spectrum affinity for their ligands. Stimulation of BTRs with known bitter tastants results in an elevation of basal intracellular calcium concentration in cultured human ASM cells, similar to stimulation with other Gq-coupled G protein coupled receptors. Studies in human and murine ASM cells have demonstrated that bitter tastant-induced calcium elevation is Gβγ-, phospholipase C-, inositol trisphosphate (IP3)-, and IP3-receptor dependent. Very interestingly, bitter tastants induce efficacious ASM relaxation and bronchodilation in airways obtained from human, mouse, and guinea-pig lungs. At least two potential mechanisms for bitter-tastant-induced ASM relaxation have been proposed: (1) activation of calcium-activated potassium channels by calcium induced by bitter tastants, resulting in membrane hyperpolarization and ASM relaxation, and (2) inhibition of calcium entry via voltage-dependent calcium channels upon stimulation of ASM with contractile agonists, thereby inhibiting contraction. Nevertheless, the paradoxical effect of bitter tastants on ASM tone is intriguing and establishes Tas2 receptors as a novel class of therapeutic targets in the treatment of obstructive airway diseases such as asthma and chronic obstructive pulmonary disease.