Bitter Taste Receptor Agonist (Quinine) Induces Traction Force Reduction and Calcium Flux Increase in Airway Smooth Muscle Cells from Ovalbumin-Sensitized and Challenged Rats

Abstract

Recently, bitter taste receptors (TAS2Rs) have been found in the lung, which can be stimulated with TAS2R agonist such as quinine to relax airway smooth muscle cells (ASMCs) via intracellular Ca²⁺ signaling generated from restricted phospholipase C activation. This provides a promising new therapy for asthma because enhanced contractility and impaired ability of relaxation of the ASMCs within the bronchial wall of asthmatic patients are thought to be ultimately responsible for airway constriction in asthma. However, further study is required for characterization of the effect of TAS2R agonist on the mechanical behaviors of ASMCs, in particular the traction force generation and associated mechanism in asthma model. Here, we sensitized Sprague Dawley rats with ovalbumin (OVA) for up to 12 weeks to simulate chronic asthma symptoms. Subsequently, we isolated ASMCs from these rats, and studied the traction force and intracellular Ca²⁺ signaling of the cells with/out treatment of quinine hydrochloride, a well-known TAS2R agonist. The results demonstrated that quinine hydrochloride relaxed the ASMC in a dose dependent manner. It also evoked dose-dependent increase of intracellular calcium ([Ca²⁺]_i) in the ASMCs. Perhaps more importantly, the quinine-induced traction force reduction and Ca²⁺ flux increase were correlated. Taken together, our findings indicate that TAS2R agonists (e.g. quinine hydrochloride) could reduce the ability of ASMCs to generate traction force via activation of the intracellular calcium signaling, which may contribute as one of the mechanisms for TAS2R agonist-induced ASMC relaxation. This provides additional evidence to support TAS2R agonists as a new class of compounds with potential in treatment of chronic asthma.