Tas2R activation relaxes airway smooth muscle by release of Gα _t targeting on AChR signaling

Abstract

Both chronic obstructive pulmonary disease (COPD) and asthma are severe respiratory diseases. Bitter receptor–mediated bronchodilation is a potential therapy for asthma, but the mechanism underlying the agonistic relaxation of airway smooth muscle (ASM) is not well defined. By exploring the ASM relaxation mechanism of bitter substances, we observed that pretreatment with the bitter substances nearly abolished the methacholine (MCh)-induced increase in the ASM cell (ASMC) calcium concentration, thereby suppressing the calcium-induced contraction release. The ASM relaxation was significantly inhibited by simultaneous deletion of three Gα t proteins, suggesting an interaction between Tas2R and AChR signaling cascades in the relaxation process. Biochemically, the Gα t released by Tas2R activation complexes with AChR and blocks the Gα q cycling of AChR signal transduction. More importantly, a bitter substance, kudinoside A, not only attenuates airway constriction but also significantly inhibits pulmonary inflammation and tissue remodeling in COPD rats, indicating its modulation of additional Gα q -associated pathological processes. Thus, our results suggest that Tas2R activation may be an ideal strategy for halting multiple pathological processes of COPD.

A Par3/LIM Kinase/Cofilin Pathway Mediates Human Airway Smooth Muscle Relaxation by TAS2R14

“…In addition, the critical findings were observed regardless of whether the HASM had been cotreated with G q -receptor agonists, which constrict the airway. Thus, the idea that TAS2R agonists signal to relaxation strictly by “competitive” mechanisms with G q -receptor actions ( 31 ) seems less likely, at least in human airway SM. Indeed, in prior work we showed that relaxation of human airway rings, and isolated HASM, was readily observed under resting (nonstimulated) conditions.…”

“…Indeed, in prior work we showed that relaxation of human airway rings, and isolated HASM, was readily observed under resting (nonstimulated) conditions. Interestingly, in a recent report with mice, gustducin expression was detected in the mouse airway SM, and when deleted the TAS2R-evoked bronchodilation was lost ( 31 ). We find in HASM that this function is likely performed by G i1,2,3 ( 6 ).…”

The Complex Journey of the Calcium Regulation Downstream of TAS2R Activation

“…For example, TAS2R46 is a poorly expressed receptor in ASM cells [ 8 , 14 ] compared to the most studied subtypes, but the high specificity and high affinity of absinthin allows the dissection of the role played by this receptor in bronchodilation [ 15 ]. In support of this evidence, Zhou and colleagues [ 69 ] recently demonstrated that the calcium increase following TAS2R activation is not sufficient to determine the phosphorylation of the myosin chain [ 69 ] and thus to trigger ASM cell contraction. Another relevant feature of TAS2Rs is their specificity and selectivity towards the contracting stimulus.…”

“…Altogether, this also suggests that TAS2Rs might behave differently in resting or activated cells and that some of the controversies in the literature may be explained by this. It has been observed that TAS2R signaling interferes with the IP3-mediated contraction pathway, lowering cytosolic calcium concentrations to a level no longer sufficient to support the contraction [ 15 , 67 , 69 ]. For example, we have recently shown that the specific TAS2R46 agonist absinthin does not perturb intracellular calcium in resting ASM cells but instead counteracts the increase in cytosolic calcium when the cells are challenged with histamine.…”

“…Altogether, these observations confirm the ability of activated TAS2Rs to impair IP3-dependent bronchoconstriction independently of the ability to activate PLC. Recently, another downstream signaling for TAS2R has been described in ASM cells co-treated with methacholine and kudinoside A (a specific ligand of TAS2R10): the bitter agonist inhibits the Gq recycling downstream of the acetylcholine receptor, resulting in the blocking of the signal transduction required for contraction [ 69 ]. All these observations, furthermore, underline the complexity of the interaction between a contracting agent and bitter ligand cascades.…”