Functional α7 nicotinic receptors in human airway smooth muscle increase intracellular calcium concentration and contractility in asthmatics

Abstract

Although nicotinic acetylcholine receptors (nAChRs) are commonly associated with neurons in the brain and periphery, recent data indicate they are also expressed in non-neuronal tissues. We recently found the alpha7 (α7nAChR) subunit is highly expressed in human airway smooth muscle (hASM) with substantial increase in asthmatics, but their functionality remains unknown. We investigated the location and functional role of α7nAChRs in hASM cells from normal vs. mild-moderate asthmatic patients. Immunostaining and protein analyses showed α7nAChR in the plasma membrane including in asthmatics. Patch clamp recordings showed functional homomeric α7nAChR channels at are significantly higher in asthmatic hASM. Real-time fluorescence imaging showed nicotine, via α7nAChR, increases intracellular Ca2+ ([Ca2+]i) independent of ACh effects, particularly in asthmatic hASM, while cellular traction force microscopy showed nicotine-induced contractility including in asthmatics. These results indicate functional homomeric and heteromeric nAChRs that are increased in asthmatic hASM, with pharmacology that likely differ owing to different subunit interfaces that form the orthosteric sites. nAChRs may represent a novel target in alleviating airway hyperresponsiveness in asthma. New and Noteworthy Cigarette smoking and vaping exacerbate asthma. Understanding mechanisms of nicotine effects in asthmatic airways is important. This study demonstrates functional alpha7 nicotinic acetylcholine receptors (α7nAChRs) are expressed in human airway smooth muscle, including from asthmatics, and enhance intracellular calcium and contractility. Although a7nAChRs are associated with neuronal pathways, α7nAChR in smooth muscle suggests inhaled nicotine (e.g. vaping) can directly influence airway contractility. Targeting α7nAChR may represent a novel approach to alleviating airway hyperresponsiveness in asthma.

Cigarette smoke impairs pulmonary vascular function through nAChR activation

“…Although its mechanism of action remains unclear, data point to an involvement of nicotinic channels in these processes (26,27). In line with this, previous reports suggest that calcium homeostasis may be affected during exposure to CS due to the influx of calcium and sodium ions through nAChR located in the plasmatic and the mitochondrial membrane (28,26,29). Because of these facts, it is plausible that signaling through these receptors would play an important role in the effects of smoking on the pulmonary artery.…”