Na⁺ /Ca²⁺ exchanger 1 is a key mechanosensitive molecule of the esophageal myenteric neurons.

AIM:Our earlier studies showed that mechanical stretch activates inhibitory motor neurons of the oesophagus; however, the underlying molecular mechanisms are unclear. Here, we sought to examine if Na⁺ /Ca²⁺ exchanger 1 (NCX1) is responsible for the mechanosensitivity in the esophageal myenteric neurons (EMN) of rats and humans. METHODS:The function of NCX1 in primary culture of neurons was determined using calcium imaging, and mechanosensitivity was tested using osmotic stretch and direct mechanical stretch. Axial stretch-induced relaxation of the lower esophageal sphincter (LES) was also studied in vivo in rats. RESULTS:The expression and co-localization of NCX1 with nNOS were identified in the EMN from both rats and humans. The extracellular Ca²⁺ entry caused by ATP through purinergic signalling in the rat EMN was significantly inhibited by selective NCX blockers. Removal of extracellular Na⁺ to activate the Ca²⁺ entry mode of NCX1 induced an increase in the cytoplasmic calcium ([Ca²⁺ ]_cyt ), which was attenuated by NCX blockers. Osmotic stretch and mechanical stretch-induced [Ca²⁺ ]_cyt signalling in the rat and human EMN were attenuated by NCX blockers as well as specific NCX1 knockdown. Osmotic stretch and mechanical stretch also induced [Ca²⁺ ]_cyt signalling in the Chinese hamster ovary (CHO) cells with NCX1 over-expression, which was attenuated by NCX blockers. Finally, NCX blockade inhibited axial stretch-activated LES relaxation in vivo experiments in the rats. CONCLUSIONS:We demonstrate a novel NCX1/Ca²⁺ pathway in the mechanosensitive neurons of rat and human oesophagus, which may provide a potential therapeutic target for the treatment of oesophageal motility disorders.

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