Contribution of tetrodotoxin-sensitive, voltage-gated sodium channels (Na1) to action potential discharge from mouse esophageal tension mechanoreceptors.

Action potentials depend on voltage-gated sodium channels (Na1s), which have nine α subtypes. Na1 inhibition is a target for pathologies involving excitable cells such as pain. However, because Na1 subtypes are widely expressed, inhibitors may inhibit regulatory sensory systems. Here, we investigated specific Na1s and their inhibition in mouse esophageal mechanoreceptors-non-nociceptive vagal sensory afferents that are stimulated by low threshold mechanical distension, which regulate esophageal motility. Using single fiber electrophysiology, we found mechanoreceptor responses to esophageal distension were abolished by tetrodotoxin. Single-cell RT-PCR revealed that esophageal-labeled TRPV1-negative vagal neurons expressed multiple tetrodotoxin-sensitive Na1s: Na1.7 (almost all neurons) and Na1.1, Na1.2, and Na1.6 (in ∼50% of neurons). Inhibition of Na1.7, using PF-05089771, had a small inhibitory effect on mechanoreceptor responses to distension. Inhibition of Na1.1 and Na1.6, using ICA-121341, had a similar small inhibitory effect. The combination of PF-05089771 and ICA-121341 inhibited but did not eliminate mechanoreceptor responses. Inhibition of Na1.2, Na1.6, and Na1.7 using LSN-3049227 inhibited but did not eliminate mechanoreceptor responses. Thus, all four tetrodotoxin-sensitive Na1s contribute to action potential initiation from esophageal mechanoreceptors terminals. This is different to those Na1s necessary for vagal action potential conduction, as demonstrated using GCaMP6s imaging of esophageal vagal neurons during electrical stimulation. Tetrodotoxin-sensitive conduction was abolished in many esophageal neurons by PF-05089771 alone, indicating a critical role of Na1.7. In summary, multiple Na1 subtypes contribute to electrical signaling in esophageal mechanoreceptors. Thus, inhibition of individual Na1s would likely have minimal effect on afferent regulation of esophageal motility.