Contribution of tetrodotoxin-sensitive, voltage-gated sodium channels (Na(V)1) to action potential discharge from mouse esophageal tension mechanoreceptors

Action potentials depend on voltage-gated sodium channels (Na(V)1s), which have nine a subtypes. Na(V)1 inhibition is a target for pathologies involving excitable cells such as pain. However, because Na(V)1 subtypes are widely expressed, inhibitors may inhibit regulatory sensory systems. Here, we investigated specific Na(V)1s 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 Na(V)1s: NaV1.7 (almost all neurons) and Na(V)1.1, Na(V)1.2, and Na(V)1.6 (in similar to 50% of neurons). Inhibition of Na(V)1.7, using PF-05089771, had a small inhibitory effect on mechanoreceptor responses to distension. Inhibition of Na(V)1.1 and Na(V)1.6, 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 Na(V)1.2, Na(V)1.6, and Na(V)1.7 using LSN-3049227 inhibited but did not eliminate mechanoreceptor responses. Thus, all four tetrodotoxin-sensitive Na(V)1s contribute to action potential initiation from esophageal mechanoreceptors terminals. This is different to those Na(V)1s 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 Na(V)1.7. In summary, multiple Na(V)1 subtypes contribute to electrical signaling in esophageal mechanoreceptors. Thus, inhibition of individual Na(V)1s would likely have minimal effect on afferent regulation of esophageal motility.