Action potential conduction in the mouse and rat vagus nerve is dependent on multiple voltage-gated sodium channels (NaV1s)

Action potential (AP) conduction depends on voltage-gated sodium channels, of which there are nine subtypes. The vagus nerve, comprising sensory afferent fibers and efferent parasympathetic fibers, provides autonomic regulation of visceral organs, but the voltage-gated sodium channels (Na(V)1) subtypes involved in its AP conduction are poorly defined. We studied the A- and C-waves of electrically stimulated compound action potentials (CAPs) of the mouse and rat vagus nerves with and without Na(V)1 inhibitor administration: tetrodotoxin (TTX), PF-05089771 (mouse Na(V)1.7), ProTX-II (Na(V)1.7), ICA-121341 (Na(V)1.1, Na(V)1.3, and Na(V)1.6), LSN-3049227 (Na(V)1.2, Na(V)1.6, and Na(V)1.7), and A-803467 (Na(V)1.8). We show that TTX-sensitive Na(V)1 channels are essential for all vagal AP conduction. PF-05089771 but not ICA-121341 inhibited the mouse A-wave, which was abolished by LSN-3049227, suggesting roles for Na(V)1.7 and Na(V)1.2. The mouse C-wave was abolished by LSN-3049227 and a combination of PF-05089771 and ICA-121341, suggesting roles for Na(V)1.7 and Na(V)1.6. The rat A-wave was inhibited by ProTX-II, ICA-121341, and a combination of these inhibitors but only abolished by LSN-3049227, suggesting roles for NaV1.7, Na(V)1.6, and Na(V)1.2. The rat C-wave was abolished by LSN-3049227 and a combination of ProTX-II and ICA-121341, suggesting roles for NaV1.7 and Na(V)1.6. A-803467 also inhibited the mouse and rat CAP suggesting a cooperative role for the TTX-resistant Na(V)1.8. Overall, our data demonstrate that multiple Na(V)1 subtypes contribute to vagal CAPs, with Na(V)1.7 and NaV1.8 playing predominant roles and Na(V)1.6 and Na(V)1.2 contributing to a different extent based on nerve fiber type and species. Inhibition of these Na(V)1 may impact autonomic regulation of visceral organs.

Automated summary

This study identified multiple Na(V)1 subtypes involved in vagal AP conduction, with Na(V)1.7 and NaV1.8 playing predominant roles and Na(V)1.6 and Na(V)1.2 contributing to a different extent based on nerve fiber type and species. Inhibition of these Na(V)1 may impact autonomic regulation of visceral organs.