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.