PF-05089771

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_V1) 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_V1 inhibitor administration: tetrodotoxin (TTX), PF-05089771 (mouse Na_V1.7), ProTX-II (Na_V1.7), ICA-121341 (Na_V1.1, Na_V1.3, and Na_V1.6), LSN-3049227 (Na_V1.2, Na_V1.6, and Na_V1.7), and A-803467 (Na_V1.8). We show that TTX-sensitive Na_V1 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_V1.7 and Na_V1.2. The mouse C-wave was abolished by LSN-3049227 and a combination of PF-05089771 and ICA-121341, suggesting roles for Na_V1.7 and Na_V1.6. 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 Na_V1.7, Na_V1.6, and Na_V1.2. The rat C-wave was abolished by LSN-3049227 and a combination of ProTX-II and ICA-121341, suggesting roles for Na_V1.7 and Na_V1.6. A-803467 also inhibited the mouse and rat CAP suggesting a cooperative role for the TTX-resistant Na_V1.8. Overall, our data demonstrate that multiple Na_V1 subtypes contribute to vagal CAPs, with Na_V1.7 and Na_V1.8 playing predominant roles and Na_V1.6 and Na_V1.2 contributing to a different extent based on nerve fiber type and species. Inhibition of these Na_V1 may impact autonomic regulation of visceral organs.NEW & NOTEWORTHY Distinct Na_V1 channels are involved in action potential (AP) initiation and conduction from afferent terminals within specific organs. Here, we have identified the Na_V1 necessary for AP conduction in the entire murine and rat vagus nerve. We show TTX-sensitive channels are essential for all AP conduction, predominantly Na_V1.7 with Na_V1.2 and Na_V1.6 playing lesser roles depending on the species and fiber type. In addition, we show that Na_V1.8 is also essential for most axonal AP conduction.