TTX-S/TTX-R Na⁺ Currents Coordinately Fine-Tune Depolarization/Firing Capability Revealed by Voltage...

To investigate how tetrodotoxin-sensitive (TTX-S) and tetrodotoxin-resistant (TTX-R) Na⁺ channels coordinately fine-tune action potential (AP) depolarization and firing capability in rat nodose visceral sensory neurons.

APs were recorded by ruptured-patch current clamp in unmyelinated C-type and myelinated Ah-type neurons from isolated and sliced nodose ganglia. Voltage derivatives and displacement current phase plots were used to determine the kick-in voltage of TTX-R following TTX-S activation. Myelinated A-type neurons, which express TTX-S exclusively, served as a model for dynamic current-clamp (DCC) simulation, in which gNa0 (TTX-S) and gNa1 (TTX-R) were injected separately or in combination.

Voltage derivatives and phase plots revealed a biphasic upstroke in C- and Ah-type neurons, indicating sequential TTX-S then TTX-R activation. The TTX-R kick-in voltage was more negative in Ah-type than in C-type neurons and was strongly inversely correlated with the maximal upstroke velocity. DCC faithfully reproduced both AP types; TTX-R reactivation generated the C-type repolarization hump, and AP peak was preserved through proportional gNa0/gNa1 compensation. Increasing the integrated step size of gNa1 delayed TTX-R recruitment, reduced the second Na⁺ peak, and progressively impaired repetitive firing, whereas the TTX-S peak remained unchanged.

TTX-S and TTX-R Na⁺ channels coordinate AP depolarization sequentially and compensatorily: TTX-S initiates the upstroke, whereas TTX-R is recruited later and reactivates during repolarization to constrain firing frequency. Combining patch-clamp with DCC simulation provides novel insight into visceral sensory neuron excitability.