TTX ‐S/ TTX ‐R Na + Currents Coordinately Fine‐Tune Depolarization/Firing Capability Revealed by Voltage Derivatives/Displacement Current Phase Plots With Dynamic Current‐Clamp Simulation in Rat Visceral Sensory Neurons

ABSTRACT Aim 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. Methods 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. Results 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. Conclusion 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.