Acid modulation of tetrodotoxin-sensitive Na⁺ channels in large-sized trigeminal ganglion neurons

Voltage-gated Na⁺ channels in primary afferent neurons can be divided into tetrodotoxin-sensitive (TTX-S) and tetrodotoxin-resistant (TTX-R) Na⁺ channels. Although previous studies have shown the acid modulation of TTX-R Na⁺ channels, the effect of acidic pH on tetrodotoxin-sensitive (TTX-S) Na⁺ channels is still unknown. Here we report the effect of acidic pH on TTX-S Na⁺ channels expressed in large-sized trigeminal ganglion (TG) neurons using a whole-cell patch clamp technique. The application of acidic extracellular solution decreased the peak amplitude of TTX-S currents (I_Na) in a pH-dependent manner, but weak acid (≥pH 6.0) had no inhibitory effect on TTX-S I_Na. Acidic pH (pH 6.0) shifted both the activation and steady-state fast inactivation relationships of TTX-S Na⁺ channels toward depolarized potentials. However, acidic pH (pH 6.0) had no effect on use-dependent inhibition in response to high-frequency stimuli, development of inactivation, and accelerated the recovery from inactivation of TTX-S Na⁺ channels, suggesting that TTX-S Na⁺ channels in large-sized TG neurons are less sensitive to acidic pH. Given that voltage-gated Na⁺ channels play a pivotal role in the generation and conduction of action potentials in neural tissues, the insensitivity of TTX-S Na⁺ channels expressed in large-sized TG neurons to acidic pH would ensure transmission of innocuous tactile sensation from orofacial regions at acidic pH conditions.