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The voltage-gated Na+ channel NaV1.9 remains an important pain target because of its preferential expression in nociceptors, its involvement in rodent models of nociception, and the association between gain- or loss-of-function NaV1.9 mutations with the presence or absence of pain in humans. At room temperature, NaV1.9 has a low threshold for activation, carrying a persistent current that may influence the resting membrane potential, action potential threshold, and burst firing. We recently demonstrated that in the absence of extracellular Na+, NaV1.9 may also contribute to a transient outward current. Here, we used whole cell patch clamp recordings of human and rat dorsal root ganglion neurons to further characterize this outward current. We found that this current had pharmacological and biophysical properties consistent with a role for NaV1.9: insensitivity to K+, Na+, Cl-, and TRP channel blockers, sensitivity to internally-administered Na+ channel blocker QX-314, and an NaV1.9-like voltage-dependence of inactivation, steady-state inactivation, recovery from inactivation. Interestingly, in contrast to TTX- and A-803467-sensitive currents, the transient outward current persisted in the absence of intracellular Na+, suggesting that NaV1.9 is less selective than other voltage-gated Na+ channels in human and rat sensory neurons. Consistent with this suggestion, the reversal potential for persistent (NaV1.9) inward currents was left shifted relative to that of TTX- and A-803467-sensitive currents. Furthermore, the outward current persisted in the presence of even relatively large intracellular cations (Cs+ and TEA+). Our results suggest NaV1.9 is a relatively non-selective ion channel. Together, these observations have at least two important implications. First, NaV1.9-mediated currents may contaminate voltage-clamp recordings of voltage-gated K+, Ca2+, and Cl- channels in sensory neurons. Second, NaV1.9 may have a more significant impact on the action potential waveform than previously appreciated, including the attenuating the action potential overshoot. Grant support from NIH R01NS122784, NIH 4UH3TR003090.
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