Tetrodotoxin-, dihydropyridine-, and riluzole-resistant persistent inward current: novel sodium channels in rodent spinal neurons

Dai Y, Jordan LM. Tetrodotoxin-, dihydropyridine-, and riluzole-resistant persistent inward current: novel sodium channels in rodent spinal neurons. J Neurophysiol 106: 1322-1340, 2011. First published June 8, 2011; doi:10.1152/jn.00918.2010.-Recently, we reported the tetrodotoxin (TTX)- and dihydropyridine (DHP)-resistant (TDR) inward currents in neonatal mouse spinal neurons. In this study, we further characterized these currents in the presence of 1-5 mu M TTX and 20-30 mu M DHP (nifedipine, nimodipine, or isradipine). TDR inward currents were recorded by voltage ramp (persistent inward current, TDR-PIC) and step (TDR-I(p)) protocols. TDR-PIC and TDR-I(p) were found in 80.2% of recorded neurons (101/126) crossing laminae I to X from T12 to L6. TDR-PIC activated at -8.6 +/- 13 mV with an amplitude of 80.6 +/- 75 pA and time constant of 470.6 +/- 240 ms (n = 75). TDR-I(p) had an amplitude of 151.2 +/- 151 pA and a voltage threshold of -7.0 +/- 9 mV (n = 54) with a wide range of kinetics parameters. The half-maximal activation was -21.5 +/- 8 mV (-37 to -12 mV, n = 29) with a time constant of 5.2 +/- 2 ms (1.2-11.2 ms, n = 19), whereas the half-maximal inactivation was -26.9 +/- 9 mV (-39 to -18 mV, n = 14) with a time constant of 1.4 +/- 0.4 s (0.5-2.2 s, n = 19). TDR-PIC and TDR-I(p) could be reduced by 60% in zero calcium and completely removed in zero sodium solutions, suggesting that they were mediated by sodium ions. Furthermore, the reversal potential of TDR-I(p) was estimated as 56.6 +/- 3 mV (n = 10). TDR-PIC and TDR-I(p) persisted in 1-205 mu M TTX, 20-100 mu M DHP, 3-30 mu M riluzole, 50-300 mu M flufenamic acid, and 2-30 mM intracellular BAPTA. They also persisted with T-, N-, P/Q-, and R-type calcium channel blockers. In conclusion, we demonstrated novel TTX-, DHP-, and riluzole-resistant sodium channels in neonatal rodent spinal neurons. The unique pharmacological and electrophysiological properties would allow these channels to play a functional role in spinal motor system.