Distinct repriming and closed-state inactivation kinetics of Nav1.6 and Nav1.7 sodium channels in mouse spinal sensory neurons

While large, myelinated dorsal root ganglion (DRG) neurons are capable of firing at high frequencies, small unmyelinated DRG neurons typically display much lower maximum firing frequencies. However, the molecular basis for this difference has not been delineated. Because the sodium currents in large DRG neurons exhibit rapid repriming (recovery from inactivation) kinetics and the sodium currents in small DRG neurons exhibit predominantly slow repriming kinetics, it has been proposed that differences in sodium channels might contribute to the determination of repetitive firing properties in DRG neurons. A recent study demonstrated that Na(v)1.7 expression is negatively correlated with conduction velocity and DRG cell size, while the Na(v)1.6 voltage-gated sodium channel has been implicated as the predominant isoform present at nodes of Ranvier of myelinated fibres. Therefore we characterized and compared the functional properties, including repriming, of recombinant Na(v)1.6 and Na(v)1.7 channels expressed in mouse DRG neurons. Both Na(v)1.6 and Na(v)1.7 channels generated fast-activating and fast-inactivating currents. However recovery from inactivation was significantly faster (similar to5-fold at -70 mV) for Na(v)1.6 currents than for Na(v)1.7 currents. The recovery from inactivation of Na(v)1.6 channels was also much faster than that of native tetrodotoxin-sensitive sodium currents recorded from small spinal sensory neurons, but similar to that of tetrodotoxin-sensitive sodium currents recorded from large spinal sensory neurons. Development of closed-state inactivation was also much faster for Na(v)1.6 currents than for Na(v)1.7 currents. Our results indicate that the firing properties of DRG neurons can be tuned by regulating expression of different sodium channel isoforms that have distinct repriming and closed-state inactivation kinetics.