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Distinct repriming and closed-state inactivation kinetics of Na_v1.6 and Na_v1.7 sodium channels in mouse spinal sensory neurons

Raimund I. Herzog, Theodore R. Cummins, Farshid Ghassemi, Sulayman D. Dib-Hajj and Stephen G. Waxman

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_v1.7 expression is negatively correlated with conduction velocity and DRG cell size, while the Na_v1.6 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_v1.6 and Na_v1.7 channels expressed in mouse DRG neurons. Both Na_v1.6 and Na_v1.7 channels generated fast-activating and fast-inactivating currents. However recovery from inactivation was significantly faster (~5-fold at -70 mV) for Na_v1.6 currents than for Na_v1.7 currents. The recovery from inactivation of Na_v1.6 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_v1.6 currents than for Na_v1.7 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.

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