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The Journal of Neuroscience, August 15, 2001, 21(16):5952-5961
Nav1.3 Sodium Channels: Rapid Repriming and Slow
Closed-State Inactivation Display Quantitative Differences after
Expression in a Mammalian Cell Line and in Spinal Sensory Neurons
Theodore R.
Cummins,
Fabio
Aglieco,
Mathurkrisnan
Renganathan,
Raimund I.
Herzog,
Sulayman D.
Dib-Hajj, and
Stephen G.
Waxman
Department of Neurology and Paralyzed Veterans of America/Eastern
Paralyzed Veterans Association Neuroscience Research Center, Yale
Medical School, New Haven, Connecticut 06510, and Rehabilitation
Research Center, Veterans Connecticut Healthcare Center, West Haven,
Connecticut 06516
Although rat brain Nav1.3 voltage-gated sodium channels have been
expressed and studied in Xenopus oocytes, these channels have not been studied after their expression in mammalian cells. We
characterized the properties of the rat brain Nav1.3 sodium channels
expressed in human embryonic kidney (HEK) 293 cells. Nav1.3 channels
generated fast-activating and fast-inactivating currents. Recovery from
inactivation was relatively rapid at negative potentials (< 80 mV)
but was slow at more positive potentials. Development of closed-state
inactivation was slow, and, as predicted on this basis, Nav1.3 channels
generated large ramp currents in response to slow depolarizations.
Coexpression of  3 subunits had small but significant effects on the
kinetic and voltage-dependent properties of Nav1.3 currents in HEK 293 cells, but coexpression of 1 and 2 subunits had little or no
effect on Nav1.3 properties. Nav1.3 channels, mutated to be
tetrodotoxin-resistant (TTX-R), were expressed in SNS-null dorsal root
ganglion (DRG) neurons via biolistics and were compared with the same
construct expressed in HEK 293 cells. The voltage dependence of
steady-state inactivation was ~7 mV more depolarized in SNS-null DRG
neurons, demonstrating the importance of background cell type in
determining physiological properties. Moreover, consistent with the
idea that cellular factors can modulate the properties of Nav1.3, the
repriming kinetics were twofold faster in the neurons than in the HEK
293 cells. The rapid repriming of Nav1.3 suggests that it contributes
to the acceleration of repriming of TTX-sensitive (TTX-S) sodium currents that are seen after peripheral axotomy of DRG neurons. The
relatively rapid recovery from inactivation and the slow closed-state inactivation kinetics of Nav1.3 channels suggest that neurons expressing Nav1.3 may exhibit a reduced threshold and/or a relatively high frequency of firing.
Key words:
ion channel; -subunits; spinal sensory neurons; biolistics; nerve injury; ramp current
Copyright © 2001 Society for Neuroscience 0270-6474/01/21165952-10$05.00/0
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