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The Journal of Neuroscience, December 15, 2001, 21(24):9629-9637

Glycosylation Alters Steady-State Inactivation of Sodium Channel Na_v1.9/NaN in Dorsal Root Ganglion Neurons and Is Developmentally Regulated

Lynda Tyrrell^{1, 2, 3}, Muthukrishnan Renganathan^{1, 2, 3}, Sulayman D. Dib-Hajj^{1, 2, 3}, and Stephen G. Waxman^{1, 2, 3}

¹ Department of Neurology and ² Paralyzed Veterans of America/Eastern Paralyzed Veterans Association Neuroscience Research Center, Yale University School of Medicine, New Haven, Connecticut 06510, and ³ Rehabilitation Research Center, Veterans Administration Connecticut Healthcare System, West Haven, Connecticut 06516

Na channel NaN (Na_v1.9) produces a persistent TTX-resistant (TTX-R) current in small-diameter neurons of dorsal root ganglia (DRG) and trigeminal ganglia. Na_v1.9-specific antibodies react in immunoblot assays with a 210 kDa protein from the membrane fractions of adult DRG and trigeminal ganglia. The size of the immunoreactive protein is in close agreement with the predicted Na_v1.9 theoretical molecular weight of 201 kDa, suggesting limited glycosylation of this channel in adult tissues. Neonatal rat DRG membrane fractions, however, contain an additional higher molecular weight immunoreactive protein. Reverse transcription-PCR analysis did not show additional longer transcripts that could encode the larger protein. Enzymatic deglycosylation of the membrane preparations converted both immunoreactive proteins into a single faster migrating band, consistent with two states of glycosylation of Na_v1.9. The developmental change in the glycosylation state of Na_v1.9 is paralleled by a developmental change in the gating of the persistent TTX-R Na⁺ current attributable to Na_v1.9 in native DRG neurons. Whole-cell patch-clamp analysis demonstrates that the midpoint of steady-state inactivation is shifted 7 mV in a hyperpolarized direction in neonatal (postnatal days 0-3) compared with adult DRG neurons, although there is no significant difference in activation. Pretreatment of neonatal DRG neurons with neuraminidase causes an 8 mV depolarizing shift in the midpoint of steady-state inactivation of Na_v1.9, making it indistinguishable from that of adult DRG neurons. Our data show that extensive glycosylation of rat Na_v1.9 is developmentally regulated and changes a critical property of this channel in native neurons.

Key words: spinal sensory neurons; ion channel; tetrodotoxin resistant; persistent Na current; desialidation; voltage clamp

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Copyright © 2001 Society for Neuroscience  0270-6474/01/21249629-09$05.00/0

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