title: Differential role of GDNF and NGF in the maintenance of two TTX-resistant sodium channels in adult DRG neurons.
abstract: Following sciatic nerve transection, the electrophysiological properties of small dorsal root ganglion (DRG) neurons are markedly altered, with attenuation of TTX-R sodium currents and the appearance of rapidly repriming TTX-S currents. The reduction in TTX-R currents has been attributed to a down-regulation of sodium channels SNS/PN3 and NaN. While infusion of exogenous NGF to the transected nerve restores SNS/PN3 transcripts to near-normal levels in small DRG neurons, TTX-R sodium currents are only partially rescued. Binding of the isolectin IB4 distinguishes two subpopulations of small DRG neurons: IB4+ neurons, which express receptors for the GDNF family of neurotrophins, and IB4- neurons that predominantly express TrkA. We show here that SNS/PN3 is expressed in approximately one-half of both IB4+ and IB4- DRG neurons, while NaN is preferentially expressed in IB4+ neurons. Whole-cell patch-clamp studies demonstrate that TTX-R sodium currents in IB4+ neurons have a more hyperpolarized voltage-dependence of activation and inactivation than do IB4- neurons, suggesting different electrophysiological properties for SNS/PN3 and NaN. We confirm that NGF restores SNS/PN3 mRNA levels in DRG neurons in vitro and demonstrate that the trk antagonist K252a blocks this rescue. The down-regulation of NaN mRNA is, nevertheless, not rescued by NGF-treatment in either IB4+ or IB4- neurons and NGF-treatment in vitro does not significantly increase the peak amplitude of the TTX-R current in small DRG neurons. In contrast, GDNF-treatment causes a twofold increase in the peak amplitude of TTX-R sodium currents and restores both SNS/PN3 and NaN mRNA to near-normal levels in IB4+ neurons. These observations provide a mechanism for the partial restoration of TTX-R sodium currents by NGF in axotomized DRG neurons, and demonstrate that the neurotrophins NGF and GDNF differentially regulate sodium channels SNS/PN3 and NaN.
authors.affiliation: Department of Neurology, Yale University School of Medicine, New Haven, CT 06510, USA.
authors.forename: J
authors.initials: J
authors.lastname: Fjell
authors.forename: T R
authors.initials: TR
authors.lastname: Cummins
authors.forename: S D
authors.initials: SD
authors.lastname: Dib-Hajj
authors.forename: K
authors.initials: K
authors.lastname: Fried
authors.forename: J A
authors.initials: JA
authors.lastname: Black
authors.forename: S G
authors.initials: SG
authors.lastname: Waxman
mesh_terms: D000367:Age Factors; D000818:Animals; D019771:Axotomy; D048429:Cell Size / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D015536:Down-Regulation / Q000187:drug effects; D004351:Drug Resistance; D005260:Female; D005727:Ganglia, Spinal / Q000737:chemistry / Q000166:cytology; D015870:Gene Expression / Q000187:drug effects; D051100:Glial Cell Line-Derived Neurotrophic Factor; D037102:Lectins; D008564:Membrane Potentials / Q000187:drug effects; D062559:NAV1.8 Voltage-Gated Sodium Channel; D062558:NAV1.9 Voltage-Gated Sodium Channel; D009414:Nerve Growth Factors / Q000494:pharmacology*; D009419:Nerve Tissue Proteins / Q000494:pharmacology*; D009475:Neurons, Afferent / Q000737:chemistry* / Q000502:physiology; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism; D018408:Patch-Clamp Techniques; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D012584:Sciatic Nerve / Q000166:cytology / Q000502:physiology; D015222:Sodium Channels / Q000235:genetics* / Q000378:metabolism; D013779:Tetrodotoxin / Q000494:pharmacology*; D015854:Up-Regulation / Q000502:physiology
chemical_list: C495041:Gdnf protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor; D037102:Lectins; D062559:NAV1.8 Voltage-Gated Sodium Channel; D062558:NAV1.9 Voltage-Gated Sodium Channel; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; D012333:RNA, Messenger; C568319:Scn10a protein, rat; C113705:Scn11a protein, rat; D015222:Sodium Channels; D013779:Tetrodotoxin