title: Glial-derived neurotrophic factor upregulates expression of functional SNS and NaN sodium channels and their currents in axotomized dorsal root ganglion neurons.
abstract: Dorsal root ganglion (DRG) neurons produce multiple sodium currents, including several different TTX-sensitive (TTX-S) currents and TTX-resistant (TTX-R) currents, which are produced by distinct sodium channels. We previously demonstrated that, after sciatic nerve transection, the levels of SNS and NaN sodium channel alpha-subunit transcripts and protein in small (18-30 micrometer diameter) DRG neurons are reduced, as are the amplitudes and densities of the slowly inactivating and persistent TTX-R currents produced by these two channels. In this study, we asked whether glial-derived neurotrophic factor (GDNF), which has been shown to prevent some axotomy-induced changes such as the loss of somatostatin expression in DRG neurons, can ameliorate the axotomy-induced downregulation of SNS and NaN TTX-R sodium channels. We show here that exposure to GDNF can significantly increase both slowly inactivating and persistent TTX-R sodium currents, which are paralleled by increases in SNS and NaN mRNA and protein levels, in axotomized DRG neurons in vitro. We also show that intrathecally administered GDNF increases the amplitudes of the slowly inactivating and persistent TTX-R currents, and SNS and NaN protein levels, in peripherally axotomized DRG neurons in vivo. Finally, we demonstrate that GDNF upregulates the persistent TTX-R current in SNS-null mice, thus demonstrating that the upregulated persistent sodium current is not produced by SNS. Because TTX-R sodium channels have been shown to be important in nociception, the effects of GDNF on axotomized DRG neurons may have important implications for the regulation of nociceptive signaling by these cells.
authors: Department of Neurology and Paralyzed Veterans of America and Eastern Paralyzed Veterans Association Neuroscience Research Center, Yale Medical School, New Haven, Connecticut 06510, USA.
authors: T R
authors: TR
authors: Cummins
authors: J A
authors: JA
authors: Black
authors: S D
authors: SD
authors: Dib-Hajj
authors: S G
authors: SG
authors: Waxman
mesh_terms: D000818:Animals; D019771:Axotomy; D002478:Cells, Cultured; D005260:Female; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051100:Glial Cell Line-Derived Neurotrophic Factor; D007150:Immunohistochemistry; D007278:Injections, Spinal; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D062559:NAV1.8 Voltage-Gated Sodium Channel; D062558:NAV1.9 Voltage-Gated Sodium Channel; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins / Q000008:administration & dosage / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012584:Sciatic Nerve / Q000601:surgery; D012964:Sodium / Q000378:metabolism; D015222:Sodium Channels / Q000235:genetics / Q000378:metabolism*; D013779:Tetrodotoxin / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C495040:Gdnf protein, mouse; C495041:Gdnf protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor; 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; C568318:Scn10a protein, mouse; C568319:Scn10a protein, rat; C491885:Scn11a protein, mouse; C113705:Scn11a protein, rat; D015222:Sodium Channels; D013779:Tetrodotoxin; D012964:Sodium