Neurotrophin-3 down-regulates trkA mRNA, NGF high-affinity binding sites, and associated phenotype in adult DRG neurons.
Neurotrophin-3 (NT-3) binds to multiple trks, not only its initially identified receptor trkC. Recent studies in our laboratory show that NT-3 negatively regulates nociceptive phenotype associated with the trkA subpopulation. Due to the extensive overlap in trkA and trkC expression it is uncertain whether there is a direct influence of NT-3 on trkA in adult sensory neurons. Thus, the aim of this study was to examine whether NT-3 might alter trkA and associated neuronal phenotype outside of the trkC subpopulation. The effect of a seven-day intrathecal infusion of NT-3 on intact, uninjured adult rat dorsal root ganglion neurons was investigated. Serial sections were processed for receptor radioautography or in situ hybridization to identify and colocalize neurons expressing high-affinity nerve growth factor (NGF) binding sites, substance P (SP), trkC, or trkA mRNAs and to examine the influence of NT-3 on these populations. NT-3 does not appear to alter trkC expression, but evokes a notable reduction in trkA, high-affinity NGF binding sites, and SP levels. It is unlikely that signalling by trkC greatly influences this response because the down-regulation of SP occurs most notably in trkA neurons that lack trkC. Moreover, we have shown here that message levels of two trkA isoforms are differentially modulated by NT-3; infusion results in greater down-regulation of the noninsert containing isoform. These findings suggest a clinically relevant role for NT-3 as an antagonist to NGF, but also raise the caution that not just trkC-positive neurons are influenced following exposure to the neurotrophin.
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D048429:Cell Size; D015536:Down-Regulation; D005727:Ganglia, Spinal / Q000166:cytology* / Q000187:drug effects; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D015918:Infusion Pumps, Implantable; D007456:Iodine Isotopes / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D020932:Nerve Growth Factor / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D020933:Neurotrophin 3 / Q000008:administration & dosage / Q000378:metabolism*; D011485:Protein Binding; D020033:Protein Isoforms / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011859:Radiography; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D020917:Receptor, trkA; D018709:Statistics, Nonparametric; D013373:Substance P / Q000235:genetics / Q000378:metabolism; D013460:Sulfur Isotopes
D002352:Carrier Proteins; D007456:Iodine Isotopes; D008565:Membrane Proteins; D020933:Neurotrophin 3; D020033:Protein Isoforms; D012333:RNA, Messenger; D013460:Sulfur Isotopes; D013373:Substance P; D020932:Nerve Growth Factor; D020917:Receptor, trkA