Abstract
Plasticity in dorsal root ganglion (DRG) neurons that promotes pain requires activity-dependent mRNA translation. Protein synthesis inhibitors block the ability of many pain-promoting molecules to enhance excitability in DRG neurons and attenuate behavioral signs of pain plasticity. In line with this, we have recently shown that phosphorylation of the 5′ cap-binding protein, eIF4E, plays a pivotal role in plasticity of DRG nociceptors in models of hyperalgesic priming. However, mRNA targets of eIF4E phosphorylation have not been elucidated in the DRG. Brain-derived neurotrophic factor (BDNF) signaling from nociceptors in the DRG to spinal dorsal horn neurons is an important mediator of hyperalgesic priming. Regulatory mechanisms that promote pain plasticity via controlling BDNF expression that is involved in promoting pain plasticity have not been identified. We show that phosphorylation of eIF4E is paramount for Bdnf mRNA translation in the DRG. Bdnf mRNA translation is reduced in mice lacking eIF4E phosphorylation (eIF4ES209A) and pro-nociceptive factors fail to increase BDNF protein levels in the DRGs of these mice despite robust upregulation of Bdnf-201 mRNA levels. Importantly, bypassing the DRG by giving intrathecal injection of BDNF in eIF4ES209A mice creates a strong hyperalgesic priming response that is normally absent or reduced in these mice. We conclude that eIF4E phosphorylation-mediated translational control of BDNF expression is a key mechanism for nociceptor plasticity leading to hyperalgesic priming.
Highlights
Translational control of gene expression is a key process for the regulation of plasticity in the nervous system
To test our hypothesis that Bdnf mRNA translation is regulated by eIF4E phosphorylation, we first determined the specificity of antibodies for immunodetection of Brain-derived neurotrophic factor (BDNF) protein in dorsal root ganglion (DRG) isolated from WT and Bdnf +/− mice (Ernfors et al, 1994)
Bdnf-201 transcript is shown by the red arrow. (G) Structure of Bdnf exon 1 5 untranslated region (5 UTRs) as predicted by mfold: http://unafold.rna.albany.edu/?q=mfold. (H) Bdnf-201 mRNA expression was equal in DRG between eIF4ES209A and WT DRG (n ≥ 4, t-test)
Summary
Translational control of gene expression is a key process for the regulation of plasticity in the nervous system. Multiple lines of evidence indicate that translation control plays a critical role in pathological pain plasticity (Khoutorsky and Price, 2017). In the DRG, pain-inducing ligands act via their receptors to activate two major kinase pathways, mechanistic target of rapamycin (mTOR) and mitogen-activated protein kinase (MAPK). These pathways converge on the 5 cap of mRNAs to initiate protein synthesis via the eukaryotic translation initiation factor (eIF) 4F complex formation (Melemedjian et al, 2010). This complex is comprised of three proteins: the scaffolding protein eIF4G, the RNA helicase eIF4A, and the 5 cap-binding p-eIF4E Influences BDNF Expression protein eIF4E. Specific mRNA targets of eIF4E phosphorylation in the DRG have not been elucidated
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
