2. Academic Validation
  3. eEF2K regulates pain through translational control of BDNF

eEF2K regulates pain through translational control of BDNF

  • Mol Cell. 2025 Feb 20;85(4):756-769.e5. doi: 10.1016/j.molcel.2024.11.023.
Patrick R Smith 1,  Guadalupe Garcia 1,  Angela R Meyer 1,  Alexey G Ryazanov 2,  Tao Ma 3,  Sarah Loerch 4,  Zachary T Campbell 5
Affiliations

Affiliations

  • 1 Department of Anesthesiology, University of Wisconsin, Madison, Madison, WI, USA.
  • 2 Department of Pharmacology, Rutgers Robert Wood Johnson Medical School, Piscataway, NJ, USA.
  • 3 Department of Internal Medicine, Gerontology and Geriatric Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA; Department of Translational Neuroscience, Wake Forest School of Medicine, Winston-Salem, NC, USA.
  • 4 Department of Chemistry and Biochemistry, University of California, Santa Cruz, Santa Cruz, CA, USA; Center for Molecular Biology of RNA, University of California, Santa Cruz, CA 95064, USA.
  • 5 Department of Anesthesiology, University of Wisconsin, Madison, Madison, WI, USA. Electronic address: zcampbell@wisc.edu.
PMID: 39694034 DOI: 10.1016/j.molcel.2024.11.023
Abstract

mRNA translation is integral to pain, yet the key regulatory factors and their target mRNAs are unclear. Here, we uncover a mechanism that bridges noxious insults to multiple phases of translational control in murine sensory neurons. We find that a painful cue triggers repression of peptide chain elongation through activation of elongation factor 2 kinase (eEF2K). Attenuated elongation is sensed by a ribosome-coupled mechanism that triggers the integrated stress response (ISR). Both eEF2K and the ISR are required for pain-associated behaviors in vivo. This pathway simultaneously induces biosynthesis of brain-derived neurotrophic factor (BDNF). Selective blockade of Bdnf translation has analgesic effects in vivo. Our data suggest that precise spatiotemporal regulation of Bdnf translation is critical for appropriate behavioral responses to painful stimuli. Overall, our results demonstrate that eEF2K resides at the nexus of an intricate regulatory network that links painful cues to multiple layers of translational control.

Keywords

BDNF; GCN2; P-stalk; eEF2K; eIF2α; integrated stress response; pain; selective translation.

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