eIF2α Phosphorylation Controls Thermal Nociception

Proc Natl Acad Sci U S A. 2016 Oct 18;113(42):11949-11954. doi: 10.1073/pnas.1614047113. Epub 2016 Oct 3.

Abstract

A response to environmental stress is critical to alleviate cellular injury and maintain cellular homeostasis. Eukaryotic initiation factor 2 (eIF2) is a key integrator of cellular stress responses and an important regulator of mRNA translation. Diverse stress signals lead to the phosphorylation of the α subunit of eIF2 (Ser51), resulting in inhibition of global protein synthesis while promoting expression of proteins that mediate cell adaptation to stress. Here we report that eIF2α is instrumental in the control of noxious heat sensation. Mice with decreased eIF2α phosphorylation (eIF2α+/S51A) exhibit reduced responses to noxious heat. Pharmacological attenuation of eIF2α phosphorylation decreases thermal, but not mechanical, pain sensitivity, whereas increasing eIF2α phosphorylation has the opposite effect on thermal nociception. The impact of eIF2α phosphorylation (p-eIF2α) on thermal thresholds is dependent on the transient receptor potential vanilloid 1. Moreover, we show that induction of eIF2α phosphorylation in primary sensory neurons in a chronic inflammation pain model contributes to thermal hypersensitivity. Our results demonstrate that the cellular stress response pathway, mediated via p-eIF2α, represents a mechanism that could be used to alleviate pathological heat sensation.

Keywords: TRPV1; cellular stress response pathway; eIF2α; pain.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Behavior, Animal
  • Biomarkers
  • Calcium / metabolism
  • Cells, Cultured
  • Eukaryotic Initiation Factor-2 / genetics
  • Eukaryotic Initiation Factor-2 / metabolism*
  • Ganglia, Spinal / metabolism
  • Immunohistochemistry
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Molecular Imaging
  • Neurons / metabolism
  • Nociception*
  • Pain / etiology
  • Pain / metabolism
  • Pain Threshold
  • Phosphorylation
  • Signal Transduction
  • Spinal Cord / metabolism
  • Stress, Physiological
  • TRPV Cation Channels / metabolism
  • Temperature*
  • eIF-2 Kinase / metabolism

Substances

  • Biomarkers
  • Eukaryotic Initiation Factor-2
  • TRPV Cation Channels
  • TRPV1 protein, mouse
  • eIF-2 Kinase
  • Calcium