ATF4 selectively regulates heat nociception and contributes to kinesin-mediated TRPM3 trafficking

Nat Commun. 2021 Mar 3;12(1):1401. doi: 10.1038/s41467-021-21731-1.


Effective treatments for patients suffering from heat hypersensitivity are lacking, mostly due to our limited understanding of the pathogenic mechanisms underlying this disorder. In the nervous system, activating transcription factor 4 (ATF4) is involved in the regulation of synaptic plasticity and memory formation. Here, we show that ATF4 plays an important role in heat nociception. Indeed, loss of ATF4 in mouse dorsal root ganglion (DRG) neurons selectively impairs heat sensitivity. Mechanistically, we show that ATF4 interacts with transient receptor potential cation channel subfamily M member-3 (TRPM3) and mediates the membrane trafficking of TRPM3 in DRG neurons in response to heat. Loss of ATF4 also significantly decreases the current and KIF17-mediated trafficking of TRPM3, suggesting that the KIF17/ATF4/TRPM3 complex is required for the neuronal response to heat stimuli. Our findings unveil the non-transcriptional role of ATF4 in the response to heat stimuli in DRG neurons.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activating Transcription Factor 4 / genetics
  • Activating Transcription Factor 4 / metabolism*
  • Animals
  • Cell Membrane / metabolism
  • Chemokine CXCL12 / metabolism
  • Ganglia, Spinal / cytology
  • Ganglia, Spinal / physiology
  • HEK293 Cells
  • Hot Temperature
  • Humans
  • Injections, Spinal
  • Kinesins / metabolism
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Nociception / physiology*
  • Patch-Clamp Techniques
  • Protein Transport
  • Receptors, CXCR4 / metabolism
  • Sensory Receptor Cells / physiology*
  • TRPM Cation Channels / genetics
  • TRPM Cation Channels / metabolism*


  • Atf4 protein, mouse
  • CXCR4 protein, mouse
  • Chemokine CXCL12
  • Cxcl12 protein, mouse
  • KIF17 protein, mouse
  • Receptors, CXCR4
  • TRPM Cation Channels
  • TRPM3 protein, mouse
  • Activating Transcription Factor 4
  • Kinesins