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

Abstract

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.

SARS-CoV-2 airway infection results in the development of somatosensory abnormalities in a hamster model

“…3F). Preclinical and clinical literatures support a positive association among up-regulation/activation of IL-6R (65-67), MEK (68-70), RUNX2 (71,72), FSH (73), and ATF4 (74,75) and nociceptive states, and several laboratories have validated interventions in relevant pathways as promising antinociceptive therapeutic strategies. Only AMPKα2 activity was expressed toward a pronociceptive direction in this list, because preclinical literature suggests that activation of this protein is associated with the alleviation of nociceptive symptoms (76,77).…”

SARS-CoV-2 Airway Infection Results in Time-dependent Sensory Abnormalities in a Hamster Model

“…Nine URs met this criterion: Interleukin 6 Receptor (IL6R), Mitogen-activated Protein Kinase Kinase (MEK), Interleukin Enhancer-binding Factor 3 (ILF3), Runt-related Transcription Factor 2 (RUNX2), Protein Kinase AMP-Activated Catalytic Subunit Alpha 2 (PRKAA2) (UR was AMPKα2 gene), Follicle Stimulating Hormone (FSH), Activating Transcription Factor 4 (ATF4), Snail Family Transcriptional Repressor 1 (SNAI1), and Inhibin Subunit Alpha (INHA) ( Figure 3F ). Interestingly, pre-clinical and clinical literature supports a positive association between upregulation/activation of IL6R ( 62–64 ), MEK ( 65–67 ), RUNX2 ( 68, 69 ), FSH ( 70 ), & ATF4 ( 71, 72 ) and nociceptive states, and several laboratories have validated interventions in relevant pathways as promising anti-nociceptive therapeutic strategies. Only AMPKα2 activity was expressed towards a pro-nociceptive direction in this list, as pre-clinical literature suggests activation of this protein is associated with the alleviation of nociceptive symptoms ( 73, 74 ).These data suggest that other targets in this list may serve as novel therapeutic avenues of pain management.…”

A compendium of validated pain genes

“…A joint siRNA knockdown and knockout study indicated that ATF4‐deficient animals display reduced baseline, inflammatory, and neuropathic thermal sensitivities, yet fail to show changes in mechanical thresholds (M.‐X. Xie, Cao, et al, 2021 ). These results suggest that ATF4‐mediated transcription might affect transcripts involved in thermosensation, but not mechanosensation.…”