TRPV4 channels stimulate Ca2+-induced Ca2+ release in mouse neurons and trigger endoplasmic reticulum stress after intracerebral hemorrhage

Brain Res Bull. 2019 Mar:146:143-152. doi: 10.1016/j.brainresbull.2018.11.024. Epub 2018 Nov 30.

Abstract

Individuals with intracerebral hemorrhage (ICH) suffer varying degrees of neurological dysfunction as a result of neuronal apoptosis, and thus, maintenance of neuronal survival may be crucial to prevent ICH brain injury. Here, we report that the expression of transient receptor potential vanilloid 4 (TRPV4) was upregulated in mouse neurons after ICH. The selective TRPV4 agonist GSK1016790 A aggravated neuronal death whereas the TRPV4 antagonist HC-067047 promoted neuronal survival after ICH. We found that GSK1016790 A triggered Ca2+ signals that were amplified and propagated by Ca2+-induced Ca2+ release (CICR) from the endoplasmic reticulum (ER) in the neurons. ICH recruited inositol triphosphate receptors (IP3Rs) into the TRPV4 protein complex, which positively regulated the activity of TRPV4 channels. Excessive activation of TRPV4 channels destroyed Ca2+ homeostasis and induced ER unfolded protein response (UPR). Blocking TRPV4 receptors decreased UPR, inhibited the PERK-CHOP-Bcl-2 signaling pathway and increased neuron survival. Overall, these results suggested that overactivation of TRPV4 channels after ICH ledto the destruction of Ca2+ homeostasis, which in turn caused UPR and neural apoptosis. Inhibition of TRPV4 channels is a promising therapy to promote neurons recover, and to ameliorate disability after ICH.

Keywords: Ca(2+)-induced Ca(2+) release; Endoplasmic reticulum stress; Intracerebral hemorrhage; Neuronal apoptosis; TRPV4 channel.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / physiology
  • Brain Injuries / metabolism
  • Calcium / metabolism
  • Cell Death / physiology
  • Cell Survival / physiology
  • Cerebral Hemorrhage / metabolism*
  • Cerebral Hemorrhage / pathology
  • Endoplasmic Reticulum Stress / physiology
  • Inositol 1,4,5-Trisphosphate Receptors / metabolism
  • Leucine / analogs & derivatives
  • Leucine / pharmacology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Morpholines / pharmacology
  • Neurons / metabolism
  • Pyrroles / pharmacology
  • Sulfonamides / pharmacology
  • TRPV Cation Channels / metabolism*
  • Unfolded Protein Response

Substances

  • HC-067047
  • Inositol 1,4,5-Trisphosphate Receptors
  • Morpholines
  • N-(1-((4-(2-(((2,4-dichlorophenyl)sulfonyl)amino)-3-hydroxypropanoyl)-1-piperazinyl)carbonyl)-3-methylbutyl)-1-benzothiophene-2-carboxamide
  • Pyrroles
  • Sulfonamides
  • TRPV Cation Channels
  • Trpv4 protein, mouse
  • Leucine
  • Calcium