Mechanism of ER stress-induced brain damage by IP(3) receptor

Neuron. 2010 Dec 9;68(5):865-78. doi: 10.1016/j.neuron.2010.11.010.


Deranged Ca(2+) signaling and an accumulation of aberrant proteins cause endoplasmic reticulum (ER) stress, which is a hallmark of cell death implicated in many neurodegenerative diseases. However, the underlying mechanisms are elusive. Here, we report that dysfunction of an ER-resident Ca(2+) channel, inositol 1,4,5-trisphosphate receptor (IP(3)R), promotes cell death during ER stress. Heterozygous knockout of brain-dominant type1 IP(3)R (IP(3)R1) resulted in neuronal vulnerability to ER stress in vivo, and IP(3)R1 knockdown enhanced ER stress-induced apoptosis via mitochondria in cultured cells. The IP(3)R1 tetrameric assembly was positively regulated by the ER chaperone GRP78 in an energy-dependent manner. ER stress induced IP(3)R1 dysfunction through an impaired IP(3)R1-GRP78 interaction, which has also been observed in the brain of Huntington's disease model mice. These results suggest that IP(3)R1 senses ER stress through GRP78 to alter the Ca(2+) signal to promote neuronal cell death implicated in neurodegenerative diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / metabolism
  • Brain / pathology
  • Calcium / metabolism
  • Calcium Signaling / physiology*
  • Cell Death / physiology
  • Endoplasmic Reticulum / metabolism*
  • Endoplasmic Reticulum / pathology
  • Endoplasmic Reticulum Chaperone BiP
  • Energy Metabolism / physiology
  • Gene Knockdown Techniques
  • Heat-Shock Proteins / metabolism*
  • Inositol 1,4,5-Trisphosphate Receptors / genetics
  • Inositol 1,4,5-Trisphosphate Receptors / metabolism*
  • Mice
  • Mice, Knockout
  • Molecular Chaperones / metabolism
  • Neurodegenerative Diseases / metabolism*
  • Neurodegenerative Diseases / pathology
  • Neurons / metabolism*
  • Neurons / pathology


  • Endoplasmic Reticulum Chaperone BiP
  • Heat-Shock Proteins
  • Hspa5 protein, mouse
  • Inositol 1,4,5-Trisphosphate Receptors
  • Molecular Chaperones
  • Calcium