Mechanism of ER Stress-Induced Brain Damage by IP₃ Receptor

Deranged Ca²⁺ 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 Ca²⁺ channel, inositol 1,4,5-trisphosphate receptor (IP₃R), promotes cell death during ER stress. Heterozygous knockout of brain-dominant type1 IP₃R (IP₃R1) resulted in neuronal vulnerability to ER stress in vivo, and IP₃R1 knockdown enhanced ER stress-induced apoptosis via mitochondria in cultured cells. The IP₃R1 tetrameric assembly was positively regulated by the ER chaperone GRP78 in an energy-dependent manner. ER stress induced IP₃R1 dysfunction through an impaired IP₃R1-GRP78 interaction, which has also been observed in the brain of Huntington's disease model mice. These results suggest that IP₃R1 senses ER stress through GRP78 to alter the Ca²⁺ signal to promote neuronal cell death implicated in neurodegenerative diseases.