Mechanism of ER Stress-Induced Brain Damage by IP3 Receptor

Summary: 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. [Copyright &y& Elsevier]