Mechanism of ER Stress-Induced Brain Damage by IP3 Receptor

Abstract

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.

ERp44 C160S/C212S mutants regulate IP3R1 channel activity

“…The present study suggested that ERp44 C160S/C212S mutants affected the binding between ERp44 and 1L3V. Based on all of the evidences considered, we hypothesize that the binding between ERp44 C160S/ C212S mutants and IP 3 R 1 may be inner-molecular disulfide bond dependent, which is different from the previously report that the binding is intermolecular disulfide bond dependent (Higo et al, 2005;Kang et al, 2008;Higo et al, 2010).…”

“…Surprisingly, contrary to previous studies (Higo et al, 2005;Kang et al, 2008;Higo et al, 2010), our experimental results show that ERp44 C160S/C212S mutants significantly decrease the inhibition of IICR by ERp44 (Fig. 3), suggesting that the intermolecular disulfide bond between ERp44 and IP 3 R 1 is not involved in the inhibition of IICR by ERp44.…”

“…It has been reported that ERp44 affects calcium transient (Higo et al, 2005;Pan et al, 2011) and gene transcription (Pan et al, 2011) by binding to and inhibiting IP 3 receptor subtype 1 (IP 3 R 1 ). Capable of interacting with both Ero1α and IP 3 R 1 , ERp44 may function as a signal integrator to link redox and Ca 2+ signaling Cortini and Sitia, 2010;Higo et al, 2010). However, the mechanism by which ERp44 and its mutants regulate IP 3 R activity and Ca 2+ release remains unknown.…”

Aberrant calcium signaling by transglutaminase-mediated posttranslational modification of inositol 1,4,5-trisphosphate receptors

“…The brain P2/P3 vesicles were obtained from the cerebrum including the striatum and the cortex or the cerebellum (CB) of three litter pairs of 4-wk-old and 12-wk-old HD model mice (R6/2 Tg or WT); we observed endogenous IP 3 R1 using αE2746 and 4C11 that detects both modified and unmodified IP 3 R1. The IP 3 R1 expression levels were suppressed particularly in 12-wk-old HD mice (16,28); thus, we normalized the αE2746 signal to the 4C11 signal. The relative level of the αE2746 signal was significantly higher in the brains of both 4-wk-old and 12-wk-old R6/2 Tg mice compared with WT mice (Fig.…”

“…Dysregulation of IP 3 R1 is also implicated in neurodegenerative diseases including Huntington disease (HD) (16)(17)(18)) and Alzheimer's disease (AD) (19)(20)(21)(22). IP 3 Rs also control fundamental cellular processes-for example, mitochondrial energy production (23,24), autophagy regulation (24)(25)(26)(27), ER stress (28), hepatic gluconeogenesis (29), pancreatic exocytosis (30), and macrophage inflammasomes (31). On the other hand, excessive IP 3 R function promotes cell death processes including apoptosis by activating mitochondrial or calpain pathways (2,17).…”