Regulatory Mechanisms of Endoplasmic Reticulum Resident IP3 Receptors (original) (raw)
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Molecular neurobiology, 2016
It is well known that calcium (Ca(2+)) is involved in the triggering of neuronal death. Ca(2+) cytosolic levels are regulated by Ca(2+) release from internal stores located in organelles, such as the endoplasmic reticulum. Indeed, Ca(2+) transit from distinct cell compartments follows complex dynamics that are mediated by specific receptors, notably inositol trisphosphate receptors (IP3Rs). Ca(2+) release by IP3Rs plays essential roles in several neurological disorders; however, details of these processes are poorly understood. Moreover, recent studies have shown that subcellular location, molecular identity, and density of IP3Rs profoundly affect Ca(2+) transit in neurons. Therefore, regulation of IP3R gene products in specific cellular vicinities seems to be crucial in a wide range of cellular processes from neuroprotection to neurodegeneration. In this regard, microRNAs seem to govern not only IP3Rs translation levels but also subcellular accumulation. Combining new data from mol...
Endoplasmic reticulum Ca 2+ homeostasis and neuronal death
Journal of Cellular and Molecular Medicine, 2003
The endoplasmic reticulum (ER) is a universal signalling organelle, which regulates a wide range of neuronal functional responses. Calcium release from the ER underlies various forms of intracellular Ca2+ signalling by either amplifying Ca2+ entry through voltage-gated Ca2+ channels by Ca2+-induced Ca2+ release (CICR) or by producing local or global cytosolic calcium fluctuations following stimulation of metabotropic receptors through inositol-1,4,5-trisphosphate-induced Ca2+ release (IICR). The ER Ca2+ store emerges as a single interconnected pool, thus allowing for a long-range Ca2+ signalling via intra-ER tunnels. The fluctuations of intra-ER free Ca2+ concentration regulate the activity of numerous ER resident proteins responsible for post-translational protein folding and modification. Disruption of ER Ca2+ homeostasis results in the developing of ER stress response, which in turn controls neuronal survival. Altered ER Ca2+ handling may be involved in pathogenesis of various, neurodegenerative diseases including brain ischemia and Alzheimer dementia.
Roles of IP3R and RyR Ca2+ Channels in Endoplasmic Reticulum Stress and -Cell Death
Diabetes, 2008
OBJECTIVE-Endoplasmic reticulum (ER) stress has been implicated in the pathogenesis of diabetes, but the roles of specific ER Ca 2ϩ release channels in the ER stress-associated apoptosis pathway remain unknown. Here, we examined the effects of stimulating or inhibiting the ER-resident inositol trisphosphate receptors (IP 3 Rs) and the ryanodine receptors (RyRs) on the induction of -cell ER stress and apoptosis. RESEARCH DESIGN AND METHODS-Kinetics of -cell death were tracked by imaging propidium iodide incorporation and caspase-3 activity in real time. ER stress and apoptosis were assessed by Western blot. Mitochondrial membrane potential was monitored by flow cytometry. Cytosolic Ca 2ϩ was imaged using fura-2, and genetically encoded fluorescence resonance energy transfer (FRET)-based probes were used to measure Ca 2ϩ in ER and mitochondria. RESULTS-Neither RyR nor IP 3 R inhibition, alone or in combination, caused robust death within 24 h. In contrast, blocking sarco/endoplasmic reticulum ATPase (SERCA) pumps depleted ER Ca 2ϩ and induced marked phosphorylation of PKR-like ER kinase (PERK) and eukaryotic initiation factor-2␣ (eIF2␣), C/EBP homologous protein (CHOP)-associated ER stress, caspase-3 activation, and death. Notably, ER stress following SERCA inhibition was attenuated by blocking IP 3 Rs and RyRs. Conversely, stimulation of ER Ca 2ϩ release channels accelerated thapsigargin-induced ER depletion and apoptosis. SERCA block also activated caspase-9 and induced perturbations of the mitochondrial membrane potential, resulting eventually in the loss of mitochondrial polarization. CONCLUSIONS-This study demonstrates that the activity of ER Ca 2ϩ channels regulates the susceptibility of -cells to ER stress resulting from impaired SERCA function. Our results also suggest the involvement of mitochondria in -cell apoptosis associated with dysfunctional -cell ER Ca 2ϩ homeostasis and ER stress.
Nature Communications, 2014
Inositol 1, 4, 5-trisphosphate receptor (IP 3 R)-mediated Ca 2 þ release from the endoplasmic reticulum (ER) triggers many physiological responses in neurons, and when uncontrolled can cause ER stress that contributes to neurological disease. Here we show that the unfolded protein response (UPR) in neurons induces rapid translocation of nuclear receptor-interacting protein 140 (RIP140) to the cytoplasm. In the cytoplasm, RIP140 localizes to the ER by binding to the IP 3 R. The carboxyl-terminal RD4 domain of RIP140 interacts with the carboxylterminal gate-keeping domain of the IP 3 R. This molecular interaction disrupts the IP 3 R's 'head-tail' interaction, thereby suppressing channel opening and attenuating IP 3 R-mediated Ca 2 þ release. This contributes to a rapid suppression of the ER stress response and provides protection from apoptosis in both hippocampal neurons in vitro and in an animal model of ER stress. Thus, RIP140 translocation to the cytoplasm is an early response to ER stress and provides protection against neuronal death.
Cell Calcium, 2006
Presenilins (PS) are proteins involved in the pathogenesis of autosomal-dominant familial cases of Alzheimer's disease. Mutations in PS are known to induce specific alterations in cellular Ca 2+ signaling which might be involved in the pathogenesis of neurodegenerative diseases. Mouse embryonic fibroblasts (MEF) deficient in PS1 and PS2 (PS DKO) as well as the latter rescued with PS1 (Rescue), were used to investigate the underlying mechanism of these alterations in Ca 2+ signaling. PS DKO cells were characterized by a decrease in the [Ca 2+ ] ER as measured by ER-targeted aequorin luminescence and an increased level of type 1 inositol 1,4,5-trisphosphate receptor (IP 3 R1). The lower [Ca 2+ ] ER was associated with an increase in a Ca 2+ leak from the ER. The increased IP 3 R1 expression and the concomitant changes in ER Ca 2+ handling were reversed in the Rescue cells. Moreover using RNA-interference mediated reduction of IP 3 R1 we could demonstrate that the up-regulation of this isoform was responsible for the increased Ca 2+ leak and the lowered [Ca 2+ ] ER in PS DKO cells. Finally, we show that the decreased [Ca 2+ ] ER in PS DKO cells was protective against apoptosis.
Endoplasmic reticulum stress induces a novel Ca2+signalling system initiated by Ca2+microdomains
2020
The accumulation of unfolded proteins within the Endoplasmic Reticulum (ER) activates a signal transduction pathway termed theunfoldedprotein response (UPR), which attempts to restore ER homeostasis. If homeostasis cannot be restored, UPR signalling ultimately induces apoptosis. Ca2+depletion in the ER is a potent inducer of ER stress. Despite the ubiquity of Ca2+as intracellular messenger, the precise mechanism (s) by which Ca2+release affects the UPR remains unknown. Use of a genetically encoded Ca2+indicator (GCamP6) that is tethered to the ER membrane, uncovered novel Ca2+signalling events initiated by Ca2+microdomains in human astrocytes under ER stress, as well as in a cell model deficient in all three IP3Receptor isoforms. Pharmacological and molecular studies indicate that these local events are mediated by translocons. Together, these data reveal the existence of a previously unrecognized mechanism by which stressor-mediated Ca2+release regulates ER stress.
Cell Signalling: IP3 Receptors Channel Calcium into Cell Death
Current Biology, 2004
There is substantial evidence that Ca 2+ fluxes occur during most forms of apoptosis, and that inhibiting such fluxes protects cells from death. IP 3 receptorsligand-gated channels that release Ca 2+ from intracellular stores -are emerging as key sites for regulation by pro-and anti-apoptotic factors.
Journal of Cell Biology, 2009
Endoplasmic reticulum (ER) stress–induced apoptosis is involved in many diseases, but the mechanisms linking ER stress to apoptosis are incompletely understood. Based on roles for C/EPB homologous protein (CHOP) and ER calcium release in apoptosis, we hypothesized that apoptosis involves the activation of inositol 1,4,5-triphosphate (IP3) receptor (IP3R) via CHOP-induced ERO1-α (ER oxidase 1 α). In ER-stressed cells, ERO1-α is induced by CHOP, and small interfering RNA (siRNA) knockdown of ERO1-α suppresses apoptosis. IP3-induced calcium release (IICR) is increased during ER stress, and this response is blocked by siRNA-mediated silencing of ERO1-α or IP3R1 and by loss-of-function mutations in Ero1a or Chop. Reconstitution of ERO1-α in Chop−/− macrophages restores ER stress–induced IICR and apoptosis. In vivo, macrophages from wild-type mice but not Chop−/− mice have elevated IICR when the animals are challenged with the ER stressor tunicamycin. Macrophages from insulin-resistant ob...