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WIREs Membr Transp Signal

IP 3 receptor‐binding partners in cell‐death mechanisms

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A multiprotein complex, which involves the inositol 1,4,5‐trisphosphate receptor (IP3R) on the endoplasmic reticulum (ER) and the voltage‐dependent anion channel (VDAC) on the outer mitochondrial membrane (OMM) along with multiple other IP3R‐binding partners, is responsible for a privileged and tightly controlled transfer of Ca2+ from the ER to the mitochondria. To stimulate cell metabolism and survival, the mitochondrial Ca2+ level [Ca2+]mit has to be kept within a small physiological range. Decreased or increased Ca2+ fluxes result in an adaptive cellular response involving, respectively, autophagy to meet cellular energy demands or mitophagy to remove damaged mitochondria. Failure of these autophagic responses eventually leads to initiation of cell death. Malfunction of the interaction between the IP3R and its binding partners may have pathological consequences. In cancer cells, such malfunctions lead to an inability to generate large proapoptotic mitochondrial Ca2+ signals. In familial Alzheimer's disease (FAD) and Huntington's disease (HD) on the other hand, exaggerated Ca2+ signals may result in neuronal damage and cell death. WIREs Membr Transp Signal 2012, 1:201–210. doi: 10.1002/wmts.5

Figure 1.

IP3R and Ca2+ regulation in ER‐mitochondrial microdomains. (a) Precise regulation of mitochondrial Ca2+ determines cell fate. Persistently increased mitochondrial [Ca2+] causes mitochondrial swelling, increases OMM permeability and leads to mitophagy, while lowered mitochondrial [Ca2+] reduces ATP production and causes autophagy. Lack of autophagic responses that result in extreme or persistent disturbances in mitochondrial Ca2+ levels will eventually lead to cell death. Proapoptotic (red) and antiapoptotic (green) binding partners regulate IP3R activity (b and c) and/or affect the ER Ca2+ content (d). (b) apoptotic mechanisms: Increased IP3R activity will disrupt Ca2+ homeostasis and cause an apoptotic phenotype. Direct mitochondrial Ca2+ transfer from ER to mitochondria is facilitated by the IP3R/GRP75/VDAC complex. Also cytochrome c (Cyt c), PML and mutated proteins involved in neurodegenerative diseases (ND‐mut) are able to induce IP3R Ca2+ flux. ERO1‐α mediates oxidation‐induced activation of the IP3R in oxidative stress. (c) Protective mechanisms: Mechanisms facilitated by Bcl2 or GIT1 involve direct inhibition of the IP3R. In cancer cells lacking PML, PKB phosphorylates and inhibits the IP3R, thereby enabling cancer cells to escape apoptosis. In contrast, IP3R activation by BclXL or GRP78 is protective as it assists in maintaining the mitochondrial Ca2+ supply to support ATP production. In reducing conditions or upon severe Ca2+ depletion, ERp44 binds to the same site as GRP78 and acts protective by inhibiting further Ca2+ release. D, ER Ca2+ leak: Protective mechanisms also include lowering of the ER Ca2+ content by leak pathways via Bcl2‐promoted IP3R hyperphosphorylation or by other less well defined Ca2+‐leak channels (indicated by a ‘?’) such as the BI‐1 family members and presenilins. However, the exact role of these channels in regulating ER [Ca2+] requires further investigation.

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Intracellular Channels and Receptors > Inositol-1,4,5 trisphosphate (IP3) Receptors

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