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Type 3 inositol 1,4,5-trisphosphate receptor modulates cell death
S Blackshaw1, A Sawa, A H Sharp
1Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Abstract:
Mechanisms accounting for the cellular entry of calcium that mediates cellular proliferation and apoptosis have been obscure. Previously we reported selective augmentation of type 3 inositol (1,4,5) trisphosphate receptors (IP(3)R3) in lymphocytes undergoing programmed cell death, which was prevented by antisense constructs to IP(3)R3. We now report increases in mRNA and protein levels for IP(3)R3 associated with cell death in several apoptotic paradigms in diverse tissues. Elevations of IP(3)R3 occur during developmental apoptosis in early postnatal cerebellar granule cells, dorsal root ganglia, embryonic hair follicles, and intestinal villi. Neurotoxic damage elicited by the glutamate agonist kainate is also associated with IP(3)R3 augmentation. In chick dorsal root ganglia neurons undergoing apoptosis due to deprivation of nerve growth factor, levels of IP(3)R3 are selectively increased and cell death is selectively prevented by antisense oligonucleotides to IP(3)R3. Thus, IP(3)R3 appears to participate actively in cell death in a diversity of tissues.
Insights
Type 3 inositol trisphosphate receptors (IP(3)R3) play a key role in programmed cell death (apoptosis). Increased IP(3)R3 levels are observed across diverse tissues undergoing apoptosis, suggesting a broad involvement in cell death mechanisms.
Area of Science:
- Cell Biology
- Molecular Biology
- Neuroscience
Background:
- The cellular mechanisms of calcium entry regulating cell proliferation and apoptosis remain unclear.
- Previous research indicated selective augmentation of type 3 inositol (1,4,5) trisphosphate receptors (IP(3)R3) in lymphocytes during programmed cell death.
Purpose of the Study:
- To investigate the role of IP(3)R3 in various apoptotic paradigms across different tissues.
- To determine if IP(3)R3 augmentation is a common feature of apoptosis.
Main Methods:
- Analysis of IP(3)R3 mRNA and protein levels in diverse apoptotic models.
- Utilizing antisense oligonucleotides to inhibit IP(3)R3 function in specific cell types.
Main Results:
- IP(3)R3 mRNA and protein levels were found to increase in multiple tissues undergoing apoptosis, including cerebellar granule cells, dorsal root ganglia, hair follicles, and intestinal villi.
- Elevated IP(3)R3 levels were also observed in neurotoxic damage induced by kainate.
- In chick dorsal root ganglia neurons, antisense inhibition of IP(3)R3 selectively prevented nerve growth factor deprivation-induced apoptosis.
Conclusions:
- Type 3 inositol trisphosphate receptors (IP(3)R3) are actively involved in the process of cell death (apoptosis).
- The augmentation of IP(3)R3 is a conserved mechanism observed in diverse tissues during apoptosis.