Hypoxia modifies nuclear calcium uptake pathways in the cerebral cortex of the guinea-pig fetus.
Nuclear Ca2+ signals are thought to play a critical role in the initiation and progression of programmed cell death. The present study tests the hypothesis that hypoxia alters nuclear Ca2+ transport pathways and leads to an increase in nuclear Ca(2+)-influx in cerebral cortical neuronal nuclei. To test this hypothesis the effect of tissue hypoxia on high affinity Ca(2+)-ATPase activity and the binding characteristics of inositol 1,4,5-triphosphate (IP3) and inositol 1,3,4,5-tetrakisphosphate (IP4) receptors were studied in neuronal nuclei from the cerebral cortex of guinea-pig fetuses. Results show increased high-affinity Ca(2+)-ATPase activity (nmol/mg protein/h) in the hypoxic group 969.7+/-79 as compared with 602.4+/-90.9 in the normoxic group, P<0.05. The number of IP3 receptors (Bmax, fmol/mg protein) increased from 61+/-21 in the normoxic group to 164+/-49 in the hypoxic group, P<0.05. K(d) values did not change following hypoxia. In contrast, IP4 receptor Bmax (fmol/mg protein) and K(d) (nM) values increased from 360+/-32 in the normoxic group to 626+/-136 in the hypoxic group (P<0.001) and, from 26+/-1 in the normoxic group to 61+/-9 in the hypoxic group (P<0.001), respectively. 45Ca(2+)-influx (pmol/mg protein) significantly increased from 6.3+/-1.9 in the normoxic group to 10.9+/-1.1 the hypoxic group (P<0.001). The data show that hypoxia modifies nuclear Ca2+ transport pathways and results in increased nuclear Ca(2+)-influx. We speculate that hypoxia increases nuclear Ca2+ uptake from the cytoplasm to the nucleoplasm, resulting in increased transcription of proapoptotic genes and subsequent activation of programmed cell death pathways.
Zanelli
S A
SA
Department of Pediatrics, University of Virginia, Charlottesville, VA, USA.
Spandou
E
E
Mishra
O P
OP
Delivoria-Papadopoulos
M
M
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism; D020013:Calcium Signaling / Q000502:physiology; D000252:Calcium-Transporting ATPases / Q000378:metabolism; D016923:Cell Death / Q000502:physiology; D002467:Cell Nucleus / Q000378:metabolism*; D002540:Cerebral Cortex / Q000196:embryology / Q000378:metabolism* / Q000503:physiopathology; D003593:Cytoplasm / Q000378:metabolism; D004195:Disease Models, Animal; D005311:Fetal Hypoxia / Q000378:metabolism* / Q000503:physiopathology; D006168:Guinea Pigs; D002534:Hypoxia, Brain / Q000378:metabolism* / Q000503:physiopathology; D053496:Inositol 1,4,5-Trisphosphate Receptors; D009410:Nerve Degeneration / Q000378:metabolism* / Q000503:physiopathology; D009474:Neurons / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D015854:Up-Regulation / Q000502:physiology
D015220:Calcium Channels; D053496:Inositol 1,4,5-Trisphosphate Receptors; D018160:Receptors, Cytoplasmic and Nuclear; C061107:inositol-1,3,4,5-tetrakisphosphate receptor; D000252:Calcium-Transporting ATPases; D002118:Calcium