Previous studies have shown that nuclear
calcium signals control a variety of nuclear functions including gene transcription,
DNA synthesis, DNA repair and nuclear envelope breakdown. The present study tested the hypothesis that the activity of the neuronal nuclear high affinity Ca2+-
ATPase increases as a function of decreased energy metabolism in the cerebral cortex. Studies were performed in 11 ventilated newborn piglets, age 3-5 days, divided into normoxic (Nx, n = 4) and hypoxic (Hx, n = 7) groups. The animals were exposed to a single FiO2 in the range from 0.21 to 0.05 for one hr. Cerebral tissue
hypoxia was confirmed biochemically by determining brain tissue
ATP and
phosphocreatine levels. Neuronal nuclei were isolated and the high-affinity Ca2+-
ATPase activity determined. During graded
hypoxia, cerebral tissue
ATP decreased from 4.80 +/- 0.58 (normoxic) to 1.03 +/- 0.38 (ranging from 0.61-1.63) micromol/g brain (p < 0.05) and PCr decreased from 3.94 +/- 0.75 (normoxic) to 0.99 +/- 0.27 (ranging from 0.50 to 1.31) micromol/g brain (p < 0.05). The total high affinity Ca2+-
ATPase activity in the hypoxic nuclei increased and ranged from 541 to 662 nmol/mg
protein/hr, compared to activity in normoxic group of 327 to 446 nmol/mg
protein/hr. During graded
hypoxia, the level of nuclear high affinity Ca2+-
ATPase activity correlated inversely with
ATP (r = 0.91) and PCr levels (r = 0.82), with activity increasing as tissue high energy
phosphates decreased. The results demonstrate that the decrease in cerebral energy metabolism during
hypoxia is linearly correlated with an increase in activity of high affinity Ca2+-
ATPase in cerebral cortical nuclei from immature brain. We propose that increased nuclear membrane high affinity Ca2+-
ATPase activity, leading to increased nuclear Ca2+, will result in altered expression of apoptotic genes that could initiate programmed neuronal death.