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Inositol Tetrakisphosphate (IP4)- and Inositol Triphosphate (IP3)-Dependent Ca2+ Influx in Cortical Neuronal Nuclei of Newborn Piglets Following Graded Hypoxia

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Abstract

Previous studies have shown that hypoxia results in a modification of the binding characteristics of the neuronal nuclear membrane inositol tetrakisphosphate (IP4) and inositol triphosphate (IP3) receptors. The present study tests the hypothesis that hypoxia-induced modification of the IP4 and IP3 receptors results in increased IP4 and IP3 dependent Ca2+ influx in neuronal nuclei as a function of the degree of cerebral tissue hypoxia in newborn piglets. Studies were performed in piglets, 3–5 days old, divided into normoxic (N = 5) and hypoxic (N = 6) groups. The hypoxic group was exposed to decreased Fio2 ranging from 0.15 to 0.05 for 1 h. Brain tissue hypoxia was documented biochemically by determining ATP and phosphocreatine (PCr) levels. Neuronal nuclei were isolated and 45Ca2+ influx was determined in a medium containing 50 mM Tris buffer (pH 7.4), neuronal nuclei (150 μg protein), 1 μM 45Ca2+, with or without 10 μM IP4 or IP3. In normoxic and hypoxic groups, ATP levels were 4.27 ± 0.80 and 1.40 ± 0.69 μmoles/g brain, respectively, P < .001 (ranging from 4.78 to 0.82). PCr levels were 3.40 ± 0.99 and 0.91 ± 0.57 μmoles/g brain, respectively, P < .001 (raning from 4.07 to 0.60). During hypoxia, IP4-dependent intranuclear 45Ca2+ influx increased from 3.39 ± 0.64 in normoxic nuclei to 13.30 ± 2.18 pM/mg protein in hypoxic nuclei (P < .01). There was an inverse correlation between the 45Ca2+ influx in neuronal nuclei and the levels of cerebral tissue ATP (r = 0.83) and PCr (r = 0.85). Similarly, IP3-dependent intranuclear 45Ca2+ influx increased from 2.26 ± 0.38 pmoles/mg protein in normoxic nuclei to 11.12 ± 1.65 pmoles/mg protein in hypoxic nuclei and showed an inverse correlation between 45Ca2+ influx in neuronal nuclei and the levels of cerebral tissue ATP (r = 0.86) and PCr (r = 0.71). The data demonstrate that there is an IP4- as well as IP3-dependent increase in nuclear Ca2+ influx with increasing cerebral tissue hypoxia, suggesting a hypoxia-induced modification of the nuclear membrane IP4 and IP3 receptors. We propose that there is a specific level of tissue hypoxia that results in a critical increase of intranuclear Ca2+ that leads to altered transcription of apoptotic genes and activation of nuclear endonucleases resulting in hypoxia-induced programmed neuronal death.

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Authors and Affiliations

  1. Department of Pediatrics, Drexel University College of Medicine and St. Christopher's Hospital for Children, Philadelphia, Pennsylvania

    Om Prakash Mishra & Maria Delivoria-Papadopoulos

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  1. Om Prakash Mishra
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  2. Maria Delivoria-Papadopoulos
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Correspondence to Om Prakash Mishra.

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Mishra, O.P., Delivoria-Papadopoulos, M. Inositol Tetrakisphosphate (IP4)- and Inositol Triphosphate (IP3)-Dependent Ca2+ Influx in Cortical Neuronal Nuclei of Newborn Piglets Following Graded Hypoxia. Neurochem Res 29, 391–396 (2004). https://doi.org/10.1023/B:NERE.0000013742.19074.7e

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  • DOI: https://doi.org/10.1023/B:NERE.0000013742.19074.7e

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