Yacobi Assaf, Stern Bach Yael, Horowitz Michal
Laboratory of Environmental Physiology; Faculty of Dental Medicine; The Hebrew University; Jerusalem, Israel.
Department of Biochemistry and Molecular Biology; IMRIC; The Hebrew University; Jerusalem, Israel.
Temperature (Austin). 2014 Jul 1;1(1):57-65. doi: 10.4161/temp.29719. eCollection 2014 Apr-Jun.
Long-term heat acclimation (34 °C, 30d) alters the physiological responses and the metabolic state of organisms. It also improves ability to cope with hypoxic stress via a cross-tolerance mechanism. Within the brain, the hippocampal and frontal cortex neurons are the most sensitive to hypoxia and cell death is mainly caused by calcium influx via glutamate-gated ion channels, specifically NMDA and AMPA receptors. GluN1 subunit levels of NMDA-R correspond to NMDA-R levels. GluN2B/GluN2A subunit ratio is a qualitative index of channel activity; a higher ratio implies lower calcium permeability. The GluA2 subunit of AMPA-R controls channel permeability by inhibiting calcium penetration. Here, in rats model we (i)used behavioral-assessment tests to evaluate heat acclimation mediated hypoxic (15' 4.5 ± 0.5% O2) neuroprotection, (ii) measured protein and transcript levels of NMDA-R and AMPA-R subunits before and after hypoxia in the hippocampus and the frontal cortex, to evaluate the role of Ca(2+) in neuro-protection/cross-tolerance. Behavioral tests confirmed hypoxic tolerance in long-term (30d) but not in short-term (2d) heat acclimated rats. Hypoxic tolerance in the long-term acclimated phenotype was accompanied by a significant decrease in basal NMDA receptor GluN1 protein and an increase in its mRNA. The long-term acclimated rats also showed post ischemic increases in the GluN2B/GluN2A subunit ratio and GluA2 subunit of the AMPA receptor, supporting the hypothesis that reduced calcium permeability contributes to heat acclimation mediated hypoxia cross-tolerance. Abrupt post ischemic change in GluN2B/GluN2A subunit ratio with no change in NMDA-R subunits transcript levels implies that post-translational processes are inseparable acclimatory cross-tolerance mechanism.
长期热适应（34°C，30天）会改变生物体的生理反应和代谢状态。它还通过交叉耐受机制提高应对缺氧应激的能力。在大脑中，海马体和额叶皮质神经元对缺氧最为敏感，细胞死亡主要由谷氨酸门控离子通道（特别是NMDA和AMPA受体）介导的钙内流引起。NMDA受体的GluN1亚基水平与NMDA受体水平相对应。GluN2B/GluN2A亚基比率是通道活性的定性指标；比率越高，钙通透性越低。AMPA受体的GluA2亚基通过抑制钙渗透来控制通道通透性。在此，在大鼠模型中，我们（i）使用行为评估测试来评估热适应介导的缺氧（15分钟，4.5±0.5%氧气）神经保护作用，（ii）测量海马体和额叶皮质缺氧前后NMDA受体和AMPA受体亚基的蛋白质和转录水平，以评估Ca(2+)在神经保护/交叉耐受中的作用。行为测试证实长期（30天）热适应的大鼠具有缺氧耐受性，而短期（2天）热适应的大鼠则没有。长期适应表型的缺氧耐受性伴随着基础NMDA受体GluN1蛋白的显著降低及其mRNA的增加。长期热适应的大鼠在缺血后还表现出AMPA受体的GluN2B/GluN2A亚基比率和GluA2亚基增加，支持钙通透性降低有助于热适应介导的缺氧交叉耐受这一假说。缺血后GluN2B/GluN2A亚基比率的突然变化而NMDA受体亚基转录水平无变化，这意味着翻译后过程是不可分割的适应性交叉耐受机制。
