Smith-Swintosky V L, Zimmer S, Fenton J W, Mattson M P
Sanders-Brown Research Center on Aging, University of Kentucky, Lexington 40536-0230, USA.
J Neurosci. 1995 Aug;15(8):5840-50. doi: 10.1523/JNEUROSCI.15-08-05840.1995.
Protease nexin-I (PN-1) is a 44 kDa serine proteinase inhibitor that rapidly inhibits thrombin by forming SDS stable complexes with serine at the catalytic site of the protease. Levels of both PN-1 and thrombin are increased in the brain in response to insults such as ischemia, suggesting roles in neural injury and repair processes. We now report that PN-1-protected cultured rat hippocampal neurons against glucose deprivation- induced damage (GDID), and the protection was abolished by equimolar thrombin. PN-1 reduced resting intracellular free calcium levels ([Ca2+]i) and attenuated the elevation of [Ca2+]i normally associated with GDID. Thrombin reduced neuronal survival and caused a significant increase in [Ca2+]i. Submaximally toxic levels of thrombin exacerbated GDID. Calcium responses to thrombin were attenuated in neurons contacting PN-1 immunoreactive astrocytes. These findings suggest that PN-1 and thrombin play important roles in modulating neuronal calcium responses, and vulnerability, to metabolic/excitotoxic insults.
蛋白酶抑制因子I（PN-1）是一种44 kDa的丝氨酸蛋白酶抑制剂，它通过与蛋白酶催化位点的丝氨酸形成SDS稳定复合物来快速抑制凝血酶。在诸如局部缺血等损伤刺激下，大脑中PN-1和凝血酶的水平都会升高，这表明它们在神经损伤和修复过程中发挥作用。我们现在报告，PN-1可保护培养的大鼠海马神经元免受葡萄糖剥夺诱导的损伤（GDID），而等摩尔的凝血酶可消除这种保护作用。PN-1降低了静息细胞内游离钙水平（[Ca2+]i），并减弱了通常与GDID相关的[Ca2+]i升高。凝血酶降低了神经元的存活率，并导致[Ca2+]i显著增加。亚毒性水平的凝血酶加剧了GDID。在与PN-1免疫反应性星形胶质细胞接触的神经元中，对凝血酶的钙反应减弱。这些发现表明，PN-1和凝血酶在调节神经元钙反应以及对代谢/兴奋性毒性损伤的易感性方面发挥重要作用。
