Marinelli S, Federici M, Giacomini P, Bernardi G, Mercuri N B
Fondazione Santa Lucia, Istituto di Ricovero e Cura a Carattere Scientifico, Universita' di Roma "La Sapienza," 00179 Rome, Italy.
J Neurophysiol. 2001 Mar;85(3):1159-66. doi: 10.1152/jn.2001.85.3.1159.
It is widely accepted that energy deprivation causes a neuronal death that is mainly determined by an increase in the extracellular level of glutamate. Consequently an excessive membrane depolarization and a rise in the intracellular concentration of sodium and calcium are produced. In spite of this scenario, the function of excitatory and inhibitory amino acids during an episode of energy failure has not been studied yet at a cellular level. In a model of cerebral hypoglycemia in the rat substantia nigra pars compacta, we measured neuronal responses to excitatory amino acid agonists. Under single-electrode voltage-clamp mode at -60 mV, the application of the ionotropic glutamate receptor agonists N-methyl-D-aspartate, alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid, kainate, and the metabotropic group I agonist (S)-3,5-dihydroxyphenilglycine (DHPG) produced reversible inward currents in the dopaminergic cells. In addition, an outward current was caused by the superfusion of the metabotropic GABA(B) agonist baclofen. Glucose deprivation enhanced the inward responses caused by each ionotropic glutamate agonist. In contrast, hypoglycemia depressed the DHPG-induced inward current and the baclofen-induced outward current. These effects of hypoglycemia were reversible. To test whether a failure of the Na(+)/K(+) ATPase pump could account for the modification of the agonist-induced currents during hypoglycemia, we treated the midbrain slices with strophanthidin (1-3 microM). Strophanthidin enhanced the inward currents caused by glutamate agonists. However, it did not modify the GABA(B)-induced outward current. Our data suggest that glucose deprivation enhances the inward current caused by the stimulation of ionotropic glutamate receptors while it dampens the responses caused by the activation of metabotropic receptors. Thus a substantial component of the augmented neuronal response to glutamate, during energy deprivation, is very likely due to the failure of Na(+) and Ca(2+) extrusion and might ultimately favor excitotoxic processes in the dopaminergic cells.
能量剥夺会导致神经元死亡，这一点已被广泛接受，而这种死亡主要由细胞外谷氨酸水平的升高所决定。因此，会产生过度的膜去极化以及细胞内钠和钙浓度的升高。尽管如此，在能量衰竭期间兴奋性和抑制性氨基酸的功能尚未在细胞水平上进行研究。在大鼠黑质致密部的脑低血糖模型中，我们测量了神经元对兴奋性氨基酸激动剂的反应。在 -60 mV 的单电极电压钳模式下，应用离子型谷氨酸受体激动剂 N-甲基-D-天冬氨酸、α-氨基-3-羟基-5-甲基-4-异恶唑丙酸、海人藻酸以及代谢型 I 组激动剂 (S)-3,5-二羟基苯甘氨酸 (DHPG) 在多巴胺能细胞中产生了可逆的内向电流。此外，代谢型 GABA(B) 激动剂巴氯芬的灌流引起了外向电流。葡萄糖剥夺增强了每种离子型谷氨酸激动剂引起的内向反应。相比之下，低血糖抑制了 DHPG 诱导的内向电流和巴氯芬诱导的外向电流。低血糖的这些作用是可逆的。为了测试 Na(+)/K(+) ATP 酶泵功能衰竭是否可以解释低血糖期间激动剂诱导电流的改变，我们用毒毛花苷（1 - 3 microM）处理中脑切片。毒毛花苷增强了谷氨酸激动剂引起的内向电流。然而，它并未改变 GABA(B) 诱导的外向电流。我们的数据表明，葡萄糖剥夺增强了离子型谷氨酸受体刺激引起的内向电流，同时减弱了代谢型受体激活引起的反应。因此，在能量剥夺期间神经元对谷氨酸增强反应的一个重要组成部分很可能是由于 Na(+) 和 Ca(2+) 外排功能衰竭，并且最终可能有利于多巴胺能细胞中的兴奋毒性过程。
