Argininosuccinate as a possible neuromodulator and localization of its metabolizing enzymes

根据我们先前对精氨酸琥珀酸合成酶(ASS)和精氨酸琥珀酸裂解酶(ASL)在大鼠脑内定位的免疫组织化学研究，我们推测精氨酸琥珀酸可能是一种新的神经调节剂。这是因为有些神经细胞含有ASS，但不含ASL，另一些神经细胞含有ASL，但不含ASS。我们发现，ASS/ASL在不同组织中的活性比从肝、肾和睾丸的接近于1到在脾和骨骼肌中几乎为零。作为整个大脑，这一比例为0.27，但每个核团或大脑部分的值在0.78到0.06之间变化很大。这些结果表明，这两种酶并不总是在精氨酸合成系统中协同发挥作用。在许多组织和细胞中，精氨酸合成系统可能起到为合成一氧化氮(NO)提供精氨酸的作用。在位于胰腺的副交感神经节中，未检测到NADP脱氢酶合成酶的神经细胞内有ASS。相反，ASS和NO合成酶在纹状体神经细胞中的定位不同，这再次表明ASS可能作为神经调节剂合成精氨酸琥珀酸供细胞分泌。我们发现，即使在10-10M浓度下，精氨酸琥珀酸也能降低体外培养的小脑细胞对谷氨酸的反应，但不影响嗅觉细胞对谷氨酸的反应和朗格汉斯胰岛细胞对葡萄糖的反应。精氨酸丁二酸酯作为神经调节剂的建立还需要进一步的广泛工作。

From our previous immunohistochemical study on the localization of argininosuccinate synthetase (ASS) and argininosuccinate lyase (ASL) in the rat brain, we postulate that argininosuccinate may be a novel neuromodulator. It is because some neuronal cells contain ASS, but not ASL, and some others contain ASL, but not ASS. We showed that the activity ratios of ASS to ASL in various tissues varied from about unity in the liver, kidney and testis to nearly zero in the spleen and skeletal muscle. As the whole brain, the ratio was 0.27, but the each nucleus or brain part shows quite a varied value from 0.78 to 0.06. These results suggest that the two enzymes do not always play a role cooperatively in arginine-synthesizing system. In many tissues and cells, arginine-synthesizing system may play a role in supplying arginine for the synthesis of nitric oxide (NO). In the parasympathetic ganglia located in the pancreas, ASS was found in the nerve cells where NO synthase detected as NADP dehydrogenase was located. On the contrary, ASS and NO synthase were differently localized in the neuronal cells of striatum, again suggesting that ASS might synthesize argininosuccinate for secretion from the cells as a neuromodulator. We found that argininosuccinate decreased the response of isolated cerebellar cells to glutamte even at the concentration of 10-10M, but it did not affect the response of cultured olfactory cells to glutamate and of Langerhans islet cells to glucose. Further extensive works are needed for the establishment of argininosuccinate as a neuromodulator.