Pituitary adenylate cyclase-activating polypeptide (PACAP), a neuron-derived peptide regulating glial glutamate transport and metabolism
Pituitary adenylate cyclase-activating polypeptide (PACAP), a neuron-derived peptide regulating glial glutamate transport and metabolism
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DOI：
10.1523/jneurosci.20-10-03596.2000
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发表时间：
2000-05-15
影响因子：
5.3
通讯作者：
Engele, J
中科院分区：
文献类型：
--
作者：
Figiel, M;Engele, J
在脑中，谷氨酸能神经传递主要通过突触释放的谷氨酸通过Na+依赖性谷氨酸转运蛋白GLT-1和GLAST快速摄取到星形胶质细胞中并随后通过谷氨酰胺合成酶（GS）转化为谷氨酰胺而终止。到目前为止，已经确定了几个因素，迅速改变神经胶质细胞谷氨酸摄取的谷氨酸转运蛋白的翻译后修饰。已知影响胶质细胞谷氨酸转运体和GS表达的唯一条件是胶质细胞与神经元的共培养。我们现在证明，神经元调节神经胶质细胞谷氨酸营业额通过垂体腺苷酸环化酶激活多肽（PACAP）。在大脑皮层中，PACAP由神经元合成，并作用于参与谷氨酸周转的星形胶质细胞亚群。暴露于PACAP的星形胶质细胞通过促进GLT-1、GLAST和GS的表达而增加[H-3]谷氨酸摄取的最大速度。此外，神经元条件培养基对神经胶质谷氨酸转运蛋白表达的刺激作用在PACAP失活抗体或PACAP受体拮抗剂PACAP 6-38的存在下减弱。与PACAP相比，血管活性肠肽仅在明显较高的浓度下促进谷氨酸转运体的表达，表明PACAP通过PAC 1受体对胶质细胞谷氨酸周转产生影响。虽然PAC 1受体依赖性蛋白激酶A（PKA）的激活足以促进GLAST的表达，但PKA和蛋白激酶C（PKC）的激活需要最佳地促进GLT-1的表达。鉴于存在不同的PAC 1受体亚型，激活PKA和PKC到不同的水平，这些发现指出了一个复杂的机制，PACAP调节神经胶质细胞谷氨酸转运和代谢。这些调节机制的紊乱可能是谷氨酸相关神经和精神疾病的主要原因。
In the brain, glutamatergic neurotransmission is terminated predominantly by the rapid uptake of synaptically released glutamate into astrocytes through the Na+-dependent glutamate transporters GLT-1 and GLAST and its subsequent conversion into glutamine by the enzyme glutamine synthetase (GS). To date, several factors have been identified that rapidly alter glial glutamate uptake by post-translational modification of glutamate transporters. The only condition known to affect the expression of glial glutamate transporters and GS is the coculturing of glia with neurons. We now demonstrate that neurons regulate glial glutamate turnover via pituitary adenylate cyclase-activating polypeptide (PACAP). In the cerebral cortex PACAP is synthesized by neurons and acts on the subpopulation of astroglia involved in glutamate turnover. Exposure of astroglia to PACAP increased the maximal velocity of [H-3]glutamate uptake by promoting the expression of GLT-1, GLAST, and GS. Moreover, the stimulatory effects of neuron-conditioned medium on glial glutamate transporter expression were attenuated in the presence of PACAP-inactivating antibodies or the PACAP receptor antagonist PACAP 6-38. In contrast to PACAP, vasoactive intestinal peptide promoted glutamate transporter expression only at distinctly higher concentrations, suggesting that PACAP exerts its effects on glial glutamate turnover via PAC1 receptors. Although PAC1 receptor-dependent activation of protein kinase A (PKA) was sufficient to promote the expression of GLAST, the activation of both PKA and protein kinase C (PKC) was required to promote GLT-1 expression optimally. Given the existence of various PAC1 receptor isoforms that activate PKA and PKC to different levels, these findings point to a complex mechanism by which PACAP regulates glial glutamate transport and metabolism. Disturbances of these regulatory mechanisms could represent a major cause for glutamate-associated neurological and psychiatric disorders.