Phosphorylation and modulation of recombinant GluR6 glutamate receptors by cAMP-dependent protein kinase
Phosphorylation and modulation of recombinant GluR6 glutamate receptors by cAMP-dependent protein kinase
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DOI：
10.1038/361637a0
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发表时间：
1993-02
期刊：
影响因子：
64.8
通讯作者：
L. Raymond;C. Blackstone;R. Huganir
中科院分区：
文献类型：
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作者：
L. Raymond;C. Blackstone;R. Huganir
谷氨酸门控离子通道介导中枢神经系统中的大多数兴奋性突触传递，并在突触可塑性、神经元发育和一些神经病理学状况中发挥关键作用1 -3。这些离子型谷氨酸受体已根据其优选激动剂分类为NMDA（N-甲基-D-天冬氨酸）、AMPA（α-氨基-3-羟基-5-甲基-4-异恶唑丙酸酯）和KA（红藻氨酸）受体4。基于序列相似性和药理学性质，最近克隆的谷氨酸受体亚基已被指定为NMDA（NMDAR 1，2A-D）、AMPA（GluR 1 -4）和KA（GluR 5 -7，KA 1，KA 2）受体的组分5 -7。已表明蛋白激酶C和环AMP依赖性蛋白激酶（PKA）对谷氨酸受体的蛋白磷酸化调节其功能8 -18，可能在某些形式的突触可塑性中发挥突出作用，例如长时程增强19和长时程抑制9。在这里，我们报告说，GluR 6谷氨酸受体，瞬时表达在哺乳动物细胞中，直接磷酸化PKA，并在细胞内应用PKA增加谷氨酸反应的幅度。代表PKA共有位点的丝氨酸残基（Ser 684）的位点特异性诱变完全消除了PKA介导的该位点的磷酸化以及谷氨酸反应的增强。这些结果为谷氨酸受体的直接磷酸化调节其功能提供了证据。
GLUTAMATE-GATED ion channels mediate most excitatory synaptic transmission in the central nervous system and play crucial roles in synaptic plasticity, neuronal development and some neuropathological conditions1–3. These ionotropic glutamate receptors have been classified according to their preferred agonists as NMDA (N-methyl-D-aspartate), AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionate) and KA (kainate) receptors4. On the basis of sequence similarity and pharmacological properties, the recently cloned glutamate receptor subunits have been assigned as components of NMDA (NMDAR1, 2A–D), AMPA (GluRl–4) and KA (GluR5–7, KA1, KA2) receptors5–7. Protein phosphorylation of glutamate receptors by protein kinase C and cyclic AMP-dependent protein kinase (PKA) has been suggested to regulate their function8–18, possibly playing a prominent role in certain forms of synaptic plasticity such as long-term potentiation19and long-term depression9. Here we report that the GluR6 glutamate receptor, transiently expressed in mammalian cells, is directly phosphorylated by PKA, and that intracellularly applied PKA increases the amplitude of the glutamate response. Site-specific mutagenesis of the serine residue (Ser 684) representing a PKA consensus site completely eliminates PKA-mediated phosphorylation of this site as well as the potentiation of the glutamate response. These results provide evidence that direct phosphorylation of glutamate receptors modulates their function.