Inhibition of Astrocytic Glutamate Transporter and Stimulation of Glutamate Release from Astrocytes Mediated via an A_<2a> Adenosine Receptor/PKA Signaling Pathway

通过 A_<2a> 腺苷受体/PKA 信号通路介导的星形胶质细胞谷氨酸转运蛋白的抑制和星形胶质细胞谷氨酸释放的刺激

• 批准号: 14570049
• 负责人: NISHIZAKI Tomoyuki
• 金额: $ 2.62万
• 依托单位: Hyogo College of Medicine
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14570049/
• 关键词: Astrocyte; Neurotransmission; A_<2a> adenosine receptor; Protein kinase A; Glutamate transporter; Glutamate release; 細胞内カルシウム

A low concentration(10nM) of adenosine facilitated hippocampal neurotransmission via an A_<2a> adenosine receptor/protein kinase A(PKA) signaling pathway, and a similar effect was obtained with mice lacking the astrocytic glutamate transporter GLT-1. Adenosine had no effect on transmitter release from presynaptic terminals or postsynaptic membrane conductances. Adenosine inhibited GLT-1 function, i.e., uptake of glutamate into astrocytes, as mediated via an A_<2a> adenosine receptor/PKA signaling pathway. Furthermore, adenosine stimulated vesicular glutamate release from astrocytes via an A_<2a> adenosine receptor/PKA signaling pathway, independently of reverse transport of glutamate by glutamate transporters. Adenosine also enhanced intracellular Ca^<2+> concentrations in astrocytes via A_<2a> adenosine receptors involving PKA activation, perhaps by vesicular Ca^<2+> release from an unknown intracellular calcium store, which may trigger glutamate release. The effects of adenosine on astrocytic glutamate transporters and astrocytic glutamate release would cause an increase in glutamate concentrations in the synaptic clefts, responsible for the facilitatory action on hippocampal neurotransmission. The results of the present study, thus, may represent a new neuromodulatory pathway with an astrocytic contribution mediated via an A_<2a> adenosine receptor/PKA signaling pathway.

低浓度（10nM）腺苷通过A_<2a>腺苷受体/蛋白激酶A（PKA）信号通路促进海马神经传递，在缺乏星形细胞谷氨酸转运体GLT-1的小鼠中也获得类似的效果。腺苷对突触前末端或突触后膜传导的递质释放无影响。腺苷抑制GLT-1功能，即通过A_<2a>腺苷受体/PKA信号通路介导谷氨酸进入星形胶质细胞。此外，腺苷通过A_<2a>腺苷受体/PKA信号通路刺激星形胶质细胞释放囊状谷氨酸，而不依赖于谷氨酸转运体对谷氨酸的反向转运。腺苷还通过参与PKA激活的A_<2a>腺苷受体增强星形胶质细胞内Ca^<2+>浓度，可能是通过未知的细胞内钙储存释放囊泡Ca^<2+>，这可能触发谷氨酸释放。腺苷对星形胶质细胞谷氨酸转运体和星形胶质细胞谷氨酸释放的影响会引起突触间隙谷氨酸浓度的增加，从而对海马神经传递起促进作用。因此，本研究的结果可能代表了一种新的神经调节途径，通过A_<2a>腺苷受体/PKA信号通路介导星形细胞的贡献。

项目成果

Nishizaki T, Nagai K, Nomura T, Tada H, Kanno T, Tozaki H, Li XX, Kondoh T, Kodama N, Takahashi E, Sakai N, Tanaka K, Saito N: "A new neuromodulatory pathway with a glial contribution mediated via A_<2a> adenosine receptors."Glia. 39(2). 133-147 (2002)

Nishizaki T、Nagai K、Nomura T、Tada H、Kanno T、Tozaki H、Li XX、Kondoh T、Kodama N、Takahashi E、Sakai N、Tanaka K、Saito N：“一种新的神经调节途径，通过神经胶质细胞介导

Nishizaki T: "ATP-and Adenosine-mediated signaling in the central nervous system : Adenosine stimulates glutamate release from astrocytes via A_<2a> adenosine receptors."J.Pharmacol.Sci.. 94(2). 100-102 (2004)

Nishizaki T：“中枢神经系统中ATP和腺苷介导的信号传导：腺苷通过A_2a腺苷受体刺激星形胶质细胞释放谷氨酸。”J.Pharmacol.Sci.. 94(2)。

Tomoyuki Nisizaki: "Adenosine stimulates gultamate release from astrocytes via A_<2a> adenosine receptors"Journal of Pharmacological Sciences. 94. 100-102 (2004)

Tomoyuki Nisizaki：“腺苷通过A_2a腺苷受体刺激星形胶质细胞释放谷氨酸”药理学科学杂志。

Ohta K, Nomura T, Kanno T, Nagai K, Yamamoto S, Yajima Y, Kondoh T, Kohmura E, Saito N, Nishizaki T: "L-trans-PDC enhances hippocampal neuronal activity by stimulating glial glutamate release independently of blocking transporters."Biochem.Biophys.Res.Com

Ohta K、Nomura T、Kanno T、Nagai K、Yamamoto S、Yajima Y、Kondoh T、Kohmura E、Saito N、Nishizaki T：“L-trans-PDC 通过独立于阻断转运蛋白刺激神经胶质谷氨酸释放来增强海马神经元活动。

Tada H, Uchino M, Nagai K, Nomura T, Kondoh T, Saito N, Yamamura T, Yajima Y, Nishizaki T: "The anti-dementia drug FK960 stimulates glial glutamate release via a PKA pathway."Mol.Brain Res.. 109(1-2). 63-68 (2002)

Tada H、Uchino M、Nagai K、Nomura T、Kondoh T、Saito N、Yamamura T、Yajima Y、Nishizaki T：“抗痴呆药物 FK960 通过 PKA 途径刺激胶质细胞谷氨酸释放。”Mol.Brain Res..