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ADENOSINE FACILITATES HIPPOCAMPAL NEUROTRANSMISSION BY BLOCKING GLIAL GLUTAMATE REUPTAKE VIA THE GLUTAMATE TRANSPORTER GLT-1

腺苷通过谷氨酸转运蛋白 GLT-1 阻断胶质细胞谷氨酸再摄取，促进海马神经传递

基本信息

批准号：
11670043
负责人：
NISHIZAKI Tomoyuki
金额：
$ 2.18万
依托单位：
HYOGO COLLEGE OF MEDICINE (2000)Kobe University (1999)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2000
项目状态：
已结题

项目摘要

Adenosine (100nM) increased the amplitude of population spikes (PSs) elicited from the granular cell layer, to approximately 150% of basal levels during the initial 18 min, being evident throughout application, and the effect reversed at 30-min washing-out of the drug. The increase was inhibited by the selective A_<2a> adenosine receptor antagonist, DMPX, and the selective A_<2a> adenosine receptor agonist, CGS21680 (0.1 μM) enhanced PS amplitude to a similar extent as adenosine did, suggesting that the facilitatory action of adenosine on hippocampal neurotransmission is mediated by A_<2a> adenosine receptors. A similar facilitation was found with the glutamate transporter inhibitor, PDC ; PDC gradually increased the PS amplitude, reaching about 180% at 120-min treatment, and the effect reversed 30 min after washing-out of the drug. Notably, the saturable effect of PDC on neurotransmission occluded the enhancement induced by adenosine, suggesting that the facilitatory actions of adenos … More ine and PDC share a common mechanism ; in other words, adenosine facilitates neurotransmission by targeting glutamate transporters. To examine whether adenosine actually acts on glial glutamate transporters or not, we expressed A_1 or A_<2a> adenosine receptors together with GLT-1 in Xenopus oocytes. When A_<2a> adenosine receptors were co-expressed with GLT-1, activation of A_<2a> adenosine receptors inhibited glutamate-evoked currents to 56% of control, and the effect was inhibited by DMPX.In contrast, GLT-1 currents were not affected by activation of A_1 adenosine receptors in oocytes co-expressing GLT-1 and A_1 adenosine receptors, indicating that adenosine inhibits GLT-1 glutamate uptake via adenosine A_<2a> receptors. Taken together, it appears that adenosine facilitates hippocampal neurotransmission as a result of increasing synaptic glutamate concentrations by blocking glial GLT-1 via A_<2a> adenosine receptors. This may represent the cellular mechanism underlying the facilitatory action of adenosine on hippocampal neurotransmission. Less

腺苷(100 Nm)使颗粒细胞层诱发的群体峰(PSS)的幅度在最初的18分钟内增加到基础水平的约150%，在整个应用过程中表现明显，并在药物清洗30分钟后逆转。选择性腺苷受体拮抗剂DMPX和腺苷受体激动剂CGS21680(0.1μM)对PS幅度的增强作用与腺苷相似，提示腺苷对海马神经传递的易化作用是由腺苷受体介导的。谷氨酸转运体抑制剂PDC也有类似的促进作用；PDC逐渐增加PS幅度，作用120min时达到约180%，洗脱药物30min后作用逆转。值得注意的是，pDC对神经传递的饱和效应阻断了腺苷诱导的增强，这表明腺苷…的促进作用更多的腺苷和PDC共享一个共同的机制；换句话说，腺苷通过靶向谷氨酸转运体来促进神经传递。为了验证腺苷是否确实作用于胶质谷氨酸转运体，我们在非洲爪哇卵母细胞中表达了腺苷A_1或A_1或A_1受体和GLT-1。当A&lt；2a&gt；腺苷受体与GLT-1共表达时，激活A&lt；2a&gt；受体可抑制谷氨酸诱发电流的56%，其作用可被DMPX抑制。相反，共表达GLT-1和A1腺苷受体的卵母细胞的A_1腺苷受体激活不影响GLT-1电流，表明腺苷通过腺苷A&1a&gt；受体抑制GLT-1谷氨酸摄取。综上所述，腺苷似乎促进了海马神经传递，这是由于腺苷通过腺苷受体阻断胶质细胞GLT-1而增加突触谷氨酸浓度的结果。这可能代表了腺苷促进海马神经传递的细胞机制。较少