Metabotropic mGlu5 receptors regulate adenosine A2A receptor signaling
Metabotropic mGlu5 receptors regulate adenosine A2A receptor signaling
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DOI：
10.1073/pnas.0237126100
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发表时间：
2003-02-04
影响因子：
11.1
通讯作者：
Greengard, P
中科院分区：
文献类型：
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作者：
Nishi, A;Liu, F;Greengard, P
多巴胺通过激活多巴胺 D1 型受体，腺苷通过激活腺苷 A(2A) 受体，刺激 DARPP-32（多巴胺和 cAMP 调节的 M-r 32,000 磷蛋白）在 Thr-34 处的磷酸化。在这项研究中，我们研究了新纹状体切片中代谢型谷氨酸 (mGlu) 受体对 DARPP-32 Thr-34 磷酸化的影响。广谱 mGlu 受体激动剂 trans-ACPD 和 I 组 mGlu 受体激动剂 DHPG 刺激 DARPP-32 Thr-34 磷酸化。 mGlu 受体拮抗剂的研究表明，反式 ACPD 和 DHPG 的作用是通过激活 mGlu5 受体介导的。 mGlu5 受体的作用需要内源性腺苷激活腺苷 A(2A) 受体。相反，腺苷 A2A 受体的作用需要内源性谷氨酸激活 mGlu5 受体。外源激动剂共同激活 mGlu5 和腺苷 A2A 受体可协同增加 DARPP-32 磷酸化。 mGlu5受体不需要内源性多巴胺激活多巴胺D1型受体，多巴胺D1型受体也不需要内源性谷氨酸激活mGlu5受体。 DHPG 增强了毛喉素的作用，但不增强 8-溴-cAMP 的作用，并在磷酸二酯酶抑制剂 IBMX 存在的情况下刺激 DARPP-32 磷酸化，表明 mGlu5 受体刺激与腺苷 A2A 受体偶联的 cAMP 形成速率。 mGlu5 受体的作用会被细胞外信号调节激酶的抑制剂减弱，但不会被磷脂酶 C、p38、酪蛋白激酶 1 或 Cdk5 的抑制剂减弱。结果表明，mGlu5 受体通过以细胞外信号调节激酶依赖性方式刺激腺苷 A(2A) 受体介导的 cAMP 形成，从而增强腺苷 A(2A)/DARPP-32 信号传导。
Dopamine, by activating dopamine D1-type receptors, and adenosine, by activating adenosine A(2A) receptors, stimulate phosphorylation of DARPP-32 (dopamine- and cAMP-regulated phosphoprotein of M-r 32,000) at Thr-34. In this study, we investigated the effect of metabotropic glutamate (mGlu) receptors on DARPP-32 phosphorylation at Thr-34 in neostriatal slices. A broad-spectrum mGlu receptor agonist, trans-ACPD, and a group I mGlu receptor agonist, DHPG, stimulated DARPP-32 phosphorylation at Thr-34. Studies with mGlu receptor antagonists revealed that the effects of trans-ACPD and DHPG were mediated through activation of mGlu5 receptors. The action of mGlu5 receptors required activation of adenosine A(2A) receptors by endogenous adenosine. Conversely, the action of adenosine A2A receptors required activation of mGlu5 receptors by endogenous glutamate. Coactivation of mGlu5 and adenosine A2A receptors by exogenous agonists synergistically increased DARPP-32 phosphorylation. mGlu5 receptors did not require activation of dopamine D1-type receptors by endogenous dopamine, nor did dopamine D1-type receptors require activation of mGlu5 receptors by endogenous glutamate. DHPG potentiated the effect of forskolin, but not that of 8-bromo-cAMP, and stimulated DARPP-32 phosphorylation in the presence of the phosphodiesterase inhibitor IBMX, suggesting that mGlu5 receptors stimulate the rate of cAMP formation coupled to adenosine A2A receptors. The action of mGlu5 receptors was attenuated by inhibitors of extracellular signal-regulated kinase, but not by inhibitors of phospholipase C, p38, casein kinase 1, or Cdk5. The results demonstrate that mGlu5 receptors potentiate adenosine A(2A)/DARPP-32 signaling by stimulating the adenosine A(2A) receptor-mediated formation of cAMP in an extracellular signal-regulated kinase-dependent manner.