Dopamine D2 and adenosine A2A receptors regulate NMDA-mediated excitation in accumbens neurons through A2A-D2 receptor heteromerization.
Dopamine D2 and adenosine A2A receptors regulate NMDA-mediated excitation in accumbens neurons through A2A-D2 receptor heteromerization.
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DOI：
10.1038/npp.2008.144
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发表时间：
2009-03
期刊：
影响因子：
--
通讯作者：
Schiffmann SN
中科院分区：
文献类型：
--
作者：
Azdad K;Gall D;Woods AS;Ledent C;Ferré S;Schiffmann SN
纹状体中型多棘神经元的爆发活动是由 G 蛋白偶联受体调节的向下和向上状态之间的膜电位振荡引起的。其中，多巴胺 D2 和腺苷 A2A 受体在纹状体神经元中高度富集，并表现出强烈的相互作用，其生理意义和分子机制仍部分不清楚。更具体地说，常见的细胞内信号级联和 A2A-D2 受体异聚化各自的参与仍然未知。在这里，我们通过在脑切片上进行穿孔膜片钳记录并加载竞争性肽来证明，D2 和 A2A 受体通过依赖于特定蛋白质-蛋白质相互作用的机制调节 N-甲基-D-天冬氨酸对去极化膜电位平台的诱导。事实上，D2 受体激活通过与支架蛋白 Shank1/3 相互作用调节 CaV1.3a 钙通道活性，消除了超极化静息电位和去极化平台电位之间的转变。值得注意的是，A2A 受体激活本身没有影响，但通过严格强制 A2A-D2 受体异聚化的机制完全逆转了 D2 受体激活的影响，因此证明了这些异聚体的第一个直接生理相关性。我们的结果表明，纹状体神经元中的膜电位转变和放电模式受到 D2 和 A2A 受体通过特定蛋白质-蛋白质相互作用（包括 A2A-D2 受体异聚化）的严格控制。
Bursting activity of striatal medium spiny neurons results from membrane potential oscillations between a down- and an upstate that could be regulated by G-protein-coupled receptors. Among these, dopamine D2 and adenosine A2A receptors are highly enriched in striatal neurons and exhibit strong interactions whose physiological significance and molecular mechanisms remain partially unclear. More particularly, respective involvements of common intracellular signaling cascades and A2A–D2 receptor heteromerization remain unknown. Here we show, by performing perforated-patch-clamp recordings on brain slices and loading competitive peptides, that D2 and A2A receptors regulate the induction by N-methyl-D-aspartate of a depolarized membrane potential plateau through mechanisms relying upon specific protein–protein interactions. Indeed, D2 receptor activation abolished transitions between a hyperpolarized resting potential and a depolarized plateau potential by regulating the CaV1.3a calcium channel activity through interactions with scaffold proteins Shankl/3. Noticeably, A2A receptor activation had no effect per se but fully reversed the effects of D2 receptor activation through a mechanism in which A2A–D2 receptors heteromerization is strictly mandatory, demonstrating therefore a first direct physiological relevance of these heteromers. Our results show that membrane potential transitions and firing patterns in striatal neurons are tightly controlled by D2 and A2A receptors through specific protein–protein interactions including A2A–D2 receptors heteromerization.
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