Dopamine D3 receptors regulate GABAA receptor function through a phospho-dependent endocytosis mechanism in nucleus accumbens
Dopamine D3 receptors regulate GABAA receptor function through a phospho-dependent endocytosis mechanism in nucleus accumbens
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DOI：
10.1523/jneurosci.4712-05.2006
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发表时间：
2006-03-01
影响因子：
5.3
通讯作者：
Yan, Z
中科院分区：
文献类型：
--
作者：
Chen, GJ;Kittler, JT;Yan, Z
多巴胺D-3受体高度富集于中脑核（NAc），被认为在强化和奖赏中起重要作用。为了了解D-3受体功能的潜在细胞机制，我们研究了D-3受体激活对NAc中型棘神经元GABA（A）受体（GABA（A）R）介导的电流和抑制性突触传递的影响。PD 128907 [（4aR，10 bR）-3，4a，4，10 b-tetrahydro-4-propyl-2 H，5 H-[1] benzopyrano-[4，3-B]-1，4-oxazin-9-ol hydrochloride]（一种特异性D-3受体激动剂）的应用导致急性分离的NAc神经元中GABAAR电流的显著降低和NAc切片中微小的IPSC振幅。这种作用通过用发动蛋白抑制肽透析来阻断，发动蛋白抑制肽阻止网格蛋白/激活蛋白2（AP 2）介导的GABA（A）受体内吞作用。此外，D-3对GABA（A）R电流的影响可通过操纵蛋白激酶A（PKA）活性的药物来阻止。输注源自GABA（A）β亚基的肽，其含有网格蛋白AP 2接头复合物的非典型结合基序和主要PKA磷酸化位点，并且仅在去磷酸化时以高亲和力结合AP 2，减弱了D-3对IPSC振幅的调节。肽的磷酸化等价物没有影响。此外，PD 128907增加NAc切片中GABAAR内化并减少GABA（A）受体β亚基的表面表达，这被发动蛋白抑制肽或cAMP处理所阻止。总之，我们的研究结果表明，D-3受体激活通过增加GABA（A）受体的磷酸依赖性内吞作用来抑制NAc中抑制性突触传递的功效。
The dopamine D-3 receptor, which is highly enriched in nucleus accumbens (NAc), has been suggested to play an important role in reinforcement and reward. To understand the potential cellular mechanism underlying D-3 receptor functions, we examined the effect of D-3 receptor activation on GABA(A) receptor (GABA(A)R)-mediated current and inhibitory synaptic transmission in medium spiny neurons of NAc. Application of PD128907 [(4aR, 10bR)-3,4a, 4,10b-tetrahydro-4-propyl-2H, 5H-[1] benzopyrano-[4,3-b]-1,4-oxazin-9-ol hydrochloride], a specific D-3 receptor agonist, caused a significant reduction of GABAAR current in acutely dissociated NAc neurons and miniature IPSC amplitude in NAc slices. This effect was blocked by dialysis with a dynamin inhibitory peptide, which prevents the clathrin/activator protein 2 (AP2)-mediated GABA(A) receptor endocytosis. In addition, the D-3 effect on GABA(A)R current was prevented by agents that manipulate protein kinase A (PKA) activity. Infusion of a peptide derived from GABA(A) beta subunits, which contains an atypical binding motif for the clathrin AP2 adaptor complex and the major PKA phosphorylation sites and binds with high affinity to AP2 only when dephosphorylated, diminished the D-3 regulation of IPSC amplitude. The phosphorylated equivalent of the peptide was without effect. Moreover, PD128907 increased GABAAR internalization and reduced the surface expression of GABA(A) receptor beta subunits in NAc slices, which was prevented by dynamin inhibitory peptide or cAMP treatment. Together, our results suggest that D-3 receptor activation suppresses the efficacy of inhibitory synaptic transmission in NAc by increasing the phospho-dependent endocytosis of GABA(A) receptors.