Diacylglycerol kinase β accumulates on the perisynaptic site of medium spiny neurons in the striatum
Diacylglycerol kinase β accumulates on the perisynaptic site of medium spiny neurons in the striatum
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DOI：
10.1111/j.1460-9568.2008.06547.x
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发表时间：
2008-12-01
影响因子：
3.4
通讯作者：
Goto, Kaoru
中科院分区：
文献类型：
--
作者：
Hozumi, Yasukazu;Fukaya, Masahiro;Goto, Kaoru
在Gq蛋白偶联受体活化后，磷脂酶C产生一对第二信使，即二酰基甘油（DAG）和肌醇1，4，5-三磷酸。前者激活蛋白激酶C，后者从细胞内储存中动员Ca 2+。然后DAG激酶（DGK）磷酸化DAG以产生另一种第二信使（磷脂酸）。在10种哺乳动物DGK同工酶中，DGK β在多巴胺能投射场中表达，在纹状体中表达水平最高，并且其特定的剪接变体在双相情感障碍患者中差异表达。为了获得其信号传导作用的分子解剖学证据，我们研究了DGK β在大鼠脑纹状体中的细胞表达和亚细胞定位。DGK β在构成纹状体黑质和纹状体苍白球通路的中等多刺神经元中表达，而纹状体中间神经元低于检测阈值。DGK β分布在中型多刺神经元的体树突成分中，并与滑面内质网和质膜或它们之间的狭窄胞质空间相关联地定位。特别是，DGK β在树突棘上的突触周围部位表现出密集的积累，形成不对称的突触。特征性解剖定位与微粒体和突触后密度组分中DGK β的专属富集一致。有趣的是，DGK β在免疫组织化学和免疫化学分布上与Gq偶联受体（如代谢型谷氨酸受体1和5）以及其他涉及DAG代谢的下游分子（如磷脂酶C β和DAG脂肪酶）非常相似。这些发现表明，丰富的DGK β被提供给中棘神经元的突触周围位点，使得它可以在激活Gq偶联受体后有效地产生磷脂酸，并调节纹状体输出神经元的细胞状态。
Following activation of Gq protein-coupled receptors, phospholipase C yields a pair of second messengers, i.e. diacylglycerol (DAG) and inositol 1,4,5-trisphosphate. The former activates protein kinase C and the latter mobilizes Ca2+ from intracellular store. DAG kinase (DGK) then phosphorylates DAG to produce another second messenger (phosphatidic acid). Of 10 mammalian DGK isozymes, DGK beta is expressed in dopaminergic projection fields with the highest level in the striatum and its particular splice variant is differentially expressed in patients with bipolar disorder. To gain molecular anatomical evidence for its signaling role, we investigated the cellular expression and subcellular localization of DGK beta in the striatum of rat brain. DGK beta was expressed in medium spiny neurons constituting the striatonigral and striatopallidal pathways, whereas striatal interneurons were below the detection threshold. DGK beta was distributed in somatodendritic elements of medium spiny neurons and localized in association with the smooth endoplasmic reticulum and plasma membrane or in the narrow cytoplasmic space between them. In particular, DGK beta exhibited dense accumulation at perisynaptic sites on dendritic spines forming asymmetrical synapses. The characteristic anatomical localization was consistent with exclusive enrichment of DGK beta in the microsomal and postsynaptic density fractions. Intriguingly, DGK beta was very similar in immunohistochemical and immunochemical distribution to Gq-coupled receptors, such as metabotropic glutamate receptors 1 and 5, and also to other downstream molecules involving DAG metabolism, such as phospholipase C beta and DAG lipase. These findings suggest that abundant DGK beta is provided to perisynaptic sites of medium spiny neurons so that it can effectively produce phosphatidic acid upon activation of Gq-coupled receptors and modulate the cellular state of striatal output neurons.