New twist on orphan receptor GPR88 function.
New twist on orphan receptor GPR88 function.
复制标题
孤儿受体 GPR88 功能的新变化。
DOI：
10.1038/nn.3244
复制
发表时间：
2012
影响因子：
25
通讯作者：
Lovinger,DavidM
中科院分区：
文献类型：
--
作者：
Lovinger,DavidM
为孤儿 G 蛋白偶联受体 (GPCR) 找到合适的角色通常是一个漫长而痛苦的过程，这让人想起狄更斯笔下的标志性孤儿雾都孤儿寻找自己在世界上的位置的艰难旅程。一个典型的例子是 GPR88，它被指定为孤儿受体，因为尚未鉴定出与该受体相互作用的配体1。尽管如此，GPR88 在纹状体中的富集 1、2、受体表达对抗抑郁治疗的敏感性 3 以及与精神分裂症 4 的遗传联系，激发了人们对其在纹状体生理学和涉及该大脑区域的行为中的作用的兴趣。背侧纹状体回路包含主要的 GABA 能中型多棘神经元 (MSN)，它抑制基底神经节的下游核，这是其他纹状体样前脑区域共有的特征，与皮质样结构中产生的谷氨酸能投射不同。 MSN 的分子特征也不同于前脑谷氨酸能投射神经元。事实上，MSNs2 中高度富集各种类型的神经递质受体和细胞内信号分子。其中包括 Golf5 等 G 蛋白、REM2（参考文献 2）等信号分子和腺苷 2A (A2A) GPCR6。定义这些富含纹状体的蛋白质（包括 GPR88）的作用，应该有助于我们识别协同作用以影响基底神经节回路和动作控制的分子网络。
Finding the proper role for orphan G protein–coupled receptors (GPCRs) is often a long and painful process that brings to mind the difficult journey of Dickens’ iconic orphan Oliver Twist to find his place in the world. A case in point is GPR88, which is designated as an orphan receptor because no ligand that interacts with the receptor has as yet been identified1. Nonetheless, the enrichment of GPR88 in the striatum1, 2, sensitivity of receptor expression to antidepressant treatments3, and genetic linkage to schizophrenia4, has stimulated interest in its roles in striatal physiology and behaviors involving this brain region. Dorsal striatal circuitry contains a predominance of GABAergic medium spiny neurons (MSNs) that inhibit downstream nuclei of the basal ganglia, a feature shared by other striatal-like forebrain regions that is distinct from the glutamatergic projections arising in cortical-like structures. The molecular profile of MSNs is also distinct from forebrain glutamatergic projection neurons. Indeed, neurotransmitter receptors and intracellular signaling molecules of various types are highly enriched in MSNs2. Among these are G proteins such as Golf5, signaling molecules such as REM2 (ref. 2), and the adenosine 2A (A2A) GPCR6. Defining the roles of these striatum-enriched proteins, including GPR88, should help us to identify molecular networks that act in concert to influence basal ganglia circuitry and action control.