Activation-dependent plasticity of polarized GPCR distribution on the neuronal surface.
Activation-dependent plasticity of polarized GPCR distribution on the neuronal surface.
复制标题
神经元表面极化 GPCR 分布的激活依赖性可塑性。
DOI：
10.1093/jmcb/mjt014
复制
发表时间：
2013
影响因子：
5.5
通讯作者：
Z. Lenkei
中科院分区：
文献类型：
--
作者：
A. Simon;C. Loverdo;A. Gaffuri;M. Urbański;D. Ladarré;D. Carrel;I. Rivals;Christophe Leterrier;O. Bénichou;P. Dournaud;B. Szabó;R. Voituriez;Z. Lenkei
通过神经元网络的信息流的方向性在细胞水平上由极化神经元维持。然而，特定的靶向或锚定图案负责极化分布在神经元表面上只被确定为少数神经元G蛋白偶联受体（GPCR）。在这里，通过两个模型GPCR，轴突CB1R大麻素和体树突SSTR 2生长抑素受体的构象状态的突变和药理学修饰，我们显示了重要的构象依赖性变化的极化分布。潜在的机制包括轴突中构象依赖性GPCR内吞的效率较低，与树突相比，特别是在中等活化水平，以及GPCR从体树突结构域到远端轴突部分的内吞依赖性胞吞传递，通过使用区室化微流体装置显示。动力学模型预测，GPCR分布极性是高度调节的稳态内吞作用，这是构象依赖性，并能够调节相对量的GPCR靶向轴突和轴突极化分布是一个中间表型，出现在中等基础激活水平。事实上，我们的实验表明，在基础激活依赖性内吞作用的逐渐变化导致高度相关的变化，极化GPCR分布在神经元表面上，这甚至可以导致在一个完全反向的极化分布的自然体树突或轴突GPCR。总之，极化分布的神经元GPCR可能有一个可控的组件，其中，在没有占主导地位的靶向基序，甚至可以代表的主要调节亚神经元分布。因此，慢性修改的基础GPCR激活治疗或滥用药物可能会导致以前未预料到的变化，通过扰动极化GPCR分布在神经元表面的脑功能。
Directionality of information flow through neuronal networks is sustained at cellular level by polarized neurons. However, specific targeting or anchoring motifs responsible for polarized distribution on the neuronal surface have only been identified for a few neuronal G-protein-coupled receptors (GPCRs). Here, through mutational and pharmacological modifications of the conformational state of two model GPCRs, the axonal CB1R cannabinoid and the somatodendritic SSTR2 somatostatin receptors, we show important conformation-dependent variations in polarized distribution. The underlying mechanisms include lower efficiency of conformation-dependent GPCR endocytosis in axons, compared with dendrites, particularly at moderate activation levels, as well as endocytosis-dependent transcytotic delivery of GPCRs from the somatodendritic domain to distal axonal portions, shown by using compartmentalized microfluidic devices. Kinetic modeling predicted that GPCR distribution polarity is highly regulated by steady-state endocytosis, which is conformation dependent and is able to regulate the relative amount of GPCRs targeted to axons and that axonally polarized distribution is an intermediary phenotype that appears at moderate basal activation levels. Indeed, we experimentally show that gradual changes in basal activation-dependent endocytosis lead to highly correlated shifts of polarized GPCR distribution on the neuronal surface, which can even result in a fully reversed polarized distribution of naturally somatodendritic or axonal GPCRs. In conclusion, polarized distribution of neuronal GPCRs may have a pharmacologically controllable component, which, in the absence of dominant targeting motifs, could even represent the principal regulator of sub-neuronal distribution. Consequently, chronic modifications of basal GPCR activation by therapeutic or abused drugs may lead to previously unanticipated changes in brain function through perturbation of polarized GPCR distribution on the neuronal surface.
DOI：
10.1073/pnas.0603359103
发表时间：
2006-06-20
影响因子：
11.1
作者：
Scherrer, Gregory;Tryoen-Toth, Petra;Kieffer, Brigitte L.
通讯作者：
Kieffer, Brigitte L.