Regulation of group I metabotropic glutamate receptor trafficking and signaling by the caveolar/lipid raft pathway.
Regulation of group I metabotropic glutamate receptor trafficking and signaling by the caveolar/lipid raft pathway.
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DOI：
10.1523/jneurosci.5824-08.2009
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发表时间：
2009-03-18
期刊：
影响因子：
--
通讯作者：
Zukin RS
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文献类型：
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作者：
Francesconi A;Kumari R;Zukin RS
神经递质受体的内吞运输对神经元信号传导和活动依赖性突触可塑性至关重要。虽然网格蛋白介导的内吞作用在神经元受体运输中的重要性已经得到了很好的证实，但对腔泡/脂质筏途径的贡献却知之甚少。在这里，我们发现了一种与脂筏和小窝的主要外壳蛋白相关的接头蛋白——小窝蛋白-1，与mGluR1/5结合并共定位。与小窝蛋白-1的相互作用控制组成型mGluR1内化的速率，从而调节受体在细胞表面的表达。与小泡蛋白-1在mGluR运输中的作用一致，我们发现mGluR1/5与大脑中的脂筏有关，并且在异种细胞和神经元中，它们的组成性内化是通过小泡/筏依赖的内吞作用介导的。我们进一步表明，小窝蛋白-1可以减弱mGluR1依赖的ERK-MAPK信号的激活，而在表达缺乏完整小窝蛋白结合基序的mGluR1突变体的细胞中，这种作用被消除。在I组mGluR选择性激动剂DHPG的刺激下，caveolin-1敲除小鼠的神经元显示ERK1/2基础磷酸化增强，ERK1/2激活延长。总之，这些发现强调了神经元中空泡筏的重要性，并表明这一途径可能在突触形成和可塑性中发挥重要作用。
Endocytic trafficking of neurotransmitter receptors is critical to neuronal signaling and activity-dependent synaptic plasticity. While the importance of clathrin-mediated endocytosis in receptor trafficking in neurons is well established, the contribution of the caveolar/lipid raft pathway has been little explored. Here we show that caveolin-1, an adaptor protein that associates with lipid rafts and the main coat protein of caveolae, binds to and co-localizes with mGluR1/5. The interaction with caveolin-1 controls the rate of constitutive mGluR1 internalization thereby regulating expression of the receptor at the cell surface. Consistent with a role for caveolin-1 in mGluR trafficking, we show that mGluR1/5 associate with lipid rafts in the brain and that their constitutive internalization is mediated, in both heterologous cells and neurons, by caveolar/raft-dependent endocytosis. We further show that caveolin-1 attenuates mGluR1-dependent activation of ERK-MAPK signaling, an effect that is abolished in cells expressing mutant mGluR1 lacking intact caveolin binding motifs. Neurons from caveolin-1 knockout mice show enhanced basal ERK1/2 phosphorylation and prolonged ERK1/2 activation in response to stimulation with DHPG, a group I mGluR selective agonist. Together, these findings underscore the importance of caveolar rafts in neurons and suggest that this pathway might play an important role in synapse formation and plasticity.