Differential binding of calmodulin to group I metabotropic glutamate receptors regulates receptor trafficking and signaling.
Differential binding of calmodulin to group I metabotropic glutamate receptors regulates receptor trafficking and signaling.
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DOI：
10.1523/jneurosci.6253-10.2011
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发表时间：
2011-04-20
期刊：
影响因子：
--
通讯作者：
Roche KW
中科院分区：
文献类型：
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作者：
Choi KY;Chung S;Roche KW
代谢型谷氨酸受体（mGluRs）是调节兴奋性神经传递和突触可塑性的G蛋白偶联受体。第I组mGluR（mGluR1和mGluR5）具有长的细胞内C末端结构域，其与许多蛋白质相互作用。我们以前的研究确定钙调素（CaM）作为一个强大的调节mGluR5的运输和mGluR5诱导的钙信号。虽然它已被接受，mGluR1和mGluR5与钙调素相互作用，我们现在表明，钙调素特异性结合mGluR5，而不是mGluR1。我们已经确定了一个单一的关键残基mGluR5（L896），这是钙调素结合所需的。在mGluR1中，相应残基V909突变为亮氨酸足以使CaM与mGluR1结合。为了研究钙调素结合的功能效应，我们研究了海马神经元中mGluR1和mGluR5的表面表达。赋予CaM结合的mGluR1突变（V909L）显著增加mGluR1表面表达，而破坏CaM结合的mGluR5类似突变（L896V）降低mGluR5表面表达。此外，改变钙调素结合的关键残基调节mGluR内化。此外，我们发现，mGluR介导的AMPA受体的内吞作用增强钙调素结合组I mGluRs。最后，我们表明，由I组mGluRs引起的钙反应调制这些突变，调节钙调素结合。我们的研究结果阐明了一个关键的机制，专门影响mGluR5的运输和信号，并区分mGluR1和mGluR5的调节。
Metabotropic glutamate receptors (mGluRs) are G protein-coupled receptors that modulate excitatory neurotransmission and synaptic plasticity. The group I mGluRs (mGluR1 and mGluR5) have long intracellular C-terminal domains, which interact with many proteins. Our previous studies identified calmodulin (CaM) as a strong regulator of mGluR5 trafficking and mGluR5-induced calcium signaling. Although it has been accepted that both mGluR1 and mGluR5 interact with CaM, we now show that CaM specifically binds mGluR5 and not mGluR1. We have identified a single critical residue in mGluR5 (L896) that is required for CaM binding. In mGluR1, mutation of the corresponding residue, V909, to leucine is sufficient to confer CaM binding to mGluR1. To investigate the functional effects of CaM binding, we examined the surface expression of mGluR1 and mGluR5 in hippocampal neurons. The mutation in mGluR1 (V909L) that confers CaM binding dramatically increases mGluR1 surface expression, whereas the analogous mutation in mGluR5 that disrupts CaM binding (L896V) decreases mGluR5 surface expression. In addition, the critical residue that alters CaM binding regulates mGluR internalization. Furthermore, we find that mGluR-mediated AMPA receptor endocytosis is enhanced by CaM binding to group I mGluRs. Finally, we show that calcium responses evoked by group I mGluRs are modulated by these mutations, which regulate CaM binding. Our findings elucidate a critical mechanism that specifically affects mGluR5 trafficking and signaling, and distinguishes mGluR1 and mGluR5 regulation.