Calmodulin dynamically regulates the trafficking of the metabotropic glutamate receptor mGluR5
Calmodulin dynamically regulates the trafficking of the metabotropic glutamate receptor mGluR5
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DOI：
10.1073/pnas.0712033105
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发表时间：
2008-08-26
影响因子：
11.1
通讯作者：
Roche, Katherine W.
中科院分区：
文献类型：
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作者：
Lee, Jeong Ho;Lee, Jinu;Roche, Katherine W.
代谢型谷氨酸受体（mGluRs）1-8是调节兴奋性神经传递、神经递质释放和突触可塑性的G蛋白偶联受体（GPCR）。PKC调节mGluR功能的许多方面，包括蛋白质-蛋白质相互作用、Ca 2+信号传导和受体脱敏。然而，PKC调节mGluR功能的机制知之甚少。我们现在已经确定钙调素（CaM）作为mGluR 5运输的动态调节剂。我们发现，主要的PKC磷酸化位点的mGluR 5的细胞内C末端是丝氨酸901（S901），该残基的磷酸化是上调响应受体和PKC激活。此外，S901磷酸化抑制mGluR 5与CaM结合，降低mGluR 5表面表达。此外，阻断S901上mGluR 5的PKC磷酸化通过延长Ca 2+振荡显著影响mGluR 5信号传导。因此，我们的数据表明，mGluR 5激活触发S901磷酸化，从而直接连接PKC磷酸化，CaM结合，受体运输和下游信号。
Metabotropic glutamate receptors (mGluRs) 1-8 are G protein-coupled receptors (GPCRs) that modulate excitatory neurotransmission, neurotransmitter release, and synaptic plasticity. PKC regulates many aspects of mGluR function, including protein-protein interactions, Ca2+ signaling, and receptor desensitization. However, the mechanisms by which PKC regulates mGluR function are poorly understood. We have now identified calmodulin (CaM) as a dynamic regulator of mGluR5 trafficking. We show that the major PKC phosphorylation site on the intracellular C terminus of mGluR5 is serine 901 (S901), and phosphorylation of this residue is up-regulated in response to both receptor and PKC activation. In addition, S901 phosphorylation inhibits mGluR5 binding to CaM, decreasing mGluR5 surface expression. Furthermore, blocking PKC phosphorylation of mGluR5 on S901 dramatically affects mGluR5 signaling by prolonging Ca2+ oscillations. Thus, our data demonstrate that mGluR5 activation triggers phosphorylation of S901, thereby directly linking PKC phosphorylation, CaM binding, receptor trafficking, and downstream signaling.