Functional coupling of the metabotropic glutamate receptor, InsP3 receptor and L-type Ca2+ channel in mouse CA1 pyramidal cells
Functional coupling of the metabotropic glutamate receptor, InsP3 receptor and L-type Ca2+ channel in mouse CA1 pyramidal cells
复制标题
DOI：
10.1113/jphysiol.2012.232942
复制
发表时间：
2012-07-01
影响因子：
5.5
通讯作者：
Manabe, Toshiya
中科院分区：
文献类型：
--
作者：
Kato, Hiroyuki K.;Kassai, Hidetoshi;Manabe, Toshiya
虽然代谢型谷氨酸受体（mGluR）被认为调节l型电压依赖性钙通道（L-VDCCs），但其报道的作用包括促进和抑制，因此突触活性对L-VDCCs的调节仍存在争议。在这项研究中，我们使用亚型特异性敲除小鼠的急性海马切片，发现mGluR5诱导去极化诱发钙电流的促进。这种促进并不伴随着L-VDCC本身单通道特性的改变，而是需要激活由L-VDCC打开触发的钙诱导的钙释放。L-VDCCs和mGluR5通过共免疫沉淀形成复合物，提示mGluR5、InsP3受体与L-VDCCs之间的特异性功能偶联在钙电流促进中起关键作用。我们的研究发现了mGluR和钙信号之间相互作用的新机制，并提出了mGluR5对突触可塑性的贡献。神经元细胞钙动力学的活性依赖性调节在细胞内信号传导、神经元活性和突触可塑性等许多细胞过程的调节中发挥重要作用。在许多钙流入神经元的途径中，电压依赖性钙通道（VDCC）是钙流入的主要来源，但其由突触活动调节仍存在争议。虽然代谢型谷氨酸受体（mGluR）被认为调节l型VDCCs (L-VDCCs)，但其报道的作用包括促进和抑制，这可能反映了mGluR激动剂的分子靶点和先前报道中记录的钙信号来源的不确定性。在这项研究中，我们使用亚型特异性敲除小鼠，发现mGluR5诱导去极化诱发钙电流的促进。这种促进并不伴随着VDCC本身的单通道特性的变化；相反，它需要激活由VDCC打开触发的钙诱导钙释放（CICR），这表明CICR偶联阳离子通道的打开对于促进是必不可少的。这种促进作用被l - vdccc和InsP3受体（InsP3Rs）抑制剂阻断或降低。此外，L-VDCCs和mGluR5通过共免疫沉淀形成复合物，表明mGluR5、InsP3Rs和L-VDCCs之间的特异性功能偶联在钙电流促进中发挥了关键作用。最后，我们发现mGluR5增强了vdc依赖性的突触传递的长期增强（LTP）。我们的研究发现了mGluR和钙信号之间相互作用的新机制，并提出了mGluR5对突触可塑性的贡献。
Key points While the metabotropic glutamate receptor (mGluR) is supposed to modulate L-type voltage-dependent calcium channels (L-VDCCs), its reported actions include both facilitation and suppression, and thus the modulation of L-VDCCs by synaptic activity has still been under debate. In this study, using acute hippocampal slices of subtype-specific knockout mice, we have shown that mGluR5 induces facilitation of the depolarization-evoked calcium current. This facilitation was not accompanied by the change in single-channel properties of the L-VDCC itself, but required the activation of calcium-induced calcium release that was triggered by L-VDCC opening. L-VDCCs and mGluR5 were shown to form a complex by coimmunoprecipitation, suggesting that the specific functional coupling between mGluR5, InsP3 receptors and L-VDCCs played a pivotal role in the calcium-current facilitation. Our study has identified a novel mechanism of the interaction between the mGluR and calcium signalling, and suggested a contribution of mGluR5 to synaptic plasticity. Abstract Activity-dependent regulation of calcium dynamics in neuronal cells can play significant roles in the modulation of many cellular processes such as intracellular signalling, neuronal activity and synaptic plasticity. Among many calcium influx pathways into neurons, the voltage-dependent calcium channel (VDCC) is the major source of calcium influx, but its modulation by synaptic activity has still been under debate. While the metabotropic glutamate receptor (mGluR) is supposed to modulate L-type VDCCs (L-VDCCs), its reported actions include both facilitation and suppression, probably reflecting the uncertainty of both the molecular targets of the mGluR agonists and the source of the recorded calcium signal in previous reports. In this study, using subtype-specific knockout mice, we have shown that mGluR5 induces facilitation of the depolarization-evoked calcium current. This facilitation was not accompanied by the change in single-channel properties of the VDCC itself; instead, it required the activation of calcium-induced calcium release (CICR) that was triggered by VDCC opening, suggesting that the opening of CICR-coupled cation channels was essential for the facilitation. This facilitation was blocked or reduced by the inhibitors of both L-VDCCs and InsP3 receptors (InsP3Rs). Furthermore, L-VDCCs and mGluR5 were shown to form a complex by coimmunoprecipitation, suggesting that the specific functional coupling between mGluR5, InsP3Rs and L-VDCCs played a pivotal role in the calcium-current facilitation. Finally, we showed that mGluR5 enhanced VDCC-dependent long-term potentiation (LTP) of synaptic transmission. Our study has identified a novel mechanism of the interaction between the mGluR and calcium signalling, and suggested a contribution of mGluR5 to synaptic plasticity.