Molecular and biophysical basis of glutamate and trace metal modulation of voltage-gated Ca(v)2.3 calcium channels.
Molecular and biophysical basis of glutamate and trace metal modulation of voltage-gated Ca(v)2.3 calcium channels.
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DOI：
10.1085/jgp.201110699
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发表时间：
2012-03
期刊：
影响因子：
--
通讯作者：
Perez-Reyes E
中科院分区：
文献类型：
--
作者：
Shcheglovitov A;Vitko I;Lazarenko RM;Orestes P;Todorovic SM;Perez-Reyes E
在这里，我们描述了一种新的机制，通过深刻改变Cav2.3通道的电压依赖门控，谷氨酸(Glu)和微量金属相互调制Cav2.3通道的活动。我们发现，在生理上相关的浓度下，锌和铜在Cav2.3表面占据了一个细胞外结合部位，并在去极化电压范围内保持了这些通道的激活阈值。通过螯合或取代IS1-IS2(H111)和IS2-IS3(H179和H183)环中的关键氨基酸残基来取消这种结合，通过将激活的电压依赖于更负的膜电位来增强Cav2.3。我们证明了铜通过影响门控电荷运动来调节Cav2.3的电压依赖性。因此，在铜存在的情况下，门控电荷转换到“开”位置的速度较慢，延迟了激活并降低了通道的电压灵敏度。总体而言，我们的结果表明了一种新的机制，即谷氨酸和微量金属瞬时调制Cav2.3的电压依赖门控，从而潜在地影响脑中的突触传递和可塑性。
Here, we describe a new mechanism by which glutamate (Glu) and trace metals reciprocally modulate activity of the Cav2.3 channel by profoundly shifting its voltage-dependent gating. We show that zinc and copper, at physiologically relevant concentrations, occupy an extracellular binding site on the surface of Cav2.3 and hold the threshold for activation of these channels in a depolarized voltage range. Abolishing this binding by chelation or the substitution of key amino acid residues in IS1–IS2 (H111) and IS2–IS3 (H179 and H183) loops potentiates Cav2.3 by shifting the voltage dependence of activation toward more negative membrane potentials. We demonstrate that copper regulates the voltage dependence of Cav2.3 by affecting gating charge movements. Thus, in the presence of copper, gating charges transition into the “ON” position slower, delaying activation and reducing the voltage sensitivity of the channel. Overall, our results suggest a new mechanism by which Glu and trace metals transiently modulate voltage-dependent gating of Cav2.3, potentially affecting synaptic transmission and plasticity in the brain.
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