Ca_V1 and Ca_V2 Channels Engage Distinct Modes of Ca²⁺ Signaling to Control CREB-Dependent Gene Expression

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• 作者：Damian  ; G. Wheeler¹ ; ³ ; ⁴ ; Rachel  ; D. Groth¹ ; ³ ; ⁵ ; Huan Ma¹ ; ² ; ³ ; ^{huan.ma@nyumc.org} ; Curtis  ; F. Barrett¹ ; ⁶ ; Scott  ; F. Owen¹ ; Parsa Safa¹ ; Richard  ; W. Tsien¹ ; ² ; ^{richard.tsien@nyumc.org}
• 刊名：Cell
• 出版年：2012
• 期刊代码：50_00928674
• 类别：med
• 出版时间：25 May, 2012
• 卷：149
• 期：5
• 页码：1112-1124
• 文件大小：1249 K

摘要

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Summary

Activity-dependent gene expression triggered by Ca²⁺ entry into neurons is critical for learning and memory, but whether specific sources of Ca²⁺ act distinctly or merely supply Ca²⁺ to a common pool remains uncertain. Here, we report that both signaling modes coexist and pertain to Ca_V1 and Ca_V2 channels, respectively, coupling membrane depolarization to CREB phosphorylation and gene expression. Ca_V1 channels are advantaged in their voltage-dependent gating and use nanodomain Ca²⁺ to drive local CaMKII aggregation and trigger communication with the nucleus. In contrast, Ca_V2 channels must elevate [Ca²⁺]_i microns away and promote CaMKII aggregation at Ca_V1 channels. Consequently, Ca_V2 channels are 鈭?0-fold less effective in signaling to the nucleus than are Ca_V1 channels for the same bulk [Ca²⁺]_i increase. Furthermore, Ca_V2-mediated Ca²⁺ rises are preferentially curbed by uptake into the endoplasmic reticulum and mitochondria. This source-biased buffering limits the spatial spread of Ca²⁺, further attenuating Ca_V2-mediated gene expression.