Rao Eshaan R, Thaxton Tyler, Gama Eric, Godfrey Jack, Wei Cenfu, Lin Qiaoshan, Li Yan, Pastor Daniel Parviz Hejazi, Hansel Christian, Du Xiaofei, Gomez Christopher M
Department of Neurology, University of Chicago, Chicago, IL 60637, USA.
Center for Research Informatics, University of Chicago, IL 60637, USA.
Res Sq. 2025 May 13:rs.3.rs-6180510. doi: 10.21203/rs.3.rs-6180510/v1.
VGCCs play crucial roles within the CNS, in maintaining cell excitability, enabling activity-dependent neuronal development, and forming long-term memory by regulating Ca influx. The intracellular carboxyl-terminal domains of VGCC α1 subunits help regulate VGCC function. Emerging evidence suggests that some VGCC C-termini have functions independent of channel gating and exist as stable proteins. Here, we demonstrate that all VGCC gene family members express bicistronic mRNA transcripts that produce functionally distinct C-terminal proteins (CTPs) in tandem with full-length VGCC α1 subunits. Two of these CTPs, α1CCT and α1ACT, cycle to and from the nucleus in a Ca- and calmodulin-dependent fashion. α1CCT, α1ACT, and α1HCT regulate chromatin accessibility and/or bind directly to genes, regulating gene networks involved in neuronal differentiation and synaptic function in a Ca-dependent manner. This study elucidates a conserved process of coordinated protein expression within the VGCC family, coupling the channel function with VGCC C-terminal transcription factors.
电压门控钙通道（VGCCs）在中枢神经系统中发挥着关键作用，包括维持细胞兴奋性、促进依赖活动的神经元发育以及通过调节钙离子内流形成长期记忆。VGCC α1亚基的细胞内羧基末端结构域有助于调节VGCC的功能。新出现的证据表明，一些VGCC的C末端具有独立于通道门控的功能，并以稳定蛋白的形式存在。在此，我们证明所有VGCC基因家族成员均表达双顺反子mRNA转录本，这些转录本与全长VGCC α1亚基一起产生功能不同的C末端蛋白（CTPs）。其中两种CTPs，α1CCT和α1ACT，以钙和钙调蛋白依赖的方式在细胞核内外循环。α1CCT、α1ACT和α1HCT调节染色质可及性和/或直接与基因结合，以钙依赖的方式调节参与神经元分化和突触功能的基因网络。这项研究阐明了VGCC家族中协调蛋白表达的保守过程，将通道功能与VGCC C末端转录因子联系起来。
