Mughal Amreen, Hennig Grant W, Heppner Thomas, Tsoukias Nikolaos M, Hill-Eubanks David, Nelson Mark T
Department of Pharmacology, University of Vermont, Burlington, VT 05405.
Department of Biomedical Engineering, Florida International University, Miami, FL 33174.
Proc Natl Acad Sci U S A. 2024 Dec 17;121(51):e2415047121. doi: 10.1073/pnas.2415047121. Epub 2024 Dec 11.
The routing of blood flow throughout the brain vasculature is precisely controlled by mechanisms that serve to maintain a fine balance between local neuronal demands and vascular supply of nutrients. We recently identified two capillary endothelial cell (cEC)-based mechanisms that control cerebral blood flow in vivo: 1) electrical signaling, mediated by extracellular K-dependent activation of strong inward rectifying K (Kir2.1) channels, which are steeply activated by hyperpolarization and thus are capable of cell-to-cell propagation, and 2) calcium (Ca) signaling, which reflects release of Ca via the inositol 1,4,5-trisphosphate receptor (IPR)-a target of G-protein-coupled receptor signaling. Notably, Ca signals were restricted to the cell in which they were initiated. Unexpectedly, we found that these two mechanisms, which were presumed to operate in distinct spatiotemporal realms, are linked such that Kir2.1-dependent hyperpolarization induces increases in the electrical driving force for Ca entry into cECs through resident TRPV4 channels. This process, termed electrocalcium (E-Ca) coupling, enhances IPR-mediated Ca release via a Ca-induced Ca-release mechanism, and allows focally induced hyperpolarization, including that initiated by ATP-dependent K (K) channels, to travel cell-to-cell via activation of Kir2.1 channels in adjacent cells, providing a mechanism for the "pseudopropagation" of Ca signals. Computational modeling supported the basic features of E-Ca coupling and provided insight into the intracellular processes involved. Collectively, these data provide strong support for the concept of E-Ca coupling and provide a mechanism for the spatiotemporal integration of diverse signaling pathways in the control of cerebral blood flow.
整个脑血管系统中的血流路径由多种机制精确控制，这些机制旨在维持局部神经元需求与血管营养供应之间的精细平衡。我们最近发现了两种基于毛细血管内皮细胞（cEC）的体内控制脑血流的机制：1）电信号传导，由细胞外钾离子依赖的内向整流钾通道（Kir2.1）激活介导，该通道在超极化时被强烈激活，因此能够进行细胞间传播；2）钙（Ca）信号传导，它反映了通过肌醇1,4,5-三磷酸受体（IPR）释放的Ca，IPR是G蛋白偶联受体信号传导的靶点。值得注意的是，Ca信号局限于其起始的细胞内。出乎意料的是，我们发现这两种被认为在不同时空领域运作的机制是相互关联的，即Kir2.1依赖的超极化会导致通过驻留的瞬时受体电位香草酸亚型4（TRPV4）通道进入cEC的Ca的电驱动力增加。这个过程被称为电钙（E-Ca）偶联，它通过钙诱导的钙释放机制增强IPR介导的Ca释放，并允许局部诱导的超极化，包括由ATP依赖钾通道（K）引发的超极化，通过激活相邻细胞中的Kir2.1通道在细胞间传播，为Ca信号的“假传播”提供了一种机制。计算模型支持了E-Ca偶联的基本特征，并深入了解了其中涉及的细胞内过程。总的来说，这些数据为E-Ca偶联的概念提供了有力支持，并为控制脑血流中多种信号通路的时空整合提供了一种机制。
