Electrocalcium coupling in brain capillaries: Rapidly traveling electrical signals ignite local calcium signals.

IF 9.4 1区 综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES
Amreen Mughal, Grant W Hennig, Thomas Heppner, Nikolaos M Tsoukias, David Hill-Eubanks, Mark T Nelson
{"title":"Electrocalcium coupling in brain capillaries: Rapidly traveling electrical signals ignite local calcium signals.","authors":"Amreen Mughal, Grant W Hennig, Thomas Heppner, Nikolaos M Tsoukias, David Hill-Eubanks, Mark T Nelson","doi":"10.1073/pnas.2415047121","DOIUrl":null,"url":null,"abstract":"<p><p>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<sup>+</sup>-dependent activation of strong inward rectifying K<sup>+</sup> (Kir2.1) channels, which are steeply activated by hyperpolarization and thus are capable of cell-to-cell propagation, and 2) calcium (Ca<sup>2+</sup>) signaling, which reflects release of Ca<sup>2+</sup> via the inositol 1,4,5-trisphosphate receptor (IP<sub>3</sub>R)-a target of G<sub>q</sub>-protein-coupled receptor signaling. Notably, Ca<sup>2+</sup> 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<sup>2+</sup> entry into cECs through resident TRPV4 channels. This process, termed electrocalcium (E-Ca) coupling, enhances IP<sub>3</sub>R-mediated Ca<sup>2+</sup> release via a Ca<sup>2+</sup>-induced Ca<sup>2+</sup>-release mechanism, and allows focally induced hyperpolarization, including that initiated by ATP-dependent K<sup>+</sup> (K<sub>ATP</sub>) channels, to travel cell-to-cell via activation of Kir2.1 channels in adjacent cells, providing a mechanism for the \"pseudopropagation\" of Ca<sup>2+</sup> 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.</p>","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"121 51","pages":"e2415047121"},"PeriodicalIF":9.4000,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11665868/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Proceedings of the National Academy of Sciences of the United States of America","FirstCategoryId":"103","ListUrlMain":"https://doi.org/10.1073/pnas.2415047121","RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/12/11 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"MULTIDISCIPLINARY SCIENCES","Score":null,"Total":0}
引用次数: 0

Abstract

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 (Ca2+) signaling, which reflects release of Ca2+ via the inositol 1,4,5-trisphosphate receptor (IP3R)-a target of Gq-protein-coupled receptor signaling. Notably, Ca2+ 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 Ca2+ entry into cECs through resident TRPV4 channels. This process, termed electrocalcium (E-Ca) coupling, enhances IP3R-mediated Ca2+ release via a Ca2+-induced Ca2+-release mechanism, and allows focally induced hyperpolarization, including that initiated by ATP-dependent K+ (KATP) channels, to travel cell-to-cell via activation of Kir2.1 channels in adjacent cells, providing a mechanism for the "pseudopropagation" of Ca2+ 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.

脑毛细血管中的钙电偶联:快速传播的电信号点燃局部钙信号。
血流在整个脑血管系统中的路径是由一种机制精确控制的,这种机制有助于维持局部神经元需求和血管营养供应之间的良好平衡。我们最近发现了两种基于毛细血管内皮细胞(cEC)的体内脑血流控制机制:1)电信号,由细胞外K+依赖的强内向纠偏K+ (Kir2.1)通道激活介导,该通道被超极化急剧激活,因此能够在细胞间传播;2)钙(Ca2+)信号,通过肌醇1,4,5-三磷酸受体(IP3R)反映Ca2+的释放,IP3R是gq蛋白偶联受体信号传导的靶标。值得注意的是,Ca2+信号被限制在它们被启动的细胞内。出乎意料的是,我们发现这两种机制被认为是在不同的时空领域中运作的,它们是相互关联的,以至于kir2.1依赖的超极化诱导Ca2+通过常驻TRPV4通道进入cECs的电驱动力增加。这一过程被称为钙离子(E-Ca)偶联,通过Ca2+诱导的Ca2+释放机制增强ip3r介导的Ca2+释放,并允许局部诱导的超极化,包括由atp依赖性K+ (KATP)通道启动的超极化,通过激活邻近细胞中的Kir2.1通道在细胞间传播,为Ca2+信号的“伪传播”提供了一种机制。计算模型支持E-Ca耦合的基本特征,并提供了有关细胞内过程的见解。综上所述,这些数据为E-Ca耦合的概念提供了强有力的支持,并为脑血流控制中多种信号通路的时空整合提供了机制。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 求助全文
来源期刊
CiteScore
19.00
自引率
0.90%
发文量
3575
审稿时长
2.5 months
期刊介绍: The Proceedings of the National Academy of Sciences (PNAS), a peer-reviewed journal of the National Academy of Sciences (NAS), serves as an authoritative source for high-impact, original research across the biological, physical, and social sciences. With a global scope, the journal welcomes submissions from researchers worldwide, making it an inclusive platform for advancing scientific knowledge.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信