Electrocalcium coupling in brain capillaries: Rapidly traveling electrical signals ignite local calcium signals
Year: 2024
Type: article
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 (Ca 2+ ) signaling, which reflects release of Ca 2+ via the inositol 1,4,5-trisphosphate receptor (IP 3 R)—a target of G q -protein-coupled receptor signaling. Notably, Ca 2+ 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 2+ entry into cECs through resident TRPV4 channels. This process, termed electrocalcium (E-Ca) coupling, enhances IP 3 R-mediated Ca 2+ release via a Ca 2+ -induced Ca 2+ -release mechanism, and allows focally induced hyperpolarization, including that initiated by ATP-dependent K + (K ATP ) channels, to travel cell-to-cell via activation of Kir2.1 channels in adjacent cells, providing a mechanism for the “pseudopropagation” of Ca 2+ 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.
Language: English
Topic: Ion Channels and Receptors
Subfield: Sensory Systems
Field: Neuroscience
Domain: Life Sciences
Open Access status: hybrid
Funders: American Heart Association, University of Vermont, European Commission, Fondation Leducq, Universität zu Lübeck, National Institutes of Health, Totman Medical Research Trust, University of Vermont, National Institute on Aging, National Heart, Lung, and Blood Institute, National Institute of General Medical Sciences, National Institute of Neurological Disorders and Stroke
Awards: Functional deficits in neurovascular coupling in Alzheimer's disease, G1272653669, G1721003100, Small vessel diseases in a mechanistic perspective: Targets for Intervention Affected pathways and mechanistic exploitation for prevention of stroke and dementia, G434337789, G4652114395, G4998324985, Functional deficits in neurovascular coupling in Alzheimer's disease, Endothelial Ca2+ signals in Penetrating Arterioles Control Local Blood Flow in the Brain., G780303335, G8561324583, G991489597
OpenAlex ID: W4405288630