The capillary Kir channel as sensor and amplifier of neuronal signals: Modeling insights on K + -mediated neurovascular communication.

Autor:	Moshkforoush A; Department of Biomedical Engineering, Florida International University, Miami, FL 33199., Ashenagar B; Department of Biomedical Engineering, Florida International University, Miami, FL 33199., Harraz OF; Department of Pharmacology, College of Medicine, University of Vermont, Burlington, VT 05405., Dabertrand F; Department of Pharmacology, College of Medicine, University of Vermont, Burlington, VT 05405.; Department of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045.; Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045., Longden TA; Department of Pharmacology, College of Medicine, University of Vermont, Burlington, VT 05405.; Department of Physiology, University of Maryland School of Medicine, Baltimore, MD 21201., Nelson MT; Department of Pharmacology, College of Medicine, University of Vermont, Burlington, VT 05405.; Division of Cardiovascular Sciences, University of Manchester, Manchester M13 9PL, United Kingdom., Tsoukias NM; Department of Biomedical Engineering, Florida International University, Miami, FL 33199; tsoukias@fiu.edu.; School of Chemical Engineering, National Technical University of Athens, Zografou 157 72, Greece.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2020 Jul 14; Vol. 117 (28), pp. 16626-16637. Date of Electronic Publication: 2020 Jun 29.
DOI:	10.1073/pnas.2000151117
Abstrakt:	Neuronal activity leads to an increase in local cerebral blood flow (CBF) to allow adequate supply of oxygen and nutrients to active neurons, a process termed neurovascular coupling (NVC). We have previously shown that capillary endothelial cell (cEC) inwardly rectifying K + (Kir) channels can sense neuronally evoked increases in interstitial K + and induce rapid and robust dilations of upstream parenchymal arterioles, suggesting a key role of cECs in NVC. The requirements of this signal conduction remain elusive. Here, we utilize mathematical modeling to investigate how small outward currents in stimulated cECs can elicit physiologically relevant spread of vasodilatory signals within the highly interconnected brain microvascular network to increase local CBF. Our model shows that the Kir channel can act as an "on-off" switch in cECs to hyperpolarize the cell membrane as extracellular K + increases. A local hyperpolarization can be amplified by the voltage-dependent activation of Kir in neighboring cECs. Sufficient Kir density enables robust amplification of the hyperpolarizing stimulus and produces responses that resemble action potentials in excitable cells. This Kir-mediated excitability can remain localized in the stimulated region or regeneratively propagate over significant distances in the microvascular network, thus dramatically increasing the efficacy of K + for eliciting local hyperemia. Modeling results show how changes in cEC transmembrane current densities and gap junctional resistances can affect K + -mediated NVC and suggest a key role for Kir as a sensor of neuronal activity and an amplifier of retrograde electrical signaling in the cerebral vasculature. Competing Interests: The authors declare no competing interest.
Databáze:	MEDLINE
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