Mechanosensory Signaling in Astrocytes.

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Version: Final published version
License: CC BY 4.0
Serval ID
serval:BIB_C8C72E28C6EF
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Mechanosensory Signaling in Astrocytes.
Journal
The Journal of neuroscience
Author(s)
Turovsky E.A., Braga A., Yu Y., Esteras N., Korsak A., Theparambil S.M., Hadjihambi A., Hosford P.S., Teschemacher A.G., Marina N., Lythgoe M.F., Haydon P.G., Gourine A.V.
ISSN
1529-2401 (Electronic)
ISSN-L
0270-6474
Publication state
Published
Issued date
02/12/2020
Peer-reviewed
Oui
Volume
40
Number
49
Pages
9364-9371
Language
english
Notes
Publication types: Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Abstract
Mechanosensitivity is a well-known feature of astrocytes, however, its underlying mechanisms and functional significance remain unclear. There is evidence that astrocytes are acutely sensitive to decreases in cerebral perfusion pressure and may function as intracranial baroreceptors, tuned to monitor brain blood flow. This study investigated the mechanosensory signaling in brainstem astrocytes, as these cells reside alongside the cardiovascular control circuits and mediate increases in blood pressure and heart rate induced by falls in brain perfusion. It was found that mechanical stimulation-evoked Ca <sup>2+</sup> responses in astrocytes of the rat brainstem were blocked by (1) antagonists of connexin channels, connexin 43 (Cx43) blocking peptide Gap26, or Cx43 gene knock-down; (2) antagonists of TRPV4 channels; (3) antagonist of P2Y <sub>1</sub> receptors for ATP; and (4) inhibitors of phospholipase C or IP3 receptors. Proximity ligation assay demonstrated interaction between TRPV4 and Cx43 channels in astrocytes. Dye loading experiments showed that mechanical stimulation increased open probability of carboxyfluorescein-permeable membrane channels. These data suggest that mechanosensory Ca <sup>2+</sup> responses in astrocytes are mediated by interaction between TRPV4 and Cx43 channels, leading to Cx43-mediated release of ATP which propagates/amplifies Ca <sup>2+</sup> signals via P2Y <sub>1</sub> receptors and Ca <sup>2+</sup> recruitment from the intracellular stores. In astrocyte-specific Cx43 knock-out mice the magnitude of heart rate responses to acute increases in intracranial pressure was not affected by Cx43 deficiency. However, these animals displayed lower heart rates at different levels of cerebral perfusion, supporting the hypothesis of connexin hemichannel-mediated release of signaling molecules by astrocytes having an excitatory action on the CNS sympathetic control circuits.SIGNIFICANCE STATEMENT There is evidence suggesting that astrocytes may function as intracranial baroreceptors that play an important role in the control of systemic and cerebral circulation. To function as intracranial baroreceptors, astrocytes must possess a specialized membrane mechanism that makes them exquisitely sensitive to mechanical stimuli. This study shows that opening of connexin 43 (Cx43) hemichannels leading to the release of ATP is the key central event underlying mechanosensory Ca <sup>2+</sup> responses in astrocytes. This astroglial mechanism plays an important role in the autonomic control of heart rate. These data add to the growing body of evidence suggesting that astrocytes function as versatile surveyors of the CNS metabolic milieu, tuned to detect conditions of potential metabolic threat, such as hypoxia, hypercapnia, and reduced perfusion.
Keywords
Adenosine Triphosphate/metabolism, Animals, Astrocytes/physiology, Blood Pressure/drug effects, Brain Stem/cytology, Brain Stem/drug effects, Brain Stem/physiology, Calcium Signaling/drug effects, Calcium Signaling/physiology, Cerebrovascular Circulation/physiology, Connexin 43/antagonists & inhibitors, Connexin 43/genetics, Female, Heart Rate/physiology, Male, Mechanotransduction, Cellular/drug effects, Mechanotransduction, Cellular/physiology, Mice, Mice, Knockout, Peptides/antagonists & inhibitors, Peptides/genetics, Physical Stimulation, Rats, Receptors, Purinergic P2Y1/drug effects, TRPV Cation Channels/antagonists & inhibitors, TRPV Cation Channels/genetics, astrocytes, baroreceptor, cardiovascular, glia, mechanosensory, sympathetic
Pubmed
Web of science
Open Access
Yes
Create date
09/11/2020 11:37
Last modification date
08/08/2024 7:40
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