Cation flux through SUR1-TRPM4 and NCX1 in astrocyte endfeet induces water influx through AQP4 and brain swelling after ischemic stroke

Authors

Jesse A. Stokum, Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Bosung Shim, Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Serban Negoita, Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Natalya Tsymbalyuk, Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Orest Tsymbalyuk, Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Svetlana Ivanova, Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Kaspar Keledjian, Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Joseph Bryan, Pacific Northwest Diabetes Research Institute, Seattle, WA 98122, USA.
Mordecai P. Blaustein, Department of Physiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Ruchira M. Jha, Department of Neurology, Barrow Neurological Institute and St. Joseph's Hospital and Medical Center, Phoenix, AZ 85013, USA.Follow
Kristopher T. Kahle, Department of Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
Volodymyr Gerzanich, Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
J Marc Simard, Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA.

Document Type

Article

Abstract

Brain swelling causes morbidity and mortality in various brain injuries and diseases but lacks effective treatments. Brain swelling is linked to the influx of water into perivascular astrocytes through channels called aquaporins. Water accumulation in astrocytes increases their volume, which contributes to brain swelling. Using a mouse model of severe ischemic stroke, we identified a potentially targetable mechanism that promoted the cell surface localization of aquaporin 4 (AQP4) in perivascular astrocytic endfeet, which completely ensheathe the brain's capillaries. Cerebral ischemia increased the abundance of the heteromeric cation channel SUR1-TRPM4 and of the Na/Ca exchanger NCX1 in the endfeet of perivascular astrocytes. The influx of Na through SUR1-TRPM4 induced Ca transport into cells through NCX1 operating in reverse mode, thus raising the intra-endfoot concentration of Ca. This increase in Ca stimulated calmodulin-dependent translocation of AQP4 to the plasma membrane and water influx, which led to cellular edema and brain swelling. Pharmacological inhibition or astrocyte-specific deletion of SUR1-TRPM4 or NCX1 reduced brain swelling and improved neurological function in mice to a similar extent as an AQP4 inhibitor and was independent of infarct size. Thus, channels in astrocyte endfeet could be targeted to reduce postischemic brain swelling in stroke patients.

Publication Date

6-6-2023

Publication Title

Science signaling

E-ISSN

1937-9145

Volume

16

Issue

788

First Page

eadd6364

PubMed ID

37279286

Digital Object Identifier (DOI)

10.1126/scisignal.add6364

Recommended Citation

Stokum, Jesse A.; Shim, Bosung; Negoita, Serban; Tsymbalyuk, Natalya; Tsymbalyuk, Orest; Ivanova, Svetlana; Keledjian, Kaspar; Bryan, Joseph; Blaustein, Mordecai P.; Jha, Ruchira M.; Kahle, Kristopher T.; Gerzanich, Volodymyr; and Simard, J Marc, "Cation flux through SUR1-TRPM4 and NCX1 in astrocyte endfeet induces water influx through AQP4 and brain swelling after ischemic stroke" (2023). Neurology. 1467.
https://scholar.barrowneuro.org/neurology/1467