Journal Article

DZNE-2026-00797

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Neuronal and astrocytic sodium-calcium exchanger differentially regulates calcium and sodium overload during ischemic stroke.

Hamzeitaj, S. (First author)DZNE* ; Thapaliya, P. K. ; Rakers, C.DZNE* ; Gerkau, N. J. ; Rose, C. R. ; Ullah, G. ; Petzold, G. C. (Last author)DZNE*

2026
JCI Insight Ann Arbor, Michigan

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Please use a persistent id in citations: doi:10.1172/jci.insight.200411

Abstract: Spreading depolarizations (SDs) are propagating waves of near-complete breakdown of transmembrane ion gradients that occur during acute ischemic stroke and worsen outcome by driving calcium overload and glutamate release in neurons and astrocytes. The plasmalemmal sodium-calcium exchanger (NCX) plays a key role in such changes, in that the complex ionic disequilibrium during ischemia induces reverse-mode activity of NCX, leading to cellular calcium overload in exchange for sodium. However, the cell-type-specific roles of NCX in neurons and astrocytes during SDs remain unclear. Here, we used ion and glutamate reporters in an in vivo stroke model in mice carrying inducible, cell-specific deletions of NCX isoform 1. Neuronal NCX1 deletion reduced neuronal and astrocytic calcium transients, increased neuronal sodium transients, decreased extracellular glutamate levels, and raised SD initiation threshold. In contrast, astrocytic NCX1 deletion increased sodium transients in both neurons and astrocytes, and increased neuronal calcium as well as extracellular glutamate levels. A computational model of ischemia confirmed that these effects are consistent with reverse-mode NCX1 activity. Together, these findings indicate opposing roles of reverse-mode NCX1 during ischemia. Neuronal NCX1 promotes SD susceptibility, calcium overload, and glutamate release, whereas astrocytic NCX1 exerts protective effects by attenuating glutamate elevation and neuronal calcium accumulation.

Keyword(s): Animals (MeSH) ; Sodium-Calcium Exchanger: metabolism (MeSH) ; Sodium-Calcium Exchanger: genetics (MeSH) ; Astrocytes: metabolism (MeSH) ; Astrocytes: pathology (MeSH) ; Mice (MeSH) ; Neurons: metabolism (MeSH) ; Neurons: pathology (MeSH) ; Calcium: metabolism (MeSH) ; Sodium: metabolism (MeSH) ; Ischemic Stroke: metabolism (MeSH) ; Ischemic Stroke: pathology (MeSH) ; Disease Models, Animal (MeSH) ; Mice, Knockout (MeSH) ; Glutamic Acid: metabolism (MeSH) ; Male (MeSH) ; Brain Ischemia: metabolism (MeSH) ; Neuroscience ; Stroke ; Vascular biology ; Sodium-Calcium Exchanger ; Calcium ; Sodium ; NCX1 protein, mouse ; Glutamic Acid

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Contributing Institute(s):

1. Vascular Neurology (AG Petzold)

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

Appears in the scientific report 2026

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Database coverage:
; ; ; ; Article Processing Charges ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; DOAJ Seal ; Essential Science Indicators ; Fees ; IF >= 5 ; JCR ; PubMed Central ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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