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Conditional deletion of LRRC8A in the brain reduces stroke damage independently of swelling-activated glutamate release.
Balkaya, Mustafa; Dohare, Preeti; Chen, Sophie; Schober, Alexandra L; Fidaleo, Antonio M; Nalwalk, Julia W; Sah, Rajan; Mongin, Alexander A.
Afiliação
  • Balkaya M; Department of Neuroscience and Experimental Therapeutics, Albany Medical College, Albany, NY 12208, USA.
  • Dohare P; Department of Neuroscience and Experimental Therapeutics, Albany Medical College, Albany, NY 12208, USA.
  • Chen S; Department of Neuroscience and Experimental Therapeutics, Albany Medical College, Albany, NY 12208, USA.
  • Schober AL; Department of Neuroscience and Experimental Therapeutics, Albany Medical College, Albany, NY 12208, USA.
  • Fidaleo AM; Department of Neuroscience and Experimental Therapeutics, Albany Medical College, Albany, NY 12208, USA.
  • Nalwalk JW; Department of Neuroscience and Experimental Therapeutics, Albany Medical College, Albany, NY 12208, USA.
  • Sah R; Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
  • Mongin AA; Department of Neuroscience and Experimental Therapeutics, Albany Medical College, Albany, NY 12208, USA.
iScience ; 26(5): 106669, 2023 May 19.
Article em En | MEDLINE | ID: mdl-37182109
ABSTRACT
The ubiquitous volume-regulated anion channels (VRACs) facilitate cell volume control and contribute to many other physiological processes. Treatment with non-specific VRAC blockers or brain-specific deletion of the essential VRAC subunit LRRC8A is highly protective in rodent models of stroke. Here, we tested the widely accepted idea that the harmful effects of VRACs are mediated by release of the excitatory neurotransmitter glutamate. We produced conditional LRRC8A knockout either exclusively in astrocytes or in the majority of brain cells. Genetically modified mice were subjected to an experimental stroke (middle cerebral artery occlusion). The astrocytic LRRC8A knockout yielded no protection. Conversely, the brain-wide LRRC8A deletion strongly reduced cerebral infarction in both heterozygous (Het) and full KO mice. Yet, despite identical protection, Het mice had full swelling-activated glutamate release, whereas KO animals showed its virtual absence. These findings suggest that LRRC8A contributes to ischemic brain injury via a mechanism other than VRAC-mediated glutamate release.
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Texto completo: 1 Base de dados: MEDLINE Idioma: En Ano de publicação: 2023 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Idioma: En Ano de publicação: 2023 Tipo de documento: Article