Disease-relevant upregulation of P2Y1 receptor in astrocytes enhances neuronal excitability via IGFBP2.
Nat Commun
; 15(1): 6525, 2024 Aug 08.
Article
em En
| MEDLINE
| ID: mdl-39117630
ABSTRACT
Reactive astrocytes play a pivotal role in the pathogenesis of neurological diseases; however, their functional phenotype and the downstream molecules by which they modify disease pathogenesis remain unclear. Here, we genetically increase P2Y1 receptor (P2Y1R) expression, which is upregulated in reactive astrocytes in several neurological diseases, in astrocytes of male mice to explore its function and the downstream molecule. This astrocyte-specific P2Y1R overexpression causes neuronal hyperexcitability by increasing both astrocytic and neuronal Ca2+ signals. We identify insulin-like growth factor-binding protein 2 (IGFBP2) as a downstream molecule of P2Y1R in astrocytes; IGFBP2 acts as an excitatory signal to cause neuronal excitation. In neurological disease models of epilepsy and stroke, reactive astrocytes upregulate P2Y1R and increase IGFBP2. The present findings identify a mechanism underlying astrocyte-driven neuronal hyperexcitability, which is likely to be shared by several neurological disorders, providing insights that might be relevant for intervention in diverse neurological disorders.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Regulação para Cima
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Astrócitos
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Proteína 2 de Ligação a Fator de Crescimento Semelhante à Insulina
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Receptores Purinérgicos P2Y1
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Neurônios
Limite:
Animals
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Humans
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Male
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article