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Interleukin-1β enhances GABAA receptor cell-surface expression by a phosphatidylinositol 3-kinase/Akt pathway: relevance to sepsis-associated encephalopathy

AuthorsArnalich, Francisco; Salinas, Marta; Andrés-Mateos, Eva; Renart, Jaime CSIC ORCID; Cuadrado, Antonio CSIC ORCID; Montiel, Carmen
Issue Date2006
PublisherAmerican Society for Biochemistry and Molecular Biology
CitationJournal of Biological Chemistry 281(21): 14632-14643 (2006)
AbstractSepsis-associated encephalopathy (SAE) is a frequent but poorly understood neurological complication in sepsis that negatively influences survival. Here we present clinical and experimental evidence that this brain dysfunction may be related to altered neurotransmission produced by inflammatory mediators. Compared with septic patients, SAE patients had higher interleukin-1β (IL-1β) plasma levels; interestingly, these levels decreased once the encephalopathy was resolved. A putative IL-1β effect on type A γ-aminobutyric acid receptors (GABAARs), which mediate fast synaptic transmission in most cerebral inhibitory synapses in mammals, was investigated in cultured hippocampal neurons and in Xenopus oocytes expressing native or foreign rat brain GABAARs, respectively. Confocal images in both cell types revealed that IL-1β increases recruitment of GABA ARs to the cell surface. Moreover, brief applications of IL-1β to voltage-clamped oocytes yielded a delayed potentiation of the GABA-elicited chloride currents (IGABA); this effect was suppressed by IL-1ra, the natural IL-1 receptor (IL-1RI) antagonist. Western blot analysis combined with IGABA recording and confocal images of GABAARs in oocytes showed that IL-1β stimulates the IL-1RI-dependent phosphatidylinositol 3-kinase activation and the consequent facilitation of phospho-Akt-mediated insertion of GABAARs into the cell surface. The interruption of this signaling pathway by specific phosphatidylinositol 3-kinase or Akt inhibitors suppresses the cytokine-mediated effects on GABAAR, whereas activation of the conditionally active form of Akt1 (myr-Akt1.ER*) with 4-hydroxytamoxifen reproduces the effects. These findings point to a previously unrecognized signaling pathway that connects IL-1β with increased >GABAergic tone.> We propose that through this mechanism IL-1β might alter synaptic strength at central GABAergic synapses and so contribute to the cognitive dysfunction observed in SAE. © 2006 by The American Society for Biochemistry and Molecular Biology, Inc.
Identifiersdoi: 10.1074/jbc.M512489200
issn: 0021-9258
e-issn: 1083-351X
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