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1.
Neuropharmacology ; 224: 109330, 2023 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-36375694

RESUMO

Neuroinflammation, specifically the NLRP3 inflammasome cascade, is a common underlying pathological feature of many neurodegenerative diseases. Evidence suggests that NLRP3 activation involves changes in intracellular K+. Nuclear Enriched Transcript Sort Sequencing (NETSseq), which allows for deep sequencing of purified cell types from human post-mortem brain tissue, demonstrated a highly specific expression of the tandem pore domain halothane-inhibited K+ channel 1 (THIK-1) in microglia compared to other glial and neuronal cell types in the human brain. NETSseq also showed a significant increase of THIK-1 in microglia isolated from cortical regions of brains with Alzheimer's disease (AD) relative to control donors. Herein, we report the discovery and pharmacological characterisation of C101248, the first selective small-molecule inhibitor of THIK-1. C101248 showed a concentration-dependent inhibition of both mouse and human THIK-1 (IC50: ∼50 nM) and was inactive against K2P family members TREK-1 and TWIK-2, and Kv2.1. Whole-cell patch-clamp recordings of microglia from mouse hippocampal slices showed that C101248 potently blocked both tonic and ATP-evoked THIK-1 K+ currents. Notably, C101248 had no effect on other constitutively active resting conductance in slices from THIK-1-depleted mice. In isolated microglia, C101248 prevented NLRP3-dependent release of IL-1ß, an effect not seen in THIK-1-depleted microglia. In conclusion, we demonstrated that inhibiting THIK-1 (a microglia specific gene that is upregulated in brains from donors with AD) using a novel selective modulator attenuates the NLRP3-dependent release of IL-1ß from microglia, which suggests that this channel may be a potential therapeutic target for the modulation of neuroinflammation in AD.


Assuntos
Doença de Alzheimer , Inflamassomos , Canais de Potássio de Domínios Poros em Tandem , Animais , Humanos , Camundongos , Doença de Alzheimer/metabolismo , Encéfalo/metabolismo , Inflamassomos/metabolismo , Microglia , Doenças Neuroinflamatórias , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Canais de Potássio de Domínios Poros em Tandem/antagonistas & inibidores
2.
Mol Cell Neurosci ; 33(1): 47-56, 2006 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-16870468

RESUMO

Selective antagonism of N-methyl-d-aspartate (NMDA) 2B subunit containing receptors has been suggested to have potential therapeutic application for multiple CNS disorders. The amino terminal NR2B residues 1 to 282 were found to be both necessary and sufficient for the binding and function of highly NR2B subunit specific antagonists like ifenprodil and CP-101,606. Using a genetic approach in mice, we successfully replaced the murine NR2B gene function by "knocking-in" (KI) a chimeric human NR2A/B cDNA containing the minimal domain abolishing ifenprodil binding into the endogenous NR2B locus. Patch-clamp recording from hippocampal cultures of the NR2B KI mice demonstrated that their NMDA receptors have reduced sensitivity to both ifenprodil and CP-101,606, as predicted, but also have a lower affinity for glycine. The NR2B KI mice exhibited normal locomotor activity making this ifenprodil-insensitive mouse model a valuable tool to test the specificity of NR2B selective antagonists in vivo.


Assuntos
Antagonistas de Aminoácidos Excitatórios/metabolismo , Piperidinas/metabolismo , Subunidades Proteicas/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Animais , Células Cultivadas , Maleato de Dizocilpina/metabolismo , Agonistas de Aminoácidos Excitatórios/metabolismo , Feminino , Marcação de Genes , Hipocampo/citologia , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Atividade Motora/fisiologia , N-Metilaspartato/metabolismo , Neurônios/citologia , Neurônios/metabolismo , Técnicas de Patch-Clamp , Subunidades Proteicas/genética , Receptores de N-Metil-D-Aspartato/genética , Proteínas Recombinantes de Fusão/genética , Proteínas Recombinantes de Fusão/metabolismo , Xenopus laevis
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