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1.
J Integr Neurosci ; 19(3): 449-458, 2020 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-33070524

RESUMO

We first explore the features of GluK2 endocytosis during kainate excitotoxicity and then explore the role of Ca2+ in the regulation of GluK2 endocytosis. The roles of Ca2+ were examined by treating cells with Ca2+ inhibitors or chelators. Surface biotinylation was used to examine the surface localization of GluK2. Immunoprecipitation followed by immunoblotting was used to identify the interaction of GluK2 with the endocytosis regulator protein-interacting with C kinase 1 and dynamin. Dynamin phosphorylation was examined by immunoblotting with the corresponding antibodies. Our results show that GluK2 internalization is blocked by inhibitors of clathrin-independent endocytosis and relies on intracellular Ca2+/calcineurin signaling. Protein-interacting with C kinase 1-GluK2 interaction is regulated by Ca2+/calcineurin signaling. Dynamin participates in the regulation of GluK2 surface localization. Also, calcineurin activation is related to dynamin function during kainate excitotoxicity. In conclusion, GluK2 receptor endocytosis is probably a clathrin-independent and dynamin-dependent process regulated by the peak Ca2+ transient. This work indicates the roles of the Ca2+ network in the regulation of GluK2 endocytosis during kainate excitotoxicity.


Assuntos
Sinalização do Cálcio , Clatrina/fisiologia , Dinaminas/fisiologia , Endocitose , Neurônios/fisiologia , Receptores de Ácido Caínico/fisiologia , Animais , Córtex Cerebral/fisiologia , Células HEK293 , Humanos , Fosforilação , Ratos Sprague-Dawley , Receptor de GluK2 Cainato
2.
Antioxid Redox Signal ; 32(1): 18-34, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31642335

RESUMO

Aims: Neuronal nitric oxide synthase (nNOS) and nitric oxide (NO) signaling have been implicated in learning, memory, and underlying long-lasting synaptic plasticity. In this study, we aimed at detecting whether nNOS is a target protein of SUMOylation in the hippocampus and its contributions to hippocampal long-term potentiation (LTP) of synaptic transmission. Results: We showed that N-methyl-d-aspartate receptor-dependent neuronal activity enhancement induced the attachment of small ubiquitin-like modifier 1 (SUMO1) to nNOS. Protein inhibitor of activated STAT3 (PIAS3) promoted SUMO1 conjugation at K725 and K739 on nNOS, which upregulated NO production and nNOS S1412 phosphorylation (activation). In addition, the N-terminus (amino acids 43-86) of PIAS3 bound nNOS directly. Tat-tagged PIAS3 segment representing amino acids 43-86, a cell-permeable peptide containing PIAS3 residues 43-86, suppressed activity-induced nNOS SUMOylation by disrupting PIAS3-nNOS association. It also decreased LTP-related expression of Arc and brain-derived neurotrophic factor and blocked signaling via extracellular signal-regulated kinase (ERK) 1/2 and Elk-1 in the hippocampus. More importantly, PIAS3-mediated nNOS SUMOylation was required for activity-regulated ERK1/2 activation in nNOS-positive neurons and hippocampal LTP induction. Innovation and Conclusion: These findings indicated that network activity-regulated nNOS SUMOylation underlies excitatory synaptic LTP by facilitating nNOS-NO-ERK1/2 signal cascades.


Assuntos
Hipocampo/citologia , Chaperonas Moleculares/metabolismo , Óxido Nítrico Sintase Tipo I/química , Óxido Nítrico Sintase Tipo I/metabolismo , Proteínas Inibidoras de STAT Ativados/metabolismo , Proteína SUMO-1/metabolismo , Animais , Sítios de Ligação , Células Cultivadas , Hipocampo/metabolismo , Potenciação de Longa Duração , Sistema de Sinalização das MAP Quinases , Masculino , Modelos Moleculares , Chaperonas Moleculares/química , Óxido Nítrico/metabolismo , Ligação Proteica , Proteínas Inibidoras de STAT Ativados/química , Ratos , Sumoilação , Transmissão Sináptica
3.
Proc Natl Acad Sci U S A ; 111(38): 13990-5, 2014 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-25201974

RESUMO

Although kainate receptors play important roles in ischemic stroke, the molecular mechanisms underlying postischemic regulation of kainate receptors remain unclear. In this study we demonstrate that Src family kinases contribute to the potentiation of kainate receptor function. Brain ischemia and reperfusion induce rapid and sustained phosphorylation of the kainate receptor subunit GluK2 by Src in the rat hippocampus, implicating a critical role for Src-mediated GluK2 phosphorylation in ischemic brain injury. The NMDA and kainate receptors are involved in the tyrosine phosphorylation of GluK2. GluK2 binds to Src, and the tyrosine residue at position 590 (Y590) on GluK2 is a major site of phosphorylation by Src kinases. GluK2 phosphorylation at Y590 is responsible for increases in whole-cell currents and calcium influx in response to transient kainate stimulation. In addition, GluK2 phosphorylation at Y590 facilitates the endocytosis of GluK2 subunits, and the activation of JNK3 and its substrate c-Jun after long-term kainate treatment. Thus, Src phosphorylation of GluK2 plays an important role in the opening of kainate receptor channels and downstream proapoptosis signaling after brain ischemia. The present study reveals an additional mechanism for the regulation of GluK2-containing kainate receptors by Src family kinases, which may be of pathological significance in ischemic stroke.


Assuntos
Isquemia Encefálica/metabolismo , Hipocampo/metabolismo , Receptores de Ácido Caínico/metabolismo , Transdução de Sinais/fisiologia , Acidente Vascular Cerebral/metabolismo , Regulação para Cima/fisiologia , Animais , Isquemia Encefálica/genética , Isquemia Encefálica/patologia , Células HEK293 , Hipocampo/patologia , Humanos , Masculino , Proteína Quinase 10 Ativada por Mitógeno/genética , Proteína Quinase 10 Ativada por Mitógeno/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-jun/genética , Proteínas Proto-Oncogênicas c-jun/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de Ácido Caínico/genética , Acidente Vascular Cerebral/genética , Acidente Vascular Cerebral/patologia , Tirosina/genética , Tirosina/metabolismo , Quinases da Família src/genética , Quinases da Família src/metabolismo , Receptor de GluK2 Cainato
4.
FEBS Lett ; 586(9): 1259-64, 2012 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-22483987

RESUMO

Protein SUMOylation has been implicated in the pathogenesis of ischemic stroke. However, the underlying mechanisms remain unclear. Here, we found that global brain ischemia evokes a sustained elevation of GluK2 SUMOylation in the rat hippocampal CA1 region. Over-expression of wild-type GluK2, but not SUMOylation-deficient mutant, significantly increased the activity of MLK3 and JNK3 after kainate stimulation. SUMOylation deficiency attenuated the kainate-stimulated interaction between MLK3 and GluK2. In addition, inhibition of kainate-evoked GluK2 endocytosis decreased the activation of MLK3-JNK3 signaling and the binding of MLK3-GluK2 in cultured cortical neurons. These results suggest that the internalization of GluK2 following SUMO modification promotes its binding with MLK3, thereby activating the MLK3-JNK3 pathway, which may be responsible for ischemic neuronal cell death.


Assuntos
Ácido Caínico/farmacologia , MAP Quinase Quinase Quinases/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteína Quinase 10 Ativada por Mitógeno/metabolismo , Receptores de Ácido Caínico/metabolismo , Sumoilação/efeitos dos fármacos , Animais , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Região CA1 Hipocampal/metabolismo , Região CA1 Hipocampal/patologia , Células COS , Linhagem Celular Tumoral , Chlorocebus aethiops , Ativação Enzimática/efeitos dos fármacos , Humanos , Masculino , Fosforilação/efeitos dos fármacos , Transporte Proteico/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , MAP Quinase Quinase Quinase 11 Ativada por Mitógeno , Receptor de GluK2 Cainato
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