Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 12 de 12
Filtrar
Más filtros












Base de datos
Intervalo de año de publicación
1.
Neuron ; 103(2): 217-234.e4, 2019 07 17.
Artículo en Inglés | MEDLINE | ID: mdl-31171447

RESUMEN

Synapses are fundamental information-processing units of the brain, and synaptic dysregulation is central to many brain disorders ("synaptopathies"). However, systematic annotation of synaptic genes and ontology of synaptic processes are currently lacking. We established SynGO, an interactive knowledge base that accumulates available research about synapse biology using Gene Ontology (GO) annotations to novel ontology terms: 87 synaptic locations and 179 synaptic processes. SynGO annotations are exclusively based on published, expert-curated evidence. Using 2,922 annotations for 1,112 genes, we show that synaptic genes are exceptionally well conserved and less tolerant to mutations than other genes. Many SynGO terms are significantly overrepresented among gene variations associated with intelligence, educational attainment, ADHD, autism, and bipolar disorder and among de novo variants associated with neurodevelopmental disorders, including schizophrenia. SynGO is a public, universal reference for synapse research and an online analysis platform for interpretation of large-scale -omics data (https://syngoportal.org and http://geneontology.org).


Asunto(s)
Encéfalo/citología , Ontología de Genes , Proteómica , Programas Informáticos , Sinapsis/fisiología , Animales , Encéfalo/fisiología , Bases de Datos Genéticas , Humanos , Bases del Conocimiento , Potenciales Sinápticos/fisiología , Sinaptosomas
2.
Proc Natl Acad Sci U S A ; 113(33): E4920-7, 2016 08 16.
Artículo en Inglés | MEDLINE | ID: mdl-27482106

RESUMEN

Regulation of AMPA receptor (AMPAR) function is a fundamental mechanism controlling synaptic strength during long-term potentiation/depression and homeostatic scaling. AMPAR function and membrane trafficking is controlled by protein-protein interactions, as well as by posttranslational modifications. Phosphorylation of the GluA1 AMPAR subunit at S845 and S831 play especially important roles during synaptic plasticity. Recent controversy has emerged regarding the extent to which GluA1 phosphorylation may contribute to synaptic plasticity. Here we used a variety of methods to measure the population of phosphorylated GluA1-containing AMPARs in cultured primary neurons and mouse forebrain. Phosphorylated GluA1 represents large fractions from 12% to 50% of the total population under basal and stimulated conditions in vitro and in vivo. Furthermore, a large fraction of synapses are positive for phospho-GluA1-containing AMPARs. Our results support the large body of research indicating a prominent role of GluA1 phosphorylation in synaptic plasticity.


Asunto(s)
Neuronas/metabolismo , Receptores AMPA/metabolismo , Animales , Potenciación a Largo Plazo , Ratones , Ratones Endogámicos C57BL , Microscopía Fluorescente , Plasticidad Neuronal , Fosforilación , Prosencéfalo/metabolismo , Ratas , Ratas Sprague-Dawley
3.
Proc Natl Acad Sci U S A ; 112(43): E5883-90, 2015 Oct 27.
Artículo en Inglés | MEDLINE | ID: mdl-26460013

RESUMEN

AMPA receptors (AMPARs) are the major excitatory receptors of the brain and are fundamental to synaptic plasticity, memory, and cognition. Dynamic recycling of AMPARs in neurons is regulated through several types of posttranslational modification, including phosphorylation. Here, we identify a previously unidentified signal transduction cascade that modulates phosphorylation of serine residue 863 (S863) in the GluA1 AMPAR subunit and controls surface trafficking of GluA1 in neurons. Activation of the EphR-Ephrin signal transduction pathway enhances S863 phosphorylation. Further, EphB2 can interact with Zizimin1, a guanine-nucleotide exchange factor that activates Cdc42 and stimulates S863 phosphorylation in neurons. Among the numerous targets downstream of Cdc42, we determined that the p21-activated kinase-3 (PAK3) phosphorylates S863 in vitro. Moreover, specific loss of PAK3 expression and pharmacological inhibition of PAK both disrupt activity-dependent phosphorylation of S863 in cortical neurons. EphB2, Cdc42, and PAKs are broadly capable of controlling dendritic spine formation and synaptic plasticity and are implicated in multiple cognitive disorders. Collectively, these data delineate a novel signal cascade regulating AMPAR trafficking that may contribute to the molecular mechanisms that govern learning and cognition.


Asunto(s)
Receptores AMPA/metabolismo , Quinasas p21 Activadas/metabolismo , Secuencia de Aminoácidos , Animales , Factores de Intercambio de Guanina Nucleótido/metabolismo , Datos de Secuencia Molecular , Fosforilación , Ratas , Receptores AMPA/química , Receptores de la Familia Eph/metabolismo , Homología de Secuencia de Aminoácido , Serina/metabolismo , Proteína de Unión al GTP cdc42/metabolismo , Quinasas p21 Activadas/genética
4.
Proc Natl Acad Sci U S A ; 111(32): 11840-5, 2014 Aug 12.
Artículo en Inglés | MEDLINE | ID: mdl-25071192

RESUMEN

Activity-dependent changes in synaptic strength have long been postulated as cellular correlates of learning and memory. Long-term potentiation (LTP), a well characterized form of synaptic plasticity, is often expressed as an increase in the number of postsynaptic AMPA-type glutamate receptors (AMPARs). Although the precise molecular mechanisms governing LTP remain elusive, this study identifies one member of the sorting nexin family, Sorting Nexin 27 (SNX27), as a critical component in this process. The ability of sorting nexins to bind specific phospholipids as well as their propensity to form protein-protein complexes, points to a role for these proteins in membrane trafficking and protein sorting. Here, we demonstrate that SNX27 binds to AMPARs, and that this interaction is regulated in an activity-dependent manner. Furthermore, we provide evidence that SNX27 is synaptically enriched and its level of expression regulates targeting of AMPARs to the neuronal surface. Loss of SNX27 abolishes recruitment of surface AMPARs during chemical LTP. Collectively, our data suggest a role for SNX27 in modulating synaptic plasticity through regulated interaction with AMPARs.


Asunto(s)
Potenciación a Largo Plazo/fisiología , Proteínas del Tejido Nervioso/metabolismo , Plasticidad Neuronal/fisiología , Receptores AMPA/metabolismo , Animales , Encéfalo/metabolismo , Membrana Celular/metabolismo , Proteínas del Tejido Nervioso/antagonistas & inhibidores , Proteínas del Tejido Nervioso/genética , Dominios PDZ , Densidad Postsináptica/metabolismo , Transporte de Proteínas , Ratas , Ratas Sprague-Dawley , Receptores AMPA/química
5.
Proc Natl Acad Sci U S A ; 110(3): 1077-82, 2013 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-23277581

RESUMEN

NMDA receptor activation can elicit synaptic plasticity by augmenting conductance of the AMPA receptor GluA1 subsequent to phosphorylation at S831 by Ca(2+)-dependent kinases. NMDA receptor activation also regulates synaptic plasticity by causing endocytosis of AMPA receptor GluA1. We demonstrate a unique signaling cascade for these processes mediated by NMDA receptor-dependent NO formation and GluA1 S-nitrosylation. Thus, S-nitrosylation of GluA1 at C875 enhances S831 phosphorylation, facilitates the associated AMPA receptor conductance increase, and results in endocytosis by increasing receptor binding to the AP2 protein of the endocytotic machinery.


Asunto(s)
Receptores AMPA/química , Receptores AMPA/metabolismo , Sustitución de Aminoácidos , Animales , Endocitosis , Células HEK293 , Hipocampo/metabolismo , Humanos , Ratones , Mutagénesis Sitio-Dirigida , Plasticidad Neuronal , Neuronas/metabolismo , Donantes de Óxido Nítrico/metabolismo , Fosforilación , Ratas , Receptores AMPA/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Transducción de Señal
6.
J Neurosci ; 30(44): 14786-94, 2010 Nov 03.
Artículo en Inglés | MEDLINE | ID: mdl-21048137

RESUMEN

Misshapen/NIKs (Nck-interacting kinases)-related kinase (MINK) and closely related TRAF2/Nck-interacting kinase (TNIK) are proteins that specifically bind to activated Rap2 and are thus hypothesized to relay its downstream signal transduction. Activated Rap2 has been found to stimulate dendritic pruning, reduce synaptic density and cause removal of synaptic AMPA receptors (AMPA-Rs) (Zhu et al., 2005; Fu et al., 2007). Here we report that MINK and TNIK are postsynaptically enriched proteins whose clustering within dendrites is bidirectionally regulated by the activation state of Rap2. Expression of MINK and TNIK in neurons is required for normal dendritic arborization and surface expression of AMPA receptors. Overexpression of a truncated MINK mutant unable to interact with Rap2 leads to reduced dendritic branching and this MINK-mediated effect on neuronal morphology is dependent upon Rap2 activation. While similarly truncated TNIK also reduces neuronal complexity, its effect does not require Rap2 activity. Furthermore, Rap2-mediated removal of surface AMPA-Rs from spines is entirely abrogated by coexpression of MINK, but not TNIK. Thus, although both MINK and TNIK bind GTP-bound Rap2, these kinases employ distinct mechanisms to modulate Rap2-mediated signaling. MINK appears to antagonize Rap2 signal transduction by binding to activated Rap2. We suggest that MINK interaction with Rap2 plays a critical role in maintaining the morphological integrity of dendrites and synaptic transmission.


Asunto(s)
Diferenciación Celular/fisiología , Neuronas/citología , Neuronas/fisiología , Canales de Potasio con Entrada de Voltaje/fisiología , Proteínas Serina-Treonina Quinasas/fisiología , Receptores AMPA/metabolismo , Transducción de Señal/genética , Proteínas de Unión al GTP rap/fisiología , Animales , Células Cultivadas , Dendritas/metabolismo , Dendritas/ultraestructura , Espinas Dendríticas/metabolismo , Espinas Dendríticas/ultraestructura , Mutación/genética , Neuronas/metabolismo , Canales de Potasio con Entrada de Voltaje/genética , Canales de Potasio con Entrada de Voltaje/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores AMPA/fisiología , Transmisión Sináptica/fisiología , Proteínas de Unión al GTP rap/genética , Proteínas de Unión al GTP rap/metabolismo
8.
Proc Natl Acad Sci U S A ; 101(11): 3833-8, 2004 Mar 16.
Artículo en Inglés | MEDLINE | ID: mdl-15007177

RESUMEN

Tandem MS has identified 209 proteins of clathrin-coated vesicles (CCVs) isolated from rat brain. An overwhelming abundance of peptides were assigned to the clathrin coat with a 1:1 stoichiometry observed for clathrin heavy and light chains and a 2:1 stoichiometry of clathrin heavy chain with clathrin adaptor protein heterotetramers. Thirty-two proteins representing many of the known components of synaptic vesicles (SVs) were identified, supporting that a main function for brain CCVs is to recapture SVs after exocytosis. A ratio of vesicle-N-ethylmaleimide-sensitive factor attachment protein receptors to target-N-ethylmaleimide-sensitive factor attachment protein receptors, similar to that previously detected on SVs, supports a single-step model for SV sorting during CCV-mediated recycling of SVs. The uncovering of eight previously undescribed proteins, four of which have to date been linked to clathrin-mediated trafficking, further attests to the value of the current organelle-based proteomics strategy.


Asunto(s)
Vesículas Cubiertas por Clatrina/química , Vesículas Sinápticas/metabolismo , Animales , Membrana Celular/metabolismo , Cromatografía Liquida , Vesículas Cubiertas por Clatrina/metabolismo , Citoesqueleto/metabolismo , Espectrometría de Masas , Ratas
9.
J Cell Sci ; 117(Pt 1): 9-18, 2004 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-14657269

RESUMEN

The epsin N-terminal homology (ENTH) domain is an evolutionarily conserved protein module found primarily in proteins that participate in clathrin-mediated endocytosis. Structural analyses and ligand-binding studies have shown that a set of proteins previously designated as harboring an ENTH domain in fact contain a highly similar, yet unique module referred to as an AP180 N-terminal homology (ANTH) domain. ENTH and ANTH (E/ANTH) domains bind both inositol phospholipids and proteins and contribute to the nucleation and formation of clathrin coats on membranes. ENTH domains also function in the development of membrane curvature through lipid remodeling during the formation of clathrin-coated vesicles. E/ANTH-bearing proteins have recently been shown to function with adaptor protein-1 and GGA adaptors at the trans-Golgi network, which suggests that E/ANTH domains are universal components of the machinery for clathrin-mediated membrane budding.


Asunto(s)
Proteínas Adaptadoras del Transporte Vesicular , Clatrina/metabolismo , Fusión de Membrana/fisiología , Proteínas de Transporte Vesicular , Animales , Proteínas Portadoras/metabolismo , Endocitosis/fisiología , Aparato de Golgi/metabolismo , Humanos , Lípidos de la Membrana/metabolismo , Modelos Moleculares , Proteínas de Ensamble de Clatrina Monoméricas/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Neuropéptidos/metabolismo , Fosfatidilinositoles/metabolismo , Monoéster Fosfórico Hidrolasas/metabolismo , Unión Proteica , Pliegue de Proteína , Estructura Terciaria de Proteína
10.
J Biol Chem ; 278(31): 28823-30, 2003 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-12750376

RESUMEN

The epsin N-terminal homology (ENTH) domain is a protein module of approximately 150 amino acids found at the N terminus of a variety of proteins identified in yeast, plants, nematode, frog, and mammals. ENTH domains comprise multiple alpha-helices folded upon each other to form a compact globular structure that has been implicated in interactions with lipids and proteins. In characterizing this evolutionarily conserved domain, we isolated and identified tubulin as an ENTH domain-binding partner. The interaction, which is direct and has a dissociation constant of approximately 1 microm, was observed with ENTH domains of proteins present in various species. Tubulin is co-immunoprecipitated from rat brain extracts with the ENTH domain-containing proteins, epsins 1 and 2, and punctate epsin staining is observed along the microtubule cytoskeleton of dissociated cortical neurons. Consistent with a role in microtubule processes, the over-expression of epsin ENTH domain in PC12 cells stimulates neurite outgrowth. These data demonstrate an evolutionarily conserved property of ENTH domains to interact with tubulin and microtubules.


Asunto(s)
Proteínas Portadoras/química , Proteínas de Ensamble de Clatrina Monoméricas/química , Neuropéptidos/química , Tubulina (Proteína)/metabolismo , Proteínas de Transporte Vesicular , Proteínas Adaptadoras del Transporte Vesicular , Animales , Sitios de Unión , Química Encefálica , Proteínas Portadoras/metabolismo , Secuencia Conservada , Humanos , Técnicas de Inmunoadsorción , Microtúbulos/química , Microtúbulos/metabolismo , Proteínas de Ensamble de Clatrina Monoméricas/metabolismo , Neuritas/fisiología , Neuronas/química , Neuronas/ultraestructura , Neuropéptidos/metabolismo , Pliegue de Proteína , Estructura Secundaria de Proteína , Ratas , Proteínas Recombinantes de Fusión , Homología Estructural de Proteína , Tubulina (Proteína)/análisis
11.
Trends Neurosci ; 25(8): 379-81, 2002 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-12127743

RESUMEN

The mechanism that allows a neuron to send cues received at its terminal to its cell body and nucleus has proved elusive. However, a recent study by Howe and colleagues indicates that neurotrophin signaling via the trkA receptor requires formation of a signaling endosome containing NGF and trkA. Thus, endocytosis of the neurotrophin-receptor complex is a crucial step in the generation of intracellular signaling platforms required for activation and compartmentalization of signaling events.


Asunto(s)
Endocitosis/fisiología , Endosomas/metabolismo , Factor de Crecimiento Nervioso/metabolismo , Factores de Crecimiento Nervioso/metabolismo , Sistema Nervioso/metabolismo , Terminales Presinápticos/metabolismo , Receptor trkA/metabolismo , Transducción de Señal/fisiología , Animales , Clatrina/metabolismo , Endosomas/ultraestructura , Humanos , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Sistema Nervioso/citología , Terminales Presinápticos/ultraestructura
12.
J Biol Chem ; 277(8): 6366-73, 2002 Feb 22.
Artículo en Inglés | MEDLINE | ID: mdl-11744688

RESUMEN

The Rho GTPases RhoA, Rac1, and Cdc42 play a major role in regulating the reorganization of the actin cytoskeleton. We recently identified CdGAP, a novel GTPase-activating protein with activity toward Rac1 and Cdc42. CdGAP consists of a N-terminal GAP domain, a central domain, and a C-terminal proline-rich domain. Here we show that through a subset of its Src homology 3 domains, the endocytic protein intersectin interacts with CdGAP. In platelet-derived growth factor-stimulated Swiss 3T3 cells, intersectin co-localizes with CdGAP and inhibits its GAP activity toward Rac1. Intersectin-Src homology 3 also inhibits CdGAP activity in GAP assays in vitro. Although the C-terminal proline-rich domain of CdGAP is required for the regulation of its GAP activity by intersectin both in vivo and in vitro, it is not necessary for CdGAP-intersectin interaction. Our data suggest that the central domain of CdGAP is required for CdGAP-intersectin interaction. Thus, we propose a model in which intersectin binding results in a change of CdGAP conformation involving the proline-rich domain that leads to the inhibition of its GAP activity. These observations provide the first demonstration of a direct regulation of RhoGAP activity through a protein-protein interaction and suggest a function for intersectin in Rac1 regulation and actin dynamics.


Asunto(s)
Proteínas Adaptadoras del Transporte Vesicular , Proteínas Portadoras/metabolismo , Endocitosis/fisiología , Proteínas Activadoras de GTPasa/metabolismo , Células 3T3 , Animales , Sitios de Unión , Biotinilación , Células COS , Proteínas Portadoras/química , Proteínas Portadoras/genética , Clonación Molecular , Cricetinae , Proteínas Activadoras de GTPasa/química , Proteínas Activadoras de GTPasa/genética , Cinética , Ratones , Reacción en Cadena de la Polimerasa , Proteínas Recombinantes de Fusión/metabolismo , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Transfección , Proteínas de Unión al GTP rho/metabolismo , Dominios Homologos src
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA
...