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1.
Proc Natl Acad Sci U S A ; 110(10): 4057-62, 2013 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-23345436

RESUMO

The balance between excitatory and inhibitory synaptic inputs, which is governed by multiple synapse organizers, controls neural circuit functions and behaviors. Slit- and Trk-like proteins (Slitrks) are a family of synapse organizers, whose emerging synaptic roles are incompletely understood. Here, we report that Slitrks are enriched in postsynaptic densities in rat brains. Overexpression of Slitrks promoted synapse formation, whereas RNAi-mediated knockdown of Slitrks decreased synapse density. Intriguingly, Slitrks were required for both excitatory and inhibitory synapse formation in an isoform-dependent manner. Moreover, Slitrks required distinct members of the leukocyte antigen-related receptor protein tyrosine phosphatase (LAR-RPTP) family to trigger synapse formation. Protein tyrosine phosphatase σ (PTPσ), in particular, was specifically required for excitatory synaptic differentiation by Slitrks, whereas PTPδ was necessary for inhibitory synapse differentiation. Taken together, these data suggest that combinatorial interactions of Slitrks with LAR-RPTP family members maintain synapse formation to coordinate excitatory-inhibitory balance.


Assuntos
Proteínas do Tecido Nervoso/fisiologia , Proteínas Tirosina Fosfatases Classe 2 Semelhantes a Receptores/fisiologia , Sinapses/fisiologia , Animais , Sequência de Bases , Encéfalo/fisiologia , Células Cultivadas , Técnicas de Silenciamento de Genes , Hipocampo/citologia , Hipocampo/fisiologia , Proteínas do Tecido Nervoso/antagonistas & inibidores , Proteínas do Tecido Nervoso/genética , RNA Interferente Pequeno/genética , Ratos , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Regulação para Cima
2.
Semin Cell Dev Biol ; 22(5): 492-8, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21736948

RESUMO

Synaptic adhesion molecules play important roles in various stages of neuronal development, including neurite outgrowth and synapse formation. The SALM (synaptic adhesion-like molecule) family of adhesion molecules, also known as Lrfn, belongs to the superfamily of leucine-rich repeat (LRR)-containing adhesion molecules. Proteins of the SALM family, which includes five known members (SALMs 1-5), have been implicated in the regulation of neurite outgrowth and branching, and synapse formation and maturation. Despite sharing a similar domain structure, individual SALM family proteins appear to have distinct functions. SALMs 1-3 contain a C-terminal PDZ-binding motif, which interacts with PSD-95, an abundant postsynaptic scaffolding protein, whereas SALM4 and SALM5 lack PDZ binding. SALM1 directly interacts with NMDA receptors but not with AMPA receptors, whereas SALM2 associates with both NMDA and AMPA receptors. SALMs 1-3 form homo- and heteromeric complexes with each other in a cis manner, whereas SALM4 and SALM5 do not, but instead participate in homophilic, trans-cellular adhesion. SALM3 and SALM5, but not other SALMs, possess synaptogenic activity, inducing presynaptic differentiation in contacting axons. All SALMs promote neurite outgrowth, while SALM4 uniquely increases the number of primary processes extending from the cell body. In addition to these functional diversities, the fifth member of the SALM family, SALM5/Lrfn5, has recently been implicated in severe progressive autism and familial schizophrenia, pointing to the clinical importance of SALMs.


Assuntos
Moléculas de Adesão Celular Neuronais/química , Moléculas de Adesão Celular Neuronais/metabolismo , Glicoproteínas de Membrana/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Proteínas/metabolismo , Sinapses/metabolismo , Sequência de Aminoácidos , Transtorno Autístico/genética , Proteínas de Transporte/química , Proteínas de Transporte/metabolismo , Proteína 4 Homóloga a Disks-Large , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/química , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas de Repetições Ricas em Leucina , Glicoproteínas de Membrana/química , Proteínas de Membrana/química , Proteínas de Membrana/metabolismo , Dados de Sequência Molecular , Proteínas do Tecido Nervoso/química , Proteínas/química , Receptores de AMPA/química , Receptores de AMPA/metabolismo , Receptores de N-Metil-D-Aspartato/química , Receptores de N-Metil-D-Aspartato/metabolismo , Esquizofrenia/genética
3.
J Neurosci ; 30(16): 5559-68, 2010 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-20410109

RESUMO

Synaptic cell adhesion molecules regulate various steps of synapse formation. Despite the great diversity of neuronal synapses, relatively few adhesion molecules with synaptogenic activity have been identified. Synaptic adhesion-like molecules (SALMs) are members of a family of cell adhesion molecules known to regulate neurite outgrowth and synapse maturation; however, the role of SALMs in synapse formation remains unknown. We found that expression of the SALM family proteins SALM3 and SALM5 in nonneural and neural cells induces both excitatory and inhibitory presynaptic differentiation in contacting axons. SALM3 and SALM5 proteins are enriched in synaptic fractions, and form strong (SALM3) or weak (SALM5) complexes with postsynaptic density-95 (PSD-95), an abundant postsynaptic scaffolding protein at excitatory synapses. Aggregation of SALM3, but not SALM5, on dendritic surfaces induces clustering of PSD-95. Knockdown of SALM5 reduces the number and function of excitatory and inhibitory synapses. These results suggest that selected SALM family proteins regulate synapse formation, and that SALM3 and SALM5 may promote synapse formation through distinct mechanisms.


Assuntos
Moléculas de Adesão Celular/fisiologia , Família Multigênica/fisiologia , Proteínas do Tecido Nervoso/fisiologia , Moléculas de Adesão de Célula Nervosa/fisiologia , Sinapses/fisiologia , Animais , Moléculas de Adesão Celular/genética , Comunicação Celular/genética , Diferenciação Celular/genética , Linhagem Celular , Células Cultivadas , Potenciais Pós-Sinápticos Excitadores/genética , Técnicas de Silenciamento de Genes , Hipocampo/citologia , Hipocampo/fisiologia , Humanos , Potenciais Pós-Sinápticos Inibidores/genética , Glicoproteínas de Membrana , Camundongos , Proteínas do Tecido Nervoso/genética , Moléculas de Adesão de Célula Nervosa/genética , Inibição Neural/genética , Neurônios/citologia , Neurônios/metabolismo , Neurônios/fisiologia , Ratos , Sinapses/genética
4.
J Neurosci ; 30(45): 15102-12, 2010 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-21068316

RESUMO

PSD-95 (postsynaptic density-95) is thought to play important roles in the regulation of dendritic spines and excitatory synapses, but the underlying mechanisms have not been fully elucidated. TANC1 is a PSD-95-interacting synaptic protein that contains multiple domains for protein-protein interactions but whose function is not well understood. In the present study, we provide evidence that TANC1 and its close relative TANC2 regulate dendritic spines and excitatory synapses. Overexpression of TANC1 and TANC2 in cultured neurons increases the density of dendritic spines and excitatory synapses in a manner that requires the PDZ (PSD-95/Dlg/ZO-1)-binding C termini of TANC proteins. TANC1-deficient mice exhibit reduced spine density in the CA3 region of the hippocampus, but not in the CA1 or dentate gyrus regions, and show impaired spatial memory. TANC2 deficiency, however, causes embryonic lethality. These results suggest that TANC1 is important for dendritic spine maintenance and spatial memory, and implicate TANC2 in embryonic development.


Assuntos
Venenos de Crotalídeos/metabolismo , Espinhas Dendríticas/metabolismo , Desenvolvimento Embrionário/fisiologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Lectinas Tipo C/metabolismo , Proteínas de Membrana/metabolismo , Memória/fisiologia , Percepção Espacial/fisiologia , Animais , Células Cultivadas , Proteína 4 Homóloga a Disks-Large , Hipocampo/citologia , Hipocampo/metabolismo , Imuno-Histoquímica , Camundongos , Camundongos Knockout , Microscopia Eletrônica , Neurônios/citologia , Neurônios/metabolismo , Ratos , Sinapses/metabolismo
5.
Sci Rep ; 6: 26676, 2016 05 26.
Artigo em Inglês | MEDLINE | ID: mdl-27225731

RESUMO

Synaptogenic adhesion molecules play critical roles in synapse formation. SALM5/Lrfn5, a SALM/Lrfn family adhesion molecule implicated in autism spectrum disorders (ASDs) and schizophrenia, induces presynaptic differentiation in contacting axons, but its presynaptic ligand remains unknown. We found that SALM5 interacts with the Ig domains of LAR family receptor protein tyrosine phosphatases (LAR-RPTPs; LAR, PTPδ, and PTPσ). These interactions are strongly inhibited by the splice insert B in the Ig domain region of LAR-RPTPs, and mediate SALM5-dependent presynaptic differentiation in contacting axons. In addition, SALM5 regulates AMPA receptor-mediated synaptic transmission through mechanisms involving the interaction of postsynaptic SALM5 with presynaptic LAR-RPTPs. These results suggest that postsynaptic SALM5 promotes synapse development by trans-synaptically interacting with presynaptic LAR-RPTPs and is important for the regulation of excitatory synaptic strength.


Assuntos
Processamento Alternativo/fisiologia , Axônios/metabolismo , Moléculas de Adesão Celular Neuronais/metabolismo , Proteínas Tirosina Fosfatases Classe 2 Semelhantes a Receptores/metabolismo , Sinapses/metabolismo , Transmissão Sináptica/fisiologia , Animais , Moléculas de Adesão Celular Neuronais/genética , Camundongos , Proteínas Tirosina Fosfatases Classe 2 Semelhantes a Receptores/genética , Sinapses/genética
6.
Nat Commun ; 7: 12328, 2016 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-27480238

RESUMO

Synaptic adhesion molecules regulate various aspects of synapse development, function and plasticity. These functions mainly involve trans-synaptic interactions and positive regulations, whereas cis-interactions and negative regulation are less understood. Here we report that SALM4, a member of the SALM/Lrfn family of synaptic adhesion molecules, suppresses excitatory synapse development through cis inhibition of SALM3, another SALM family protein with synaptogenic activity. Salm4-mutant (Salm4(-/-)) mice show increased excitatory synapse numbers in the hippocampus. SALM4 cis-interacts with SALM3, inhibits trans-synaptic SALM3 interaction with presynaptic LAR family receptor tyrosine phosphatases and suppresses SALM3-dependent presynaptic differentiation. Importantly, deletion of Salm3 in Salm4(-/-) mice (Salm3(-/-); Salm4(-/-)) normalizes the increased excitatory synapse number. These results suggest that SALM4 negatively regulates excitatory synapses via cis inhibition of the trans-synaptic SALM3-LAR adhesion.


Assuntos
Moléculas de Adesão Celular Neuronais/metabolismo , Diferenciação Celular/fisiologia , Moléculas de Adesão de Célula Nervosa/metabolismo , Terminações Pré-Sinápticas/fisiologia , Células Piramidais/fisiologia , Proteínas Tirosina Fosfatases Classe 2 Semelhantes a Receptores/metabolismo , Animais , Região CA1 Hipocampal/citologia , Região CA1 Hipocampal/fisiologia , Adesão Celular/fisiologia , Moléculas de Adesão Celular Neuronais/genética , Potenciais Pós-Sinápticos Excitadores/fisiologia , Feminino , Masculino , Glicoproteínas de Membrana , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Animais , Proteínas do Tecido Nervoso , Moléculas de Adesão de Célula Nervosa/genética , Transmissão Sináptica/fisiologia
7.
PLoS One ; 9(7): e103116, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25068721

RESUMO

One application of nanotechnology in medicine that is presently being developed involves a drug delivery system (DDS) employing nanoparticles to deliver drugs to diseased sites in the body avoiding damage of healthy tissue. Recently, the mild hyperthermia-triggered drug delivery combined with anticancer agent-loaded thermosensitive liposomes was widely investigated. In this study, thermosensitive liposomes (TSLs), composed of 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethyleneglycol)-2000] (DSPE-PEG), cholesterol, and a fatty acid conjugated elastin-like polypeptide (ELP), were developed and optimized for triggered drug release, controlled by external heat stimuli. We introduced modified ELP, tunable for various biomedical purposes, to our thermosensitive liposome (e-TSL) to convey a high thermoresponsive property. We modulated thermosensitivity and stability by varying the ratios of e-TSL components, such as phospholipid, ELP, and cholesterol. Experimental data obtained in this study corresponded to results from a simulation study that demonstrated, through the calculation of the lateral diffusion coefficient, increased permeation of the lipid bilayer with higher ELP concentrations, and decreased permeation in the presence of cholesterol. Finally, we identified effective drug accumulation in tumor tissues and antitumor efficacy with our optimized e-TSL, while adjusting lag-times for systemic accumulation.


Assuntos
Colesterol/química , Lipossomos/química , Peptídeos/química , Fosfolipídeos/química , Animais , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/farmacocinética , Química Farmacêutica , Modelos Animais de Doenças , Doxorrubicina/administração & dosagem , Doxorrubicina/farmacocinética , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Humanos , Bicamadas Lipídicas/química , Masculino , Camundongos , Simulação de Acoplamento Molecular , Nanopartículas/química , Nanopartículas/ultraestrutura , Tamanho da Partícula , Termodinâmica , Temperatura de Transição , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Nat Commun ; 5: 5423, 2014 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-25394468

RESUMO

Synaptic adhesion molecules orchestrate synaptogenesis. The presynaptic leukocyte common antigen-related receptor protein tyrosine phosphatases (LAR-RPTPs) regulate synapse development by interacting with postsynaptic Slit- and Trk-like family proteins (Slitrks), which harbour two extracellular leucine-rich repeats (LRR1 and LRR2). Here we identify the minimal regions of the LAR-RPTPs and Slitrks, LAR-RPTPs Ig1-3 and Slitrks LRR1, for their interaction and synaptogenic function. Subsequent crystallographic and structure-guided functional analyses reveal that the splicing inserts in LAR-RPTPs are key molecular determinants for Slitrk binding and synapse formation. Moreover, structural comparison of the two Slitrk1 LRRs reveal that unique properties on the concave surface of Slitrk1 LRR1 render its specific binding to LAR-RPTPs. Finally, we demonstrate that lateral interactions between adjacent trans-synaptic LAR-RPTPs/Slitrks complexes observed in crystal lattices are critical for Slitrk1-induced lateral assembly and synaptogenic activity. Thus, we propose a model in which Slitrks mediate synaptogenic functions through direct binding to LAR-RPTPs and the subsequent lateral assembly of LAR-RPTPs/Slitrks complexes.


Assuntos
Proteínas de Membrana/fisiologia , Proteínas do Tecido Nervoso/fisiologia , Proteínas Tirosina Fosfatases/fisiologia , Proteínas Tirosina Fosfatases Classe 2 Semelhantes a Receptores/fisiologia , Sinapses/metabolismo , Animais , Sítios de Ligação , Adesão Celular/fisiologia , Células HEK293 , Hipocampo/citologia , Humanos , Proteínas de Membrana/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Estrutura Terciária de Proteína , Proteínas Tirosina Fosfatases/metabolismo , Ratos , Reação em Cadeia da Polimerase em Tempo Real , Proteínas Tirosina Fosfatases Classe 2 Semelhantes a Receptores/metabolismo , Proteínas Repressoras/metabolismo , Proteínas Repressoras/fisiologia , Sinapses/fisiologia
9.
J Cell Biol ; 201(6): 929-44, 2013 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-23751499

RESUMO

Synaptic adhesion molecules regulate diverse aspects of synapse formation and maintenance. Many known synaptic adhesion molecules localize at excitatory synapses, whereas relatively little is known about inhibitory synaptic adhesion molecules. Here we report that IgSF9b is a novel, brain-specific, homophilic adhesion molecule that is strongly expressed in GABAergic interneurons. IgSF9b was preferentially localized at inhibitory synapses in cultured rat hippocampal and cortical interneurons and was required for the development of inhibitory synapses onto interneurons. IgSF9b formed a subsynaptic domain distinct from the GABAA receptor- and gephyrin-containing domain, as indicated by super-resolution imaging. IgSF9b was linked to neuroligin 2, an inhibitory synaptic adhesion molecule coupled to gephyrin, via the multi-PDZ protein S-SCAM. IgSF9b and neuroligin 2 could reciprocally cluster each other. These results suggest a novel mode of inhibitory synaptic organization in which two subsynaptic domains, one containing IgSF9b for synaptic adhesion and the other containing gephyrin and GABAA receptors for synaptic transmission, are interconnected through S-SCAM and neuroligin 2.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Moléculas de Adesão Celular Neuronais/metabolismo , Guanilato Quinases/metabolismo , Imunoglobulinas/metabolismo , Interneurônios/fisiologia , Proteínas do Tecido Nervoso/metabolismo , Inibição Neural/fisiologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Adesão Celular/fisiologia , Moléculas de Adesão Celular Neuronais/genética , Técnicas de Cocultura , Guanilato Quinases/genética , Células HEK293 , Hipocampo/citologia , Humanos , Imunoglobulinas/química , Imunoglobulinas/genética , Interneurônios/citologia , Camundongos , Proteínas do Tecido Nervoso/química , Proteínas do Tecido Nervoso/genética , Cultura Primária de Células , Estrutura Terciária de Proteína/fisiologia , Ratos , Receptores de GABA-A/metabolismo , Sinapses/metabolismo
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