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1.
J Neurosci ; 43(32): 5753-5768, 2023 08 09.
Artículo en Inglés | MEDLINE | ID: mdl-37344234

RESUMEN

Axon fasciculation is thought to be a critical step in neural circuit formation and function. Recent studies have revealed various molecular mechanisms that underlie axon fasciculation; however, the impacts of axon fasciculation, and its corollary, defasciculation, on neural circuit wiring remain unclear. Corticospinal (CS) neurons in the sensorimotor cortex project axons to the spinal cord to control skilled movements. In rodents, the axons remain tightly fasciculated in the brain and traverse the dorsal funiculus of the spinal cord. Here we show that plexinA1 (PlexA1) and plexinA3 (PlexA3) receptors are expressed by CS neurons, whereas their ligands, semaphorin-5A (Sema5A) and semaphorin-5B (Sema5B) are expressed in the medulla at the decussation site of CS axons to inhibit premature defasciculation of these axons. In the absence of Sema5A/5B-PlexA1/A3 signaling, some CS axons are prematurely defasciculated in the medulla of the brainstem, and those defasciculated CS axons aberrantly transverse in the spinal gray matter instead of the spinal dorsal funiculus. In the absence of Sema5A/Sema5B-PlexA1/A3 signaling, CS axons, which would normally innervate the lumbar spinal cord, are unbundled in the spinal gray matter, and prematurely innervate the cervical gray matter with reduced innervation of the lumbar gray matter. In both Sema5A/5B and PlexA1/A3 mutant mice (both sexes), stimulation of the hindlimb motor cortex aberrantly evokes robust forelimb muscle activation. Finally, Sema5A/5B and PlexA1/A3 mutant mice show deficits in skilled movements. These results suggest that proper fasciculation of CS axons is required for appropriate neural circuit wiring and ultimately affect the ability to perform skilled movements.SIGNIFICANCE STATEMENT Axon fasciculation is believed to be essential for neural circuit formation and function. However, whether and how defects in axon fasciculation affect the formation and function of neural circuits remain unclear. Here we examine whether the transmembrane proteins semaphorin-5A (Sema5A) and semaphorin-5B (Sema5B), and their receptors, plexinA1 (PlexA1) and plexinA3 (PlexA3) play roles in the development of corticospinal circuits. We find that Sema5A/Sema5B and PlexA1/A3 are required for proper axon fasciculation of corticospinal neurons. Furthermore, Sema5A/5B and PlexA1/A3 mutant mice show marked deficits in skilled motor behaviors. Therefore, these results strongly suggest that proper corticospinal axon fasciculation is required for the appropriate formation and functioning of corticospinal circuits in mice.


Asunto(s)
Semaforinas , Femenino , Masculino , Ratones , Animales , Semaforinas/metabolismo , Fasciculación Axonal , Neuronas/metabolismo , Axones/fisiología , Médula Espinal/metabolismo
2.
J Neurosci ; 42(12): 2448-2473, 2022 03 23.
Artículo en Inglés | MEDLINE | ID: mdl-35121636

RESUMEN

Signal-induced proliferation-associated 1 (SIPA1)-like 1 (SIPA1L1; also known as SPAR1) has been proposed to regulate synaptic functions that are important in maintaining normal neuronal activities, such as regulating spine growth and synaptic scaling, as a component of the PSD-95/NMDA-R-complex. However, its physiological role remains poorly understood. Here, we performed expression analyses using super-resolution microscopy (SRM) in mouse brain and demonstrated that SIPA1L1 is mainly localized to general submembranous regions in neurons, but surprisingly, not to PSD. Our screening for physiological interactors of SIPA1L1 in mouse brain identified spinophilin and neurabin-1, regulators of G-protein-coupled receptor (GPCR) signaling, but rejected PSD-95/NMDA-R-complex components. Furthermore, Sipa1l1-/- mice showed normal spine size distribution and NMDA-R-dependent synaptic plasticity. Nevertheless, Sipa1l1-/- mice showed aberrant responses to α2-adrenergic receptor (a spinophilin target) or adenosine A1 receptor (a neurabin-1 target) agonist stimulation, and striking behavioral anomalies, such as hyperactivity, enhanced anxiety, learning impairments, social interaction deficits, and enhanced epileptic seizure susceptibility. Male mice were used for all experiments. Our findings revealed unexpected properties of SIPA1L1, suggesting a possible association of SIPA1L1 deficiency with neuropsychiatric disorders related to dysregulated GPCR signaling, such as epilepsy, attention deficit hyperactivity disorder (ADHD), autism, or fragile X syndrome (FXS).SIGNIFICANCE STATEMENT Signal-induced proliferation-associated 1 (SIPA1)-like 1 (SIPA1L1) is thought to regulate essential synaptic functions as a component of the PSD-95/NMDA-R-complex. In our screening for physiological SIPA1L1-interactors, we identified G-protein-coupled receptor (GPCR)-signaling regulators. Moreover, SIPA1L1 knock-out (KO) mice showed striking behavioral anomalies, which may be relevant to GPCR signaling. Our findings revealed an unexpected role of SIPA1L1, which may open new avenues for research on neuropsychiatric disorders that involve dysregulated GPCR signaling. Another important aspect of this paper is that we showed effective methods for checking PSD association and identifying native protein interactors that are difficult to solubilize. These results may serve as a caution for future claims about interacting proteins and PSD proteins, which could eventually save time and resources for researchers and avoid confusion in the field.


Asunto(s)
Proteínas Activadoras de GTPasa/metabolismo , N-Metilaspartato , Proteínas del Tejido Nervioso , Animales , Homólogo 4 de la Proteína Discs Large , Masculino , Ratones , Ratones Noqueados , Proteínas de Microfilamentos/metabolismo , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Receptor de Adenosina A1 , Receptores Acoplados a Proteínas G/metabolismo
3.
bioRxiv ; 2024 Jun 28.
Artículo en Inglés | MEDLINE | ID: mdl-38979259

RESUMEN

Corticospinal neurons (CSNs) are located in the cortex and projecting into the spinal cord. The activation of CSNs, which is associated with skilled motor behaviors, induces the activation of interneurons in the spinal cord. Eventually, motor neuron activation is induced by corticospinal circuits to coordinate muscle activation. Therefore, elucidating how the activation of CSNs in the brain is regulated is necessary for understanding the roles of CSNs in skilled motor behaviors. However, the presynaptic partners of CSNs in the brain remain to be identified. Here, we performed transsynaptic rabies virus-mediated brain-wide mapping to identify presynaptic partners of CSNs (pre-CSNs). We found that pre-CSNs are located in all cortical layers, but major pre-CSNs are located in layer Va. A small population of pre-CSNs are also located outside the cortex, such as in the thalamus. Inactivation of layer Va neurons in Tlx3-Cre mice results in deficits in skilled reaching and grasping behaviors, suggesting that, similar to CSNs, layer Va neurons are critical for skilled movements. Finally, we examined whether the connectivity of CSNs is altered after spinal cord injury (SCI). We found that unlike connections between CNSs and postsynaptic neurons, connections between pre-CSNs and CSNs do not change after SCI.

4.
iScience ; 25(8): 104692, 2022 Aug 19.
Artículo en Inglés | MEDLINE | ID: mdl-35856033

RESUMEN

The CaMKΙΙα-Cre mouse lines, possibly the most used Cre lines in neuroscience, have resulted in over 800 articles to date. Here, we demonstrate that the second most widely used CaMKΙΙα-Cre line, Tg(Camk2a-cre)2Gsc (or CamiCre), shows ectopic overexpression of synaptotagmin 2, the most efficient Ca2+ sensor for fast synchronous neurotransmitter release, in excitatory presynapses of Cre+ brains. Moreover, the upregulation of immediate-early genes and genes incorporated in bacterial artificial chromosome (BAC) transgenes, such as L-proline transporter Slc6a7, was found in Cre+ hippocampus. The copy number and integration site of the transgene are suggested to have caused the aberrant gene expression in Cre+ brains. Most importantly, CamiCre+ mice showed functional phenotypes, such as hyperactivity and enhanced associative learning, suggesting that neural activities are affected. These unexpected results suggest difficulties in interpreting results from studies using the CamiCre line and raise a warning of potential pitfalls in using Cre driver lines in general.

5.
J Biol Chem ; 285(21): 16145-54, 2010 May 21.
Artículo en Inglés | MEDLINE | ID: mdl-20308060

RESUMEN

We have recently shown that beta-catenin-facilitated export of cadherins from the endoplasmic reticulum requires PX-RICS, a beta-catenin-interacting GTPase-activating protein for Cdc42. Here we show that PX-RICS interacts with isoforms of 14-3-3 and couples the N-cadherin-beta-catenin complex to the microtubule-based molecular motor dynein-dynactin. Similar to knockdown of PX-RICS, knockdown of either 14-3-3zeta or - resulted in the disappearance of N-cadherin and beta-catenin from the cell-cell boundaries. Furthermore, we found that PX-RICS and 14-3-3zeta/ are present in a large multiprotein complex that contains dynein-dynactin components as well as N-cadherin and beta-catenin. Both RNAi- and dynamitin-mediated inhibition of dynein-dynactin function also led to the absence of N-cadherin and beta-catenin at the cell-cell contact sites. Our results suggest that the PX-RICS-14-3-3zeta/ complex links the N-cadherin-beta-catenin cargo with the dynein-dynactin motor and thereby mediates its endoplasmic reticulum export.


Asunto(s)
Proteínas 14-3-3/metabolismo , Antígenos CD/metabolismo , Cadherinas/metabolismo , Dineínas/metabolismo , Retículo Endoplásmico/metabolismo , Proteínas Activadoras de GTPasa/metabolismo , Proteínas Asociadas a Microtúbulos/metabolismo , Complejos Multiproteicos/metabolismo , beta Catenina/metabolismo , Proteínas 14-3-3/genética , Animales , Antígenos CD/genética , Células COS , Cadherinas/genética , Chlorocebus aethiops , Complejo Dinactina , Dineínas/genética , Retículo Endoplásmico/genética , Proteínas Activadoras de GTPasa/genética , Técnicas de Silenciamiento del Gen , Células HeLa , Humanos , Proteínas Asociadas a Microtúbulos/genética , Microtúbulos/genética , Microtúbulos/metabolismo , Complejos Multiproteicos/genética , Transporte de Proteínas/fisiología , beta Catenina/genética , Proteína de Unión al GTP cdc42/genética , Proteína de Unión al GTP cdc42/metabolismo
6.
EBioMedicine ; 34: 189-200, 2018 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-30045817

RESUMEN

GABAergic dysfunction underlies many neurodevelopmental and psychiatric disorders. GABAergic synapses exhibit several forms of plasticity at both pre- and postsynaptic levels. NMDA receptor (NMDAR)-dependent inhibitory long-term potentiation (iLTP) at GABAergic postsynapses requires an increase in surface GABAARs through promoted exocytosis; however, the regulatory mechanisms and the neuropathological significance remain unclear. Here we report that the autism-related protein PX-RICS is involved in GABAAR transport driven during NMDAR-dependent GABAergic iLTP. Chemically induced iLTP elicited a rapid increase in surface GABAARs in wild-type mouse hippocampal neurons, but not in PX-RICS/RICS-deficient neurons. This increase in surface GABAARs required the PX-RICS/GABARAP/14-3-3 complex, as revealed by gene knockdown and rescue studies. iLTP induced CaMKII-dependent phosphorylation of PX-RICS to promote PX-RICS-14-3-3 assembly. Notably, PX-RICS/RICS-deficient mice showed impaired amygdala-dependent fear learning, which was ameliorated by potentiating GABAergic activity with clonazepam. Our results suggest that PX-RICS-mediated GABAAR trafficking is a key target for GABAergic plasticity and its dysfunction leads to atypical emotional processing underlying autism.


Asunto(s)
Proteínas Activadoras de GTPasa/fisiología , Plasticidad Neuronal/fisiología , Neuronas/fisiología , Receptores de GABA-A/fisiología , Amígdala del Cerebelo/fisiología , Animales , Trastorno Autístico , Células Cultivadas , Miedo/fisiología , Hipocampo/citología , Aprendizaje/fisiología , Masculino , Ratones Endogámicos C57BL , Ratones Mutantes , Ácido gamma-Aminobutírico/fisiología
7.
Nat Commun ; 7: 10861, 2016 Mar 16.
Artículo en Inglés | MEDLINE | ID: mdl-26979507

RESUMEN

Jacobsen syndrome (JBS) is a rare congenital disorder caused by a terminal deletion of the long arm of chromosome 11. A subset of patients exhibit social behavioural problems that meet the diagnostic criteria for autism spectrum disorder (ASD); however, the underlying molecular pathogenesis remains poorly understood. PX-RICS is located in the chromosomal region commonly deleted in JBS patients with autistic-like behaviour. Here we report that PX-RICS-deficient mice exhibit ASD-like social behaviours and ASD-related comorbidities. PX-RICS-deficient neurons show reduced surface γ-aminobutyric acid type A receptor (GABAAR) levels and impaired GABAAR-mediated synaptic transmission. PX-RICS, GABARAP and 14-3-3ζ/θ form an adaptor complex that interconnects GABAAR and dynein/dynactin, thereby facilitating GABAAR surface expression. ASD-like behavioural abnormalities in PX-RICS-deficient mice are ameliorated by enhancing inhibitory synaptic transmission with a GABAAR agonist. Our findings demonstrate a critical role of PX-RICS in cognition and suggest a causal link between PX-RICS deletion and ASD-like behaviour in JBS patients.


Asunto(s)
Trastorno del Espectro Autista/genética , Conducta Animal/fisiología , Proteínas Activadoras de GTPasa/genética , Síndrome de Deleción Distal 11q de Jacobsen/genética , Transporte de Proteínas/genética , Receptores de GABA-A/metabolismo , Conducta Social , Animales , Trastorno del Espectro Autista/metabolismo , Trastorno del Espectro Autista/psicología , Conducta Animal/efectos de los fármacos , Clonazepam/farmacología , Agonistas de Aminoácidos Excitadores/toxicidad , Moduladores del GABA/farmacología , Aseo Animal , Síndrome de Deleción Distal 11q de Jacobsen/metabolismo , Síndrome de Deleción Distal 11q de Jacobsen/psicología , Ácido Kaínico/toxicidad , Ratones , Ratones Noqueados , Percepción Olfatoria/efectos de los fármacos , Percepción Olfatoria/genética , Convulsiones/inducido químicamente , Convulsiones/genética , Conducta Estereotipada/efectos de los fármacos , Conducta Estereotipada/fisiología , Vocalización Animal/efectos de los fármacos , Vocalización Animal/fisiología
8.
Nat Commun ; 2: 548, 2011 Nov 22.
Artículo en Inglés | MEDLINE | ID: mdl-22109522

RESUMEN

Cell fusion has a critical role in various developmental processes, immune response, tissue homeostasis and regeneration, and possibly, in cancer. However, the signals that regulate cell fusion remain poorly understood. In a screen for novel targets of Wnt/ß-catenin signalling, we identified glial cells missing 1 (GCM1), which encodes a transcription factor that is involved in epigenetic regulation and is critical for the fusion of syncytiotrophoblast (ST) cells. Here we show that ß-catenin/BCL9-Like (BCL9L)/T-cell factor 4 (TCF4) signalling directly targets the GCM1/syncytin pathway and thereby regulates the fusion of human choriocarcinoma cells. Furthermore, we show that the GCM1/syncytin-B pathway is significantly downregulated in the placenta of BCL9L-deficient mice and that the fusion and differentiation of ST-II cells are blocked. Our results demonstrate a signal transduction pathway that regulates cell fusion, and may provide intriguing perspectives into the various biological and pathological processes that involve cell fusion.


Asunto(s)
Fusión Celular , Proteínas Wnt/metabolismo , beta Catenina/metabolismo , Animales , Línea Celular Tumoral , Inmunoprecipitación de Cromatina , Proteínas de Unión al ADN , Femenino , Productos del Gen env/genética , Productos del Gen env/metabolismo , Humanos , Masculino , Ratones , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Neuropéptidos/genética , Neuropéptidos/metabolismo , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Reacción en Cadena de la Polimerasa , Embarazo , Proteínas Gestacionales/genética , Proteínas Gestacionales/metabolismo , Transducción de Señal/genética , Transducción de Señal/fisiología , Proteína 2 Similar al Factor de Transcripción 7/genética , Proteína 2 Similar al Factor de Transcripción 7/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Trofoblastos/citología , Trofoblastos/metabolismo , Proteínas Wnt/genética , beta Catenina/genética
9.
Genes Dev ; 22(9): 1244-56, 2008 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-18451111

RESUMEN

Cadherins mediate Ca2+-dependent cell-cell adhesion. Efficient export of cadherins from the endoplasmic reticulum (ER) is known to require complex formation with beta-catenin. However, the molecular mechanisms underlying this requirement remain elusive. Here we show that PX-RICS, a beta-catenin-interacting GTPase-activating protein (GAP) for Cdc42, mediates ER-to-Golgi transport of the N-cadherin/beta-catenin complex. Knockdown of PX-RICS expression induced the accumulation of the N-cadherin/beta-catenin complex in the ER and ER exit site, resulting in a decrease in cell-cell adhesion. PX-RICS was also required for ER-to-Golgi transport of the fibroblast growth factor-receptor 4 (FGFR4) associated with N-cadherin. PX-RICS-mediated ER-to-Golgi transport was dependent on its interaction with beta-catenin, phosphatidylinositol-4-phosphate (PI4P), Cdc42, and its novel binding partner gamma-aminobutyric acid type A receptor-associated protein (GABARAP). These results suggest that PX-RICS ensures the efficient entry of the N-cadherin/beta-catenin complex into the secretory pathway, and thereby regulates the amount of N-cadherin available for cell adhesion and FGFR4-mediated signaling.


Asunto(s)
Cadherinas/metabolismo , Retículo Endoplásmico/metabolismo , Proteínas Activadoras de GTPasa/metabolismo , Aparato de Golgi/metabolismo , beta Catenina/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Proteínas Reguladoras de la Apoptosis , Línea Celular , Línea Celular Tumoral , Células Cultivadas , Células Madre Embrionarias/citología , Células Madre Embrionarias/metabolismo , Fibroblastos/citología , Fibroblastos/metabolismo , Proteínas Activadoras de GTPasa/genética , Células HeLa , Humanos , Ratones , Ratones Noqueados , Proteínas Asociadas a Microtúbulos/genética , Proteínas Asociadas a Microtúbulos/metabolismo , Fosfatos de Fosfatidilinositol/metabolismo , Unión Proteica , Transporte de Proteínas , Interferencia de ARN , Receptor Tipo 4 de Factor de Crecimiento de Fibroblastos/metabolismo , Transducción de Señal , Proteína de Unión al GTP cdc42/metabolismo
10.
Genes Cells ; 12(8): 929-39, 2007 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-17663722

RESUMEN

In our previous study, we identified RICS, a novel beta-catenin-interacting protein with the GAP activity toward Cdc42 and Rac1, and found that RICS plays an important role in the regulation of neural functions, including postsynaptic NMDA signaling and neurite outgrowth. Here we report the characterization of an N-terminal splicing variant of RICS, termed PX-RICS, which has additional phox homology (PX) and src homology 3 (SH3) domains in its N-terminal region. The PX domain of PX-RICS interacted specifically with phosphatidylinositol 3-phosphate [PtdIns(3)P], PtdIns(4)P and PtdIns(5)P. Consistent with this binding affinity, PX-RICS was found to be localized at the endoplasmic reticulum (ER), Golgi and endosomes. We also found that wild-type PX-RICS possessed much lower GAP activity than RICS, whereas a mutant form of PX-RICS whose PX domain lacks the binding ability to phosphoinositides (PIs) exhibited the GAP activity comparable to that of RICS. However, PX-RICS and RICS exhibited similar inhibitory effects on neurite elongation of Neuro-2a cells. Furthermore, we demonstrate that PX-RICS is a main isoform expressed during neural development. Our results suggest that PX-RICS is involved in early brain development including extension of axons and dendrites, and postnatal remodeling and fine-tuning of neural circuits.


Asunto(s)
Empalme Alternativo/genética , Proteínas Activadoras de GTPasa/metabolismo , Sistema Nervioso/embriología , Sistema Nervioso/metabolismo , Secuencia de Aminoácidos , Animales , Cadherinas/metabolismo , Línea Celular , Clonación Molecular , ADN Complementario , Homólogo 4 de la Proteína Discs Large , Retículo Endoplásmico/metabolismo , Endosomas/metabolismo , Proteínas Activadoras de GTPasa/química , Proteínas Activadoras de GTPasa/genética , Aparato de Golgi/metabolismo , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Proteínas de la Membrana/metabolismo , Ratones , Datos de Secuencia Molecular , Neuritas/metabolismo , Fosfatos de Fosfatidilinositol/metabolismo , Isoformas de Proteínas/química , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Estructura Terciaria de Proteína , Transporte de Proteínas , Receptores de N-Metil-D-Aspartato/metabolismo , beta Catenina/metabolismo
11.
Biochem Biophys Res Commun ; 343(4): 1186-90, 2006 May 19.
Artículo en Inglés | MEDLINE | ID: mdl-16580634

RESUMEN

The LKB1/STK11 serine/threonine kinase is mutated in Peutz-Jeghers syndrome and various sporadic cancers such as lung adenocarcinoma. We show here that LKB1 forms a complex with LMO4, GATA-6, and Ldb1, and enhances GATA-mediated transactivation in a kinase-dependent manner. We further demonstrate that LKB1 has the potential to induce p21 expression in collaboration with LMO4, GATA-6, and Ldb1 through the p53-independent mechanism. Our findings suggest that LKB1 regulates GATA-mediated gene expression and that this activity of LKB1 may be important for its tumor suppressor function.


Asunto(s)
Inhibidor p21 de las Quinasas Dependientes de la Ciclina/biosíntesis , Proteínas de Unión al ADN/metabolismo , Factor de Transcripción GATA6/metabolismo , Proteínas de Homeodominio/metabolismo , Proteínas Serina-Treonina Quinasas/metabolismo , Factores de Transcripción/metabolismo , Quinasas de la Proteína-Quinasa Activada por el AMP , Proteínas Adaptadoras Transductoras de Señales , Animales , Línea Celular , Chlorocebus aethiops , Humanos , Proteínas con Dominio LIM , Unión Proteica , Activación Transcripcional , Proteína p53 Supresora de Tumor/fisiología , Técnicas del Sistema de Dos Híbridos , Regulación hacia Arriba
12.
Biochem Biophys Res Commun ; 320(3): 680-4, 2004 Jul 30.
Artículo en Inglés | MEDLINE | ID: mdl-15240101

RESUMEN

BAMBI is a transmembrane glycoprotein related to the transforming growth factor-beta (TGF-beta)-family type I receptors and functions as a negative regulator of TGF-beta signaling during development. BAMBI is induced by BMP signaling through the evolutionary conserved BMP-responsive elements in its promoter. Furthermore, we have recently shown that Wnt/beta-catenin signaling activates transcription of BAMBI and that BAMBI expression is aberrantly elevated in most colorectal carcinomas. Here, we show that BAMBI is also directly induced by TGF-beta signaling, through the three tandem repeats of 13 bp sequences containing the SMAD-binding elements, which are distinct from the BMP-responsive element. Our findings suggest that BAMBI transcription is regulated by TGF-beta signaling through direct binding of SMAD3 and SMAD4 to the BAMBI promoter.


Asunto(s)
Hepatoblastoma/metabolismo , Proteínas de la Membrana/metabolismo , Transducción de Señal , Activación Transcripcional , Factor de Crecimiento Transformador beta/metabolismo , Proteínas de Xenopus , Línea Celular Tumoral , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Genes Reguladores/genética , Hepatoblastoma/genética , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Proteínas de la Membrana/genética , Factores de Crecimiento Nervioso , Regiones Promotoras Genéticas , Receptores de Factores de Crecimiento Transformadores beta/genética , Receptores de Factores de Crecimiento Transformadores beta/metabolismo , Proteínas Smad , Proteína smad3 , Proteína Smad4 , Transactivadores/genética , Transactivadores/metabolismo , Factor de Crecimiento Transformador beta/genética
13.
Genes Cells ; 7(6): 607-17, 2002 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-12059963

RESUMEN

BACKGROUND: The PSD-95 family of proteins possesses multiple protein binding domains, including three PDZ domains, an SH3 domain, a HOOK domain and a guanylate kinase-like (GK) domain. The PSD-95 proteins function as scaffolding proteins that link ion channels such as the N-methyl-d-aspartate-receptors (NMDA-Rs) with cytoskeletal networks and signalling molecules, thereby controlling synaptic plasticity and learning. RESULTS: We found that the PSD-95 family proteins interact via their GK domains with SPA-1-like protein (SPAL), a GTPase-activating protein (GAP) that is specific for Rap1. SPAL was contained within the NMDA-R-PSD-95 complex, and co-localized with PSD-95 and NMDA-R at the synapses in cultured hippocampal neurones. Furthermore, NMDA stimulation induced the dephosphorylation of SPAL in cultured hippocampal neurones. CONCLUSION: Our findings suggest that SPAL may be involved in the NMDA-mediated organization of cytoskeletal networks and signal transduction.


Asunto(s)
Proteínas Activadoras de GTPasa/metabolismo , Hipocampo/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Proteínas de Unión al GTP rap1/metabolismo , Animales , Células Cultivadas , Homólogo 4 de la Proteína Discs Large , Células HeLa , Humanos , Péptidos y Proteínas de Señalización Intracelular , Proteínas de la Membrana , Neuronas , Pruebas de Precipitina , Ratas , Técnicas del Sistema de Dos Híbridos
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