Purification of an Arg-Gly-Asp selective matrix receptor from brain synaptic plasma membranes

Bahr, Ben A.; Lynch, Gary

doi:10.1042/bj2810137

Cited by 35 publications

(20 citation statements)

References 36 publications

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“…2A). These observations support and extend previous studies that showed high expression of ␣5 integrin in pyramidal neurons in the hippocampus and in hippocampal synapses (21,22). Our results suggest that activity-induced changes at synapses promote ␣5 targeting to these sites, which is consistent with ␣5 signaling playing a regulatory role in synaptic function.…”

Section: Resultssupporting

confidence: 81%

α5 Integrin Signaling Regulates the Formation of Spines and Synapses in Hippocampal Neurons

Webb

Zhang

Majumdar

et al. 2007

Journal of Biological Chemistry

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The actin-based dynamics of dendritic spines play a key role in synaptic plasticity, which underlies learning and memory. Although it is becoming increasingly clear that modulation of actin is critical for spine dynamics, the upstream molecular signals that regulate the formation and plasticity of spines are poorly understood. In non-neuronal cells, integrins are critical modulators of the actin cytoskeleton, but their function in the nervous system is not well characterized. Here we show that ␣5 integrin regulates spine morphogenesis and synapse formation in hippocampal neurons. Knockdown of ␣5 integrin expression using small interfering RNA decreased the number of dendritic protrusions, spines, and synapses. Expression of constitutively active or dominant negative ␣5 integrin also resulted in alterations in the number of dendritic protrusions, spines, and synapses. ␣5 integrin signaling regulates spine morphogenesis and synapse formation by a mechanism that is dependent on Src kinase, Rac, and the signaling adaptor GIT1. Alterations in the activity or localization of these molecules result in a significant decrease in the number of spines and synapses. Thus, our results point to a critical role for integrin signaling in regulating the formation of dendritic spines and synapses in hippocampal neurons.Integrins are heterodimeric, transmembrane cell surface receptors that mediate cell-cell and cell-matrix interactions. Integrin cytoplasmic domains bind to signaling molecules and other components of the actin cytoskeleton and provide a functional link between the extracellular environment and the interior of the cell. In this way, integrins can initiate and regulate several different signal transduction pathways in both neuronal and non-neuronal cells. A modest, emerging literature implicates integrins in learning and memory in both invertebrate and vertebrate species. A mutation in a synapse-associated integrin ␣ subunit (vol) in Drosophila impairs short term memory processes (1). Mice with reduced expression of the ␣3, ␣5, or ␣8 integrins are defective in hippocampal long term potentiation and spatial memory (2). In addition, function-blocking antibodies against the ␣5 integrin significantly reduce long term potentiation stabilization in the rat hippocampus (3). Taken together, these studies suggest that integrins regulate some processes underlying memory formation; however, the mechanism by which integrins do this remains unknown.A number of studies associate changes in the number, size, and shape of dendritic spines with synaptic plasticity, which underlies learning and memory, and with neurological disorders, such as mental retardation, epilepsy, schizophrenia, and Alzheimer disease (4 -7). Dendritic spines are small, actin-rich protrusions that function as bridges between axons and dendrites and serve as sites of post-synaptic contact and signal integration for most of the excitatory synapses in the central nervous system (8 -10). Available data suggest that the morphological plasticity of dendritic spines i...

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Section: Resultssupporting

confidence: 81%

α5 Integrin Signaling Regulates the Formation of Spines and Synapses in Hippocampal Neurons

Webb

Zhang

Majumdar

et al. 2007

Journal of Biological Chemistry

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“…Adhesion responses responsible for synaptic conformation likely are mediated by integrin-type matrix receptors found expressed in the adult brain and, in many instances, appropriately localized to synaptic contacts (Bahr and Lynch, 1992;Grooms et al, 1993;Einheber et al, 1996;Nishimura et al, 1998;Pinkstaff et al, 1998Pinkstaff et al, , 1999. In concordance with the physiology studies, matrix receptors purified from synaptic membranes adhere to matrix proteins via the RGDS integrin target sequence and respond to the same diverse pharmacological agents that influence LTP stabilization (Bahr and Lynch, 1992;Bahr et al, 1997;Capaldi et al, 1997).…”

Section: Discussionmentioning

confidence: 91%

Integrin-type signaling has a distinct influence on NMDA-induced cytoskeletal disassembly

Bahr

2000

J. Neurosci. Res.

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Adhesion responses triggered by integrin-class matrix receptors have been implicated in the synaptic reorganization events necessary for certain types of neuronal plasticity. Hippocampal slice cultures were used to test whether the related structural transformations elicited by NMDA receptor stimulation are regulated by integrin-type signals. Infusing the slices with NMDA for a short period induced the expected disassembly of the cytoskeletal network, measured with antibodies that selectively recognize spectrin cleavage sites targeted by the protease calpain. Marked levels of the 150-kDa breakdown product (BDP) were produced, whereas concentrations of the parent spectrin were not changed. Interestingly, the calpain cleavage events were attenuated by 60% when integrin-type signaling was disrupted with the antagonist Gly-Arg-Gly-Asp-Ser-Pro (GRGDSP). This effect was RGDS-dependent, was largely evident in synapse-dense dendritic areas, particularly in subfield CA1, and was abolished when the NMDA exposure period was >5 min. These findings suggest that only those cytoskeletal alterations associated with brief synaptic activity are regulated by intact contact zones. AMPA-type glutamate receptors also were tested because, like spectrin, they are targets for calpain. Brief NMDA treatment caused a 15% loss of AMPA receptor GluR1 carboxytermini and this modification was augmented to 32% in the presence of GRGDSP. Thus, although blockage of matrix recognition signals decreased spectrin's susceptibility to disassembly, it increased the susceptibility of AMPA receptors to proteolysis. These data indicate that integrin-type signaling complexes are appropriately positioned to govern cytoskeletal reconfiguration while stabilizing the structural nature of AMPA receptors.

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“…Indeed, the PSD-enriched PAC 1 glycoproteins (6, 7) have been identified as members of the cadherin family (8), providing evidence for such a role. Furthermore, integrin-type adhesion molecules (9) and NCAM (10), a member of the immunoglobulin (Ig) superfamily, have been recognized as SM components. Considering the complex interplay between stabilization and plasticity at synaptic connections, it is likely that more synaptic glycoproteins with adhesive functions are to be identified.…”

mentioning

confidence: 99%

Synaptic Membrane Glycoproteins gp65 and gp55 Are New Members of the Immunoglobulin Superfamily

Langnaese

Beesley

Gundelfinger

1997

Journal of Biological Chemistry

104

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Glycoproteins gp65 and gp55 are major components of synaptic membranes prepared from rat forebrain. Both are recognized by the monoclonal antibody SMgp65. We have used SMgp65 to screen a rat brain cDNA expression library. Two sets of overlapping cDNAs that contain open reading frames of 397 and 281 amino acids were isolated. The deduced proteins are members of the immunoglobulin (Ig) superfamily containing three and two Ig domains, respectively. The common part has ϳ40% sequence identity with neurothelin/basigin. The identity of the proteins as gp65 and gp55 was confirmed by production of new antisera against a common recombinant protein fragment. These antisera immunoprecipitate gp65 and gp55. Furthermore, expression of gp65 and gp55 cDNAs in human 293 cells treated with tunicamycin results in the production of unglycosylated core proteins of identical size to deglycosylated gp65 and gp55. Northern analysis revealed that gp65 transcripts are brain-specific, whereas gp55 is expressed in most tissues and cell lines examined. The tissue distribution was confirmed at the protein level though the pattern of glycosylation of gp55 varies between tissues. In situ hybridization experiments with a common and a gp65-specific probe suggest differential expression of gp65 and gp55 transcripts in the rat brain.Synaptic junctions are highly specialized areas of contact and communication between neurons. They comprise the membranes and the underlying cytoskeleton of the pre-and postsynaptic neurons. In particular, the postsynaptic nerve ending is characterized by the presence of an electron-dense cytoskeletal structure, the postsynaptic density (PSD) 1 , which underlies the postsynaptic membrane. It is well established that synaptic structures and biochemically isolated synaptic subfractions, particularly synaptic membrane (SM) and PSD fractions, are enriched in distinct sets of glycoproteins that bind the lectin concanavalin A (1, 2). Some of these glycoproteins have been identified and their functions established. These include the major 180-kDa PSD glycoprotein that corresponds to the NR2B subunit of the N-methyl-D-aspartate receptor (3) and the SMenriched glycoprotein, gp50, that has been identified as the ␤2 subunit of the Na ϩ /K ϩ -ATPase (4, 5). SM and PSD glycoproteins, which are oriented with their oligosaccharide-containing domains facing into the synaptic cleft, are ideally placed to mediate adhesive interactions between the pre-and postsynaptic nerve endings. Indeed, the PSD-enriched PAC 1 glycoproteins (6, 7) have been identified as members of the cadherin family (8), providing evidence for such a role. Furthermore, integrin-type adhesion molecules (9) and NCAM (10), a member of the immunoglobulin (Ig) superfamily, have been recognized as SM components. Considering the complex interplay between stabilization and plasticity at synaptic connections, it is likely that more synaptic glycoproteins with adhesive functions are to be identified.Here we describe the molecular cloning of cDNAs encoding two synaptic glycopr...

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Purification of an Arg-Gly-Asp selective matrix receptor from brain synaptic plasma membranes

Cited by 35 publications

References 36 publications

α5 Integrin Signaling Regulates the Formation of Spines and Synapses in Hippocampal Neurons

α5 Integrin Signaling Regulates the Formation of Spines and Synapses in Hippocampal Neurons

Integrin-type signaling has a distinct influence on NMDA-induced cytoskeletal disassembly

Synaptic Membrane Glycoproteins gp65 and gp55 Are New Members of the Immunoglobulin Superfamily

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