Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The LDL receptor-related protein 1 (LRP1) is a multifunctional cell surface receptor that is highly expressed on neurons. Neuronal LRP1 in vitro can mediate ligand endocytosis, as well as modulate signal transduction processes. However, little is known about its role in the intact nervous system. Here, we report that mice that lack LRP1 selectively in differentiated neurons develop severe behavioral and motor abnormalities, including hyperactivity, tremor, and dystonia. Since their central nervous systems appear histoanatomically normal, we suggest that this phenotype is likely attributable to abnormal neurotransmission. This conclusion is supported by studies of primary cultured neurons that show that LRP1 is present in close proximity to the N-methyl-D-aspartate (NMDA) receptor in dendritic synapses and can be coprecipitated with NMDA receptor subunits and the postsynaptic density protein PSD-95 from neuronal cell lysates. Moreover, treatment with NMDA, but not dopamine, reduces the interaction of LRP1 with PSD-95, indicating that LRP1 participates in transmitter-dependent postsynaptic responses. Together, these findings suggest that LRP1, like other ApoE receptors, can modulate synaptic transmission in the brain.
Mol Cell Biol 2004 Oct
PMID:Neuronal LRP1 functionally associates with postsynaptic proteins and is required for normal motor function in mice. 1545 62

Synaptic cell adhesion and synaptogenesis are thought to involve the interaction of neuroligin, a postsynaptic transmembrane protein, with its presynaptic ligand neurexin. Neuroligin also interacts with SAP90/PSD95, a multidomain scaffolding protein thought to recruit proteins to postsynaptic sites. Using expression of GFP-tagged versions of neuroligin in cultured hippocampal neurons, we find that neuroligin is targeted to synapses via intracellular sequences distinct from its SAP90/PSD95 binding site. A neuroligin mutant lacking the intracellular domain fails to target to synapses. These data indicate that postsynaptic targeting of neuroligin does not rely on the scaffolding action of SAP90/PSD95 and is not induced by binding to presynaptic neurexin. Neuroligin is rather targeted to synapses via a postsynaptic mechanism, which may precede and be necessary for subsequent recruitment of neurexin and other neuroligin interactors such as SAP90/PSD95, suggesting a pivotal position for neuroligin in a putative hierarchy of interactions assembling or stabilizing synapses.
Mol Cell Neurosci 2004 Nov
PMID:Synaptic targeting of neuroligin is independent of neurexin and SAP90/PSD95 binding. 1551 38

S-SCAM has a similar molecular organization to PSD-95. Both of them interact with a cell adhesion molecule, neuroligin. We previously reported that beta-catenin binds S-SCAM and recruits it to synapses. We have here examined using rat primary cultured neurons whether neuroligin recruits S-SCAM to synapses or S-SCAM determines the localization of neuroligin. Overexpressed neuroligin formed larger clusters under co-expression of S-SCAM but not of PSD-95. Overexpressed neuroligin blocked synaptic accumulation of PSD-95 but not of S-SCAM. S-SCAM mutant containing the neuroligin-binding region interfered with synaptic accumulation of neuroligin and PSD-95, whereas the similar mutant of PSD-95 had no effect. Biochemical studies revealed that neuroligin forms a ternary complex with S-SCAM and PSD-95 through manifold interactions. These findings imply that S-SCAM is tethered by beta-catenin to synapses and induces synaptic accumulation of neuroligin, which subsequently recruits PSD-95 to synapses.
Mol Cell Neurosci 2004 Dec
PMID:Synaptic scaffolding molecule is involved in the synaptic clustering of neuroligin. 1555 27

The folding pathway of the third domain of PDZ from the synaptic protein PSD-95 was characterized using kinetic and equilibrium methods by monitoring the fluorescence signal from a Trp residue that is incorporated at a near-surface position. Kinetic folding of this domain showed multiple exponential phases, whereas unfolding showed a single exponential phase. The slow kinetic phases were attributed to isomerization of proline residues, since there are five proline residues in this domain. We found that the logarithms of the rate constants for the fast phase of folding and unfolding are linearly dependent on the concentrations of denaturant. The unfolding free energy derived from these rate constants at zero denaturant was close to the value measured using the equilibrium method, suggesting the absence of detectable sub-millisecond folding intermediates. However, native-state hydrogen exchange experiments detected a partially unfolded intermediate under native conditions. It was further confirmed by a protein engineering study. These data suggest that a hidden intermediate exists after the rate-limiting step in the folding of the third domain of PDZ.
J Mol Biol 2005 Feb 11
PMID:Detection of a hidden folding intermediate of the third domain of PDZ. 1566 49

Synaptogenesis is a highly controlled process, involving a vast array of players which include cell adhesion molecules, scaffolding and signaling proteins, neurotransmitter receptors and proteins associated with the synaptic vesicle machinery. These molecules cooperate in an intricate manner on both the pre- and postsynaptic sides to orchestrate the precise assembly of neuronal contacts. This is an amazing feat considering that a single neuron receives tens of thousands of synaptic inputs but virtually no mismatch between pre- and postsynaptic components occur in vivo. One crucial aspect of synapse formation is whether a nascent synapse will develop into an excitatory or inhibitory contact. The tight control of a balance between the types of synapses formed regulates the overall neuronal excitability, and is thus critical for normal brain function and plasticity. However, little is known about how this balance is achieved. This review discusses recent findings which provide clues to how neurons may control excitatory and inhibitory synapse formation, with focus on the involvement of the neuroligin family and PSD-95 in this process.
Mol Pain 2005 Mar 23
PMID:New players tip the scales in the balance between excitatory and inhibitory synapses. 1581 60

p55 is a membrane-associated guanylate kinase (MAGuK) family member that consists of a single PDZ followed by SH3, HOOK and guanylate kinase (GuK or GK) domains. We investigated rat p55 (r-p55) in the brain. r-p55 mRNA was expressed widely in various tissues and in various regions of the brain. r-p55 protein was also expressed widely in various rat tissues, including brain and erythrocytes. The protein was enriched in the synaptic plasma membrane and postsynaptic density (PSD) fractions of the forebrain. An immunocytochemical study using cultured cortical neurons suggested postsynaptic localization of r-p55 protein. Pull-down assay showed that r-p55 protein interacted with r-p55 itself and various PSD proteins, such as PSD-95, SAP97, GKAP, CASK, GRIP, neuroligin, cadherin, tubulin, actin, alpha-internexin, neurofilament-L and Ca(2+)/calmodulin-dependent protein kinase II, through its PDZ, SH3, HOOK or GK domains. The interaction with PSD-95 was found to occur between the PDZ domains of PSD-95 and the HOOK and GK domains of r-p55 protein. These findings, together with the presence of r-p55 puncta in a period of early synaptogenesis, suggest that r-p55 protein functions as one of postsynaptic scaffold component in an early stage of synaptogenesis in the brain. r-p55 protein may form a basic structure, which interlinks diverse functional molecules of the PSD necessary for postsynaptic signaling and synaptic adhesion.
Brain Res Mol Brain Res 2005 Apr 27
PMID:p55 protein is a member of PSD scaffold proteins in the rat brain and interacts with various PSD proteins. 1585 83

In glutamatergic synapses, glutamate receptors (GluRs) associate with many other proteins involved in scaffolding and signal transduction. The ontogeny of these postsynaptic density (PSD) proteins involves changes in their composition during development, paralleling changes in GluR type and function. In the CA1 region of the hippocampus, at postnatal day 2 (P2), many synapses already have a distinct PSD. We used immunoblot analysis, subcellular fractionation, and quantitative immunogold electron microscopy to examine the distribution of PSD proteins during development of the hippocampus. Synapses at P2 contained substantial levels of NR1 and NR2B and most GluR-associated proteins, including SAP102, SynGAP, the chain of proteins from GluRs/SAP102 through GKAP/Shank/Homer and metabotropic glutamate receptors, and the adhesion factors, cadherin, catenin, neuroligin, and Nr-CAM. Development was marked by substantial decreases in NR2B and SAP102 and increases in NR2A, PSD-95, AMPA receptors, and CaMKII. Other components showed more moderate changes.
Mol Cell Neurosci 2005 Jul
PMID:Ontogeny of postsynaptic density proteins at glutamatergic synapses. 1589 89

We examined the regulation of dendritic spines and synapses by epileptiform activity (EA) in rat hippocampal slice cultures. EA, which was induced by a GABA(A) receptor inhibitor, gabazine, reduced pyramidal neuron spine density by approximately 50% after 48 h and also caused an increase in the average length of remaining spines. To directly determine the effects of EA on synapses, we used fluorescent protein-tagged PSD95, which marks postsynaptic densities. EA induced a net loss of synapses on spines but not shafts; conversely, activity blockade (TTX) induced a loss of shaft synapses. Time-lapse confocal imaging in live tissue slices revealed that EA (1) shifts the balance of synapse gain and loss in dendrites leading to a net loss of spine synapses and (2) induces the formation of new filopodia-like dendritic structures having abnormally slow motility. These results identify EA-induced changes in the density and distribution of synaptic structures on dendrites.
Mol Cell Neurosci 2005 Aug
PMID:Regulation of hippocampal synapse remodeling by epileptiform activity. 1595 36

A variety of experimental evidence suggests that rapid, long-range propagation of conformational changes through the core of proteins plays a vital role in allosteric communication. Here, we describe a non-equilibrium molecular dynamics simulation method, anisotropic thermal diffusion (ATD), which allowed us to observe a dominant intramolecular signaling pathway in PSD-95, a member of the PDZ domain protein family. The observed pathway is in good accordance with a pathway previously inferred using a multiple sequence analysis of 276 PDZ domain proteins. In comparison with conventional solution molecular dynamics methods, the ATD method provides greatly enhanced signal-to-noise, allowing long-distance correlations to be observed clearly. The ATD method requires neither a large number of homologous proteins, nor extremely long simulation times to obtain a complete signaling pathway within a protein. Therefore, the ATD method should prove to be a powerful and general complement to experimental efforts to understand the physical basis of intramolecular signaling.
J Mol Biol 2005 Aug 12
PMID:Intramolecular signaling pathways revealed by modeling anisotropic thermal diffusion. 1600 93

Drebrin A is a neuron-specific F-actin binding protein, and plays a pivotal role in the spine formation. In this study, we expressed drebrin A tagged with green fluorescent protein (GFP-DA) in hippocampal neurons at 7-9 days in vitro when presynaptic terminals are not fully maturated. GFP-DA was accumulated in dendritic protrusions and formed large abnormal structures. Since these structures were similar to filopodia in terms of lack of MAP2 immunostaining, we named them "megapodia" meaning large dendritic filopodia. F-actin and PSD-95 were also accumulated in megapodia, and their amounts were significantly correlated with that of GFP-DA. However, the expression of GFP-DA did not result in the promotion of the morphological change from filopodia into spines. These results demonstrate that drebrin A accumulates spine-resident proteins via protein-protein interaction in filopodia, and suggest that the spine formation requires the concurrence of the increase of drebrin-A expression and the functional presynaptic contact.
Mol Cell Neurosci 2005 Sep
PMID:Overexpression of drebrin A in immature neurons induces the accumulation of F-actin and PSD-95 into dendritic filopodia, and the formation of large abnormal protrusions. 1645 30


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