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PubMed1993

Identification of a cell line that expresses a cell surface and a soluble form of the gp330/receptor-associated protein (RAP) Heymann nephritis antigenic complex.

gp330 is a large glycoprotein located in clathrin-coated pits at the surface of the glomerular and proximal tubule epithelia in the rat kidney. It was originally identified as the target of autoimmune antibodies in Heymann nephritis (HN) and has since been shown to be a member of the low density lipoprotein receptor gene family and to form a stable association with receptor-associated protein (RAP), which together constitute the HN antigen complex (HNAC). Progress in defining the normal functions of gp330 as well as the molecular mechanisms of HN has been hampered by the lack of an available kidney cell line that expresses this protein. We here report the identification of a rat yolk sac carcinoma cell line (L2) that synthesizes HNAC and expresses it in coated pits at the cell surface. gp330 and RAP from L2 cells are immunologically identical to their kidney counterparts, and peptide maps of gp330 yielded identical peptide fragments. Characterization of the cell line revealed that there are 3.3 x 10(4) gp330 molecules per L2 cell and that the cells produce a soluble form of gp330 that is released into the medium. Heparin ligand blot analysis demonstrated that RAP but not gp330 binds heparin. By heparin affinity chromatography, gp330 and RAP copurify, indicating that the glycosaminoglycan binding site within RAP is accessible when the subunit is complexed with gp330. These results indicate that the L2 cell line provides a valid and useful model for studies on the function of HNAC and the pathogenesis of HN.

Animals↗

PubMed1998

lambda Rap protein is a structure-specific endonuclease involved in phage recombination.

Bacteriophage lambda encodes a number of genes involved in the recombinational repair of DNA double-strand breaks. The product of one of these genes, rap, has been purified. Truncated Rap proteins that copurify with the full-length form are derived, at least in part, from a rho-dependent transcription terminator located within its coding sequence. Full-length and certain truncated Rap polypeptides bind preferentially to branched DNA substrates, including synthetic Holliday junctions and D-loops. In the presence of manganese ions, Rap acts as an endonuclease that cleaves at the branch point of Holliday and D-loop substrates. It shows no obvious sequence preference or symmetry of cleavage on a Holliday junction. The biochemical analysis of Rap gives an insight into how recombinants could be generated by the nicking of a D-loop without the formation of a classical Holliday junction.

Bacteriophage lambda↗

PubMed2001

Internalization of transthyretin. Evidence of a novel yet unidentified receptor-associated protein (RAP)-sensitive receptor.

Transthyretin (TTR) is a plasma carrier of thyroxine and retinol-binding protein (RBP). Though the liver is the major site of TTR degradation, its cellular uptake is poorly understood. We explored TTR uptake using hepatomas and primary hepatocytes and showed internalization by a specific receptor. RBP complexed with TTR led to a 70% decrease of TTR internalization, whereas TTR bound to thyroxine led to a 20% increase. Different TTR mutants showed differences in uptake, suggesting receptor recognition dependent on the structure of TTR. Cross-linking studies using hepatomas and (125)I-TTR revealed a approximately 90-kDa complex corresponding to (125)I-TTR bound to its receptor. Given previous evidence that a fraction of TTR is associated with high-density lipoproteins (HDL) and that in the kidney, megalin, a member of the low-density lipoprotein receptor family (LDLr) internalizes TTR, we hypothesized that TTR and lipoproteins could share related degradation pathways. Using lipid-deficient serum in uptake assays, no significant changes were observed showing that TTR uptake is not lipoprotein-dependent or due to TTR-lipoprotein complexes. However, competition studies showed that lipoproteins inhibit TTR internalization. The scavenger receptor SR-BI, a HDL receptor, and known LDLr family hepatic receptors did not mediate TTR uptake as assessed using different cellular systems. Interestingly, the receptor-associated protein (RAP), a ligand for all members of the LDLr, was able to inhibit TTR internalization. Moreover, the approximately 90-kDa TTR-receptor complex obtained by cross-linking was sensitive to the presence of RAP. To confirm that RAP sensitivity observed in hepatomas did not represent a mechanism absent in normal cells, primary hepatocytes were tested, and similar results were obtained. The RAP-sensitive TTR internalization together with displacement of TTR uptake by lipoproteins, further suggests that a common pathway might exist between TTR and lipoprotein metabolism and that an as yet unidentified RAP-sensitive receptor mediates TTR uptake.

Animals↗

PubMed2003

Activation of JNK by Epac is independent of its activity as a Rap guanine nucleotide exchanger.

Guanine nucleotide exchange factors (GEFs) and their associated GTP-binding proteins (G-proteins) are key regulatory elements in the signal transduction machinery that relays information from the extracellular environment into specific intracellular responses. Among them, the MAPK cascades represent ubiquitous downstream effector pathways. We have previously described that, analogous to the Ras-dependent activation of the Erk-1/2 pathway, members of the Rho family of small G-proteins activate the JNK cascade when GTP is loaded by their corresponding GEFs. Searching for novel regulators of JNK activity we have identified Epac (exchange protein activated by cAMP) as a strong activator of JNK-1. Epac is a member of a growing family of GEFs that specifically display exchange activity on the Rap subfamily of Ras small G-proteins. We report here that while Epac activates the JNK severalfold, a constitutively active (G12V) mutant of Rap1b does not, suggesting that Rap-GTP is not sufficient to transduce Epac-dependent JNK activation. Moreover, Epac signaling to the JNKs was not blocked by inactivation of endogenous Rap, suggesting that Rap activation is not necessary for this response. Consistent with these observations, domain deletion mutant analysis shows that the catalytic GEF domain is dispensable for Epac-mediated activation of JNK. These studies identified a region overlapping the Ras exchange motif domain as critical for JNK activation. Consistent with this, an isolated Ras exchange motif domain from Epac is sufficient to activate JNK. We conclude that Epac signals to the JNK cascade through a new mechanism that does not involve its canonical catalytic action, i.e. Rap-specific GDP/GTP exchange. This represents not only a novel way to activate the JNKs but also a yet undescribed mechanism of downstream signaling by Epac.

Amino Acid Motifs↗

PubMed2005

Transcriptional Co-activators CREB-binding protein/p300 increase chondrocyte Cd-rap gene expression by multiple mechanisms including sequestration of the repressor CCAAT/enhancer-binding protein.

Cartilage-derived retinoic acid-sensitive protein (CD-RAP) is a small secreted matrix protein expressed in developing and adult cartilage and by chondrocytes in culture. We have previously shown that the expression of Cd-rap, like many other cartilage matrix proteins, is repressed by interleukin 1beta and that the transcription factor CCAAT/enhancer-binding protein (C/EBP) beta plays an important role in the interleukin 1beta-induced repression (Okazaki, K., Li, J., Yu, H., Fukui, N., and Sandell, L. J. (2002) J. Biol. Chem. 277, 31526-31533). The co-activators CREB-binding protein (CBP) and p300 are transcriptional co-regulators that participate in the activities of many different transcription factors including C/EBP. Here we show that CBP/p300 can reverse the inhibitory effect of C/EBP and moreover can stimulate expression of Cd-rap. The mechanism of this effect is shown to involve a unique synergy whereby CBP/p300 stimulate Cd-rap gene expression by at least two mechanisms. First, binding of CBP/p300 to C/EBPbeta leads to sequestration of C/EBP eliminating DNA binding and subsequent repression; second, binding of CBP/p300 to the transcriptional activator Sox9 increases Sox9 DNA binding to the Cd-rap promoter leading to further stimulation of gene transcription. This is an example of a complementary transcriptional network whereby two very different mechanisms act together to confer a functional increase in transcription. This new paradigm is likely generally applicable to cartilage genes as Col2a1 cartilage collagen gene responds similarly.

Animals↗

PubMed1989

Neuronal development in the Drosophila compound eye: rap gene function is required in photoreceptor cell R8 for ommatidial pattern formation.

In the compound eye of Drosophila, cell-cell interactions are thought to play an important role in the determination of neuronal cell fate and pattern morphogenesis. Recent work on the bride of sevenless (boss) gene has demonstrated an inductive role for photoreceptor R8 in the differentiation of photoreceptor R7. These studies have shown that while R8 differentiates early in the scheme of ommatidial assembly, it continues to play an active role in subsequent patterning events. We describe studies on a new genetic locus rap (retina aberrant in pattern), whose functions are critical for normal pattern formation in the developing eye. Mutations in the rap gene perturb the early stages of pattern formation and lead to a variable number of photoreceptor cells (R cells) in each ommatidium. Experiments with a temperature-sensitive allele have shown that rap gene function is required during the period of development when pattern formation occurs. In addition, a somatic mosaic analysis of rap has shown that its function is required only in photoreceptor cell R8 for normal ommatidial patterning. These studies suggest an important role for rap in the initial events leading to pattern formation and are consistent with R8 playing a central role in directing ommatidial pattern formation.

Animals↗

PubMed2005

Changes in the prevalence of alcohol use in rap song lyrics, 1979-97.

AIMS: This paper explores the role of changing images of drinking and alcoholic beverage use in rap music from its beginnings in the United States in the late 1970s to the late 1990s. DESIGN: A sample of 341 rap music song lyrics released from 1979 to 1997 were selected using Billboard and Gavin rating charts. Song lyrics were coded for music genres, alcohol beverage types and brand names, drinking behaviors, drinking contexts, intoxication, attitudes towards alcohol and consequences of drinking. FINDINGS: From 1979 to 1997, songs with references to alcohol increased fivefold (from 8 to 44%); those exhibiting positive attitudes rose from 43% to 73%; and brand name mentions increased from 46% to 71%. There were also significant increases in songs mentioning champagne and liquor (mainly expensive brand names) when comparing songs released after 1994 with those from previous years. In addition, there were significant increases in references to alcohol to signify glamour and wealth, and using alcohol with drugs and for recreational purposes. The findings also showed that alcohol use in rap music was much more likely to result in positive than negative consequences. CONCLUSIONS: Many of these findings are consistent with the idea that rap music has been profoundly affected by commercial forces and the marketing of alcoholic beverages. In addition, it is possible that the increase in references to alcoholic beverages in rap music, particularly spirits, is a reflection of a broader advertising culture which increasingly associates African Americans with alcohol use.

Advertising↗

PubMed2005

cAMP blocks MAPK activation and sclerotial development via Rap-1 in a PKA-independent manner in Sclerotinia sclerotiorum.

Sclerotinia sclerotiorum is a filamentous ascomycete phytopathogen able to infect an extremely wide range of cultivated plants. Our previous studies have shown that increases in cAMP levels result in the impairment of the development of the sclerotium, a highly differentiated structure important in the disease cycle of this fungus. cAMP also inhibits the activation of a S. sclerotiorum mitogen-activated protein kinase (MAPK), which we have previously shown to be required for sclerotial maturation; thus cAMP-mediated sclerotial inhibition is modulated through MAPK. However, the mechanism(s) by which cAMP inhibits MAPK remains unclear. Here we demonstrate that a protein kinase A (PKA)-independent signalling pathway probably mediates MAPK inhibition by cAMP. Expression of a dominant negative form of Ras, an upstream activator of the MAPK pathway, also inhibited sclerotial development and MAPK activation, suggesting that a conserved Ras/MAPK pathway is required for sclerotial development. Evidence from bacterial toxins that specifically inhibit the activity of small GTPases, suggested that Rap-1 or Ras is involved in cAMP action. The Rap-1 inhibitor, GGTI-298, restored MAPK activation in the presence of cAMP, further suggesting that Rap-1 is responsible for cAMP-dependent MAPK inhibition. Importantly, inhibition of Rap-1 is able to restore sclerotial development blocked by cAMP. Our results suggest a novel mechanism involving the requirement of Ras/MAPK pathway for sclerotial development that is negatively regulated by a PKA-independent cAMP signalling pathway. Cross-talk between these two pathways is mediated by Rap-1.

Ascomycota↗

PubMed2006

Modulation of the ComA-dependent quorum response in Bacillus subtilis by multiple Rap proteins and Phr peptides.

In Bacillus subtilis, extracellular peptide signaling regulates several biological processes. Secreted Phr signaling peptides are imported into the cell and act intracellularly to antagonize the activity of regulators known as Rap proteins. B. subtilis encodes several Rap proteins and Phr peptides, and the processes regulated by many of these Rap proteins and Phr peptides are unknown. We used DNA microarrays to characterize the roles that several rap-phr signaling modules play in regulating gene expression. We found that rapK-phrK regulates the expression of a number of genes activated by the response regulator ComA. ComA activates expression of genes involved in competence development and the production of several secreted products. Two Phr peptides, PhrC and PhrF, were previously known to stimulate the activity of ComA. We assayed the roles that PhrC, PhrF, and PhrK play in regulating gene expression and found that these three peptides stimulate ComA-dependent gene expression to different levels and are all required for full expression of genes activated by ComA. The involvement of multiple Rap proteins and Phr peptides allows multiple physiological cues to be integrated into a regulatory network that modulates the timing and magnitude of the ComA response.

Bacillus subtilis↗

PubMed2006

Rap phosphatase of virulence plasmid pXO1 inhibits Bacillus anthracis sporulation.

This study shows that the Bacillus anthracis pXO1 virulence plasmid carries a Rap-Phr system, BXA0205, which regulates sporulation initiation in this organism. The BXA0205Rap protein was shown to dephosphorylate the Spo0F response regulator intermediate of the phosphorelay signal transduction system that regulates the initiation of the developmental pathway in response to environmental, metabolic, and cell cycle signals. The activity of the Rap protein was shown to be inhibited by the carboxy-terminal pentapeptide generated through an export-import processing pathway from the associated BXA0205Phr protein. Deregulation of the Rap activity by either overexpression or lack of the Phr pentapeptide resulted in severe inhibition of sporulation. Five additional Rap-Phr encoding systems were identified on the chromosome of B. anthracis, one of which, BA3790-3791, also affected sporulation initiation. The results suggest that the plasmid-borne Rap-Phr system may provide a selective advantage to the virulence of B. anthracis.

Amino Acid Sequence↗

PubMed2004

Early activation of the Kaposi's sarcoma-associated herpesvirus RTA, RAP, and MTA promoters by the tetradecanoyl phorbol acetate-induced AP1 pathway.

Kaposi's sarcoma-associated herpesvirus (KSHV) maintains a latent infection in primary effusion lymphoma (PEL) cells, but treatment with tetradecanoyl phorbol acetate (TPA) can trigger the full lytic-cycle replication in some of these cells. During lytic-cycle replication, the KSHV-encoded replication and transcription activator (RTA or ORF50), the mRNA transport and accumulation protein (MTA), and the replication-associated protein (RAP) all play crucial roles in expression of downstream viral genes as well as in mediation of viral DNA replication. The cellular CCAAT/enhancer-binding protein alpha (C/EBP alpha) is induced in TPA-treated PEL cells and contributes to transactivation of the promoters for all of these genes through both direct binding and cooperative interactions with RTA and RAP targeted to upstream C/EBP sites. However, little is known about how RTA expression is triggered initially at the earliest stages after TPA induction when the C/EBP alpha levels are still limited. Treatment with TPA proved to significantly induce both AP1 DNA-binding activity and levels of activated phosphorylated cJUN in PEL cells and ectopic expression of cJUN-plus-cFOS-induced RTA protein expression in PEL cells. Cotransfected cJUN plus cFOS or TPA treatment transactivated the KSHV RTA, RAP, and MTA promoters in an AP1-binding site-dependent manner in all three promoters. Chromatin immunoprecipitation assays confirmed that cJUN associates with these KSHV target promoters in PEL cells as early as 4 h after TPA treatment. Furthermore, the KSHV RTA and RAP proteins both interact with cJUN or both cJUN and cFOS in vitro or by coimmunoprecipitation from induced PEL cells and enhance cJUN-plus-cFOS-mediated transactivation of these viral promoters. Both increased phosphorylated cJUN and AP1 DNA-binding activity was detected as early as 1 h after TPA treatment in PEL cells, suggesting that AP1 activity may be crucial for very early activation of the RAP, MTA, and RTA promoters during the KSHV lytic cycle. Finally, expression of RTA alone increased cJUN protein levels severalfold in DG75 cells but did not induce cJUN phosphorylation. Therefore, we suggest that the initiating effects of TPA via the AP1 pathway in PEL cells need to be amplified by RTA for full lytic-cycle induction.

Basic-Leucine Zipper Transcription Factors↗

PubMed2003

The extracellular Phr peptide-Rap phosphatase signaling circuit of Bacillus subtilis.

In the field of cell-cell communication, an emerging class of extracellular signaling peptides that function intracellularly has been identified in Gram-positive bacteria. One illustrative member of this group is the Phr family of extracellular signaling peptides of Bacillus subtilis. The Phr signaling peptides are secreted by the bacterium, and then, despite the presence of intracellular peptidases, they are actively transported into the cell where they interact with intracellular receptors to regulate gene expression. The intracellular receptors are members of a family of aspartyl-phosphate phosphatases, the Rap phosphatases. These phosphatases cause the dephosphorylation of response regulator proteins, ubiquitous regulatory proteins in bacteria. Immediately downstream of the genes for the Rap phosphatases are the genes for the Phr peptides, forming rap phr signaling cassettes. There are at least seven rap phr signaling cassettes in B. subtilis, and the genome sequence of other Gram-positive, endospore-forming bacteria suggests that similar cassettes may also function in these bacteria. In B. subtilis, the rap phr cassettes regulate sporulation, genetic competence, and genes comprising the quorum response (i.e. the response to high cell density). This review will address the mechanism of extracellular Phr signaling peptide production, transport, response, and their role in quorum sensing.

Amino Acid Sequence↗

PubMed1999

39-kDa receptor-associated protein (RAP) facilitates secretion and ligand binding of extracellular region of very-low-density-lipoprotein receptor: implications for a distinct pathway from low-density-lipoprotein receptor.

We have expressed the extracellular regions of the low-density-lipoprotein (LDL) receptor and the very-low-density-lipoprotein (VLDL) receptor, along with the full-length forms of the receptors, in insect cells in a baculovirus system. The extracellular region of the LDL receptor has been secreted successfully into the culture medium, and it retained the capacities of binding 125I-labelled LDL and beta-VLDL. In contrast, the extracellular region of the VLDL receptor remained intracellular and it did not bind 125I-beta-VLDL. This difference in expression behaviour between the homologous regions of the two receptors suggests that the two receptor systems are different in receptor-protein maturation or protein targeting. Next we developed the co-expression system with 39-kDa receptor-associated protein (RAP). This co-expression facilitated the secretion of the extracellular region of the VLDL receptor into the culture medium and the secreted receptor bound 125I-beta-VLDL. The VLDL receptor remaining intracellular that was co-expressed with RAP also showed binding capacity to 125I-beta-VLDL, implying that the existence of RAP prevented receptor-protein aggregation or improved protein-folding status of the truncated VLDL receptor. On the other hand, expression of the extracellular region of the LDL receptor was not facilitated by RAP co-expression. Thus RAP plays an essential role in maintenance of the active conformation and secretion of the extracellular region of the VLDL receptor.

Animals↗

PubMedDate not supplied

Optical coherence tomography (OCT) angiomatous prolifieration (RAP) in retinal.

PURPOSE: To verify the utility of optical coherence tomography (OCT) for diagnosing retinal angiomatous proliferations (RAP) in patients with exudative age-related macular degeneration (AMD). METHODS: Multiple cross-sections were taken with OCT from 41 eyes of 39 consecutive patients with AMD and RAP. The presence and the location of the angiomatous complexes had already been documented by fluorescein angiography (FA) and high-speed confocal indocyanine green videoangiography (ICGA). RESULTS: RAP was detectable by OCT scans in all 41 eyes, appearing as a focal hyper-reflecting area in the neuroretinal layers; it was frequently located close to the inner surface of the retinal pigment epithelium (29 eyes [70. 7%]). All eyes had either no or only a low-reflecting OCTsignal surrounding the RAP, caused by serous intraretinal edema. Only 13 eyes (31.7%), however, had large serous retinal detachment (SRD). OCT detected pigment epithelium detachment in 31 eyes (75.6%), but none had underlying choroidal neovascularization. CONCLUSIONS: OCT findings confirm the intraretinal localization of the RAP which are always associated with impressive exudative phenomena. OCT is therefore a useful diagnostic tool, adding information to FA and high-speed ICGA.

Aged↗

PubMed2006

The role of optical coherence tomography (OCT) in the diagnosis and management of retinal angiomatous proliferation (RAP) in patients with age-related macular degeneration.

INTRODUCTION: The aim of this review was to describe the use of optical coherence tomography (OCT) in the diagnosis and management of retinal angiomatous proliferation (RAP) in patients with age-related macular degeneration (AMD). MATERIALS AND METHODS: We reviewed the tomographic characteristics of the eyes affected by RAP seen at our institution and imaged by OCT. Some eyes with RAP were also studied with OCT prior to and after laser treatment to determine the tomographic changes following laser photocoagulation. RESULTS: In this preliminary report, OCT showed a typical pattern of structural changes in RAP: increased foveal thickness, cystoid macular oedema (CME) consisting of large central cysts and smaller cystoid spaces located mainly in the outer retinal layers, serous retinal detachment and a highly reflective intraretinal mass overlying a highly or moderately elevated retinal pigment epithelium (RPE). This mass corresponded to the hot spot observed on ICG angiography. After successful laser photocoagulation, significant decrease in foveal thickness, complete resolution of CME and retinal detachment with thinning of the neurosensory retina overlying the treated area could be observed. CONCLUSIONS: OCT appears to be useful in evaluating and documenting RAP in AMD patients both before and after laser photocoagulation. Longitudinal studies are required to determine its exact place and utility in clinical practice.

Angiomatosis↗

PubMed1986

Histologic demonstration of antigens reactive with anti-p21 ras monoclonal antibody (RAP-5) in human stomach cancers.

The immunohistochemical reactivity of RAP-5, a monoclonal antibody (MoAb) raised against a synthetic peptide corresponding to positions 10-17 of the ras gene product from T24 bladder carcinoma, was studied in 96 surgically resected stomach cancers of humans. The cytoplasm of cancer cells in 65 cases (68%) was positively stained with MoAb RAP-5, although the staining was heterogeneous among cancer cells. There was no definite correlation between depth of tumor invasion and reactivity to MoAb RAP-5. Cancer cells of poorly differentiated tumors showed a tendency to react less frequently and less intensely to MoAb RAP-5. In nontumorous gastric mucosa, parietal cells and some portions of intestinal metaplasia were stained with MoAb RAP-5. These findings suggest an increased expression of the ras gene product (p21) in about two-thirds of gastric adenocarcinomas and in some nonneoplastic gastric epithelial cells.

Antibodies, Monoclonal↗

PubMed1996

Lipoprotein lipase degradation by adipocytes: receptor-associated protein (RAP)-sensitive and proteoglycan-mediated pathways.

Lipoprotein lipase (LPL), the major enzyme responsible for the hydrolysis of triglycerides, is primarily synthesized by adipocytes and myocytes. In addition to synthesis, degradation of cell surface-associated LPL is thought to be important in regulating production of the enzyme. We studied LPL metabolism in the LPL synthesizing adipocyte cell line BFC-1 beta and assessed the contributions of cell surface heparan sulfate proteoglycans (HSPG), low density lipoprotein receptor related protein (LRP), and glycosylphosphatidylinositol (GPI)-linked proteins to LPL uptake and degradation by these cells. Adipocytes degraded 10-12% of total cell surface I-labeled LPL in 2 h and 23-28% in 4 h. In 1 h, 30-54% of the degradation was inhibited by the 39 kDa receptor associated protein (RAP), an inhibitor of ligand binding to LRP. At 4 h, only 19-23% of the LPL degradation was RAP inhibitable. This suggested that two pathways with different kinetics were important for LPL degradation. Heparinase/heparitinase treatment of cells showed that most LPL degradation required the presence of HSPG. Treatment with phosphatidylinositol-specific phospholipase C (PIPLC) inhibited 125I-labeled LPL degradation by 13%. However, neither RAP nor PIPLC treatment of adipocytes significantly increased the amount of endogenously produced LPL activity in the media. To determine whether direct uptake of LPL bound to HSPG could account for the non-RAP sensitive LPL uptake and degradation, proteoglycan metabolism was assessed by labeling cells with 35SO4. Of the total pericellular proteoglycans, 14% were PIPLC releasable; surprisingly, 30% were dissociated from the cells with heparin. The amount of labeled pericellular proteoglycans decreased 26% in 2 h and 50% in 8 h, rapid enough to account for at least half of the degradation of cell surface LPL. We conclude that adipocytes degrade a fraction of the cell surface LPL, and that this process is mediated by both proteoglycans and RAP-sensitive receptors.

Adipose Tissue↗

PubMed2002

Ras and Rap control AMPA receptor trafficking during synaptic plasticity.

Recent studies show that AMPA receptor (-R) trafficking is important in synaptic plasticity. However, the signaling controlling this trafficking is poorly understood. Small GTPases have diverse neuronal functions and their perturbation is responsible for several mental disorders. Here, we examine the small GTPases Ras and Rap in the postsynaptic signaling underlying synaptic plasticity. We show that Ras relays the NMDA-R and CaMKII signaling that drives synaptic delivery of AMPA-Rs during long-term potentiation. In contrast, Rap mediates NMDA-R-dependent removal of synaptic AMPA-Rs that occurs during long-term depression. Ras and Rap exert their effects on AMPA-Rs that contain different subunit composition. Thus, Ras and Rap, whose activity can be controlled by postsynaptic enzymes, serve as independent regulators for potentiating and depressing central synapses.

Animals↗