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{{Infobox_gene}}
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'''Synaptic Ras GTPase-activating protein 1''', also known as '''synaptic Ras-GAP 1''' or '''SYNGAP1''', is a [[protein]] that in humans is encoded by the ''SYNGAP1'' [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: SYNGAP1 synaptic Ras GTPase activating protein 1 homolog (rat)| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=8831| accessdate = }}</ref><ref name="pmid9581761">{{cite journal |vauthors= Kim JH, Liao D, Lau LF, Huganir RL |title=SynGAP: a synaptic RasGAP that associates with the PSD-95/SAP90 protein family |journal=Neuron | volume = 20 |issue=4 |pages= 683–91 |date= Apr 1998 |pmid= 9581761 |doi= 10.1016/S0896-6273(00)81008-9 }}</ref><ref name="pmid9620694">{{cite journal | vauthors = Chen HJ, Rojas-Soto M, Oguni A, Kennedy MB |authorlink4=Mary B. Kennedy| title = A synaptic Ras-GTPase activating protein (p135 SynGAP) inhibited by CaM kinase II | journal = Neuron | volume = 20 | issue = 5 | pages = 895–904 | date = May 1998 | pmid = 9620694 | doi = 10.1016/S0896-6273(00)80471-7 }}</ref> SYNGAP1 is a [[ras (protein)|ras GTPase-activating]] protein that is critical for the development of cognition and proper [[chemical synapse|synapse]] function. Mutations in humans can cause [[intellectual disability]] or [[epilepsy]].
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<!-- The GNF_Protein_box is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
== Function ==
{{GNF_Protein_box
| image =
| image_source =
| PDB =
| Name = Synaptic Ras GTPase activating protein 1 homolog (rat)
| HGNCid = 11497
| Symbol = SYNGAP1
| AltSymbols =; RASA1; DKFZp761G1421; KIAA1938; RASA5; SYNGAP
| OMIM = 603384
| ECnumber = 
| Homologene = 84739
| MGIid = 3039785
| Function = {{GNF_GO|id=GO:0005096 |text = GTPase activator activity}}
| Component = {{GNF_GO|id=GO:0005622 |text = intracellular}}
| Process = {{GNF_GO|id=GO:0051056 |text = regulation of small GTPase mediated signal transduction}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 8831
    | Hs_Ensembl = 
    | Hs_RefseqProtein = NP_006763
    | Hs_RefseqmRNA = NM_006772
    | Hs_GenLoc_db = 
    | Hs_GenLoc_chr = 
    | Hs_GenLoc_start = 
    | Hs_GenLoc_end = 
    | Hs_Uniprot = 
    | Mm_EntrezGene = 240057
    | Mm_Ensembl = 
    | Mm_RefseqmRNA = XM_915205
    | Mm_RefseqProtein = XP_920298
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 
    | Mm_GenLoc_start = 
    | Mm_GenLoc_end = 
    | Mm_Uniprot = 
  }}
}}
'''Synaptic Ras GTPase activating protein 1 homolog (rat)''', also known as '''SYNGAP1''', is a human [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: SYNGAP1 synaptic Ras GTPase activating protein 1 homolog (rat)| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=8831| accessdate = }}</ref>


<!-- The PBB_Summary template is automatically maintained by Protein Box Bot. See Template:PBB_Controls to Stop updates. -->
SynGAP1 is a complex protein with several functions that may be regulated temporally via complex isoforms.<ref name=McMahon_2012>{{cite journal |vauthors= McMahon AC, Barnett MW, O'Leary TS, Stoney PN, Collins MO, Papadia S, Choudhary JS, Komiyama NH, Grant SG, Hardingham GE, Wyllie DJ, Kind PC |title= SynGAP isoforms exert opposing effects on synaptic strength |journal= Nature Communications |volume=3 |pages=900 |date=June 2012 |doi= 10.1038/ncomms1900 |pmid= 22692543 |pmc=3621422}}</ref> A well-documented function of SynGAP1 involves [[NMDA receptor]]-mediated synaptic plasticity and membrane insertion of [[AMPA receptor]]s through the suppression of upstream signaling pathways.<ref name=Clement_2012>{{cite journal |vauthors= Clement JP, Aceti M, Creson TK, Ozkan ED, Shi Y, Reish NJ, Almonte AG, Miller BH, Wiltgen BJ, Miller CA, Xu X, Rumbaugh G |title= Pathogenic SYNGAP1 mutations impair cognitive development by disrupting maturation of dendritic spine synapses |journal=Cell |volume=151 |issue=4 |pages= 709–23 | date= Nov 2012 |pmid=23141534 |pmc= 3500766 |doi= 10.1016/j.cell.2012.08.045 }}</ref> However, SynGAP1 has also been shown to function cooperatively with [[ULK2|Unc51.1]] in [[axon]] formation.<ref name="pmid15014045">{{cite journal |vauthors= Tomoda T, Kim JH, Zhan C, Hatten ME |title= Role of Unc51.1 and its binding partners in CNS axon outgrowth | journal= Genes & Development |volume=18 | issue = 5 |pages=541–58 |date=Mar 2004 |pmid= 15014045 |pmc=374236 |doi= 10.1101/gad.1151204 }}</ref> One way SynGAP1 affects these processes is through the [[MAPK/ERK pathway|MAP kinase signaling pathway]] by attenuation of [[Ras subfamily|Ras]] signalling.<ref name="pmid16537406">{{cite journal |vauthors = Rumbaugh G, Adams JP, Kim JH, Huganir RL | title= SynGAP regulates synaptic strength and mitogen-activated protein kinases in cultured neurons |journal= Proceedings of the National Academy of Sciences of the United States of America |volume=103 |issue=12 | pages= 4344–51 |date=Mar 2006 |pmid= 16537406 |pmc=1450173 |doi= 10.1073/pnas.0600084103 }}</ref> However, [[alternative splicing]] and multiple translational start sites have been shown to cause opposing effects, illustrating the importance of multiple functional domains that reside within the c- and n-termini. For example, the expression of an α1 or α2 c-terminal variant of SynGAP1 will either increase or decrease synaptic strength, respectively.<ref name=McMahon_2012 /> Overall, SynGAP1 is essential for development and survival, which is evident as knockout mice die perinatally.<ref name=Kim_2003>{{cite journal | vauthors = Kim JH, Lee HK, Takamiya K, Huganir RL | title = The role of synaptic GTPase-activating protein in neuronal development and synaptic plasticity | journal = The Journal of Neuroscience | volume = 23 | issue = 4 | pages = 1119–24 | date = Feb 2003 | pmid = 12598599 | doi =  }}</ref>
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==References==
===Dendritic spine development and maturation===
{{reflist|2}}
 
==Further reading==
SynGAP1 is shown to localize at the [[postsynaptic density]] on the [[dendritic spines]] of excitatory synapses.<ref name="pmid9581761" /> Cultured neurons of SynGAP heterozygotic and homozygotic knockout mice display accelerated maturation of [[dendritic spines]], including an increase in overall spine size, which produces more mushroom shaped and less stubby spines.<ref name=Clement_2012 /><ref name=pmid16537406 /><ref name=Vazquez>{{cite journal | vauthors = Vazquez LE, Chen HJ, Sokolova I, Knuesel I, Kennedy MB | title = SynGAP regulates spine formation | journal = The Journal of Neuroscience | volume = 24 | issue = 40 | pages = 8862–72 | date = Oct 2004 | pmid = 15470153 | doi = 10.1523/jneurosci.3213-04.2004 }}</ref> Spine heads are enlarged due to the increased [[phosphorylation]] of [[cofilin]], leading to a decrease in F-[[actin]] severing and turnover.<ref>{{cite journal | vauthors = Lin YC, Koleske AJ | title = Mechanisms of synapse and dendrite maintenance and their disruption in psychiatric and neurodegenerative disorders | journal = Annual Review of Neuroscience | volume = 33 | pages = 349–78 | date = July 2010 | pmid = 20367247 | pmc = 3063389 | doi = 10.1146/annurev-neuro-060909-153204 }}</ref> The increased size of the dendritic spines also corresponded to an increase in membrane bound AMPARs or a decrease in [[silent synapses]]. These neurons displayed a higher frequency and larger amplitudes of miniature [[excitatory postsynaptic potentials]] (mEPSP).<ref name=Vazquez /> Mice models with domain specific mutations led to neonatal hyperactivity of the hippocampal trisynaptic circuit. [[Mutation]]s had the greatest impact during the first 3 weeks of development, and reversal of mutations in adults did not improve behavior and cognition.<ref name=Clement_2012 />
{{refbegin | 2}}
 
{{PBB_Further_reading
==Clinical significance==
| citations =  
 
*{{cite journal | author=Fantl WJ, Escobedo JA, Martin GA, ''et al.'' |title=Distinct phosphotyrosines on a growth factor receptor bind to specific molecules that mediate different signaling pathways. |journal=Cell |volume=69 |issue= 3 |pages= 413-23 |year= 1992 |pmid= 1374684 |doi= }}
Several mutations in the SYNGAP1 gene were identified as the cause of intellectual disability. Intellectual disability is sometimes associated with syndromes of other defects caused by the same gene, but SYNGAP1-associated intellectual disability is not; it is therefore called non-syndromic intellectual disability. Since neither of the parents of children with this condition have the mutation, this means it was a sporadic mutation that occurred during division of the parents' gametes ([[meiosis]]) or fertilization of the egg. It is a [[dominance (genetics)|dominant]] mutation, which means that the individual will be developmentally disabled even if only one [[allele]] is mutated.<ref name="pmid19196676">{{cite journal | vauthors = Hamdan FF, Gauthier J, Spiegelman D, Noreau A, Yang Y, Pellerin S, Dobrzeniecka S, Côté M, Perreau-Linck E, Perreault-Linck E, Carmant L, D'Anjou G, Fombonne E, Addington AM, Rapoport JL, Delisi LE, Krebs MO, Mouaffak F, Joober R, Mottron L, Drapeau P, Marineau C, Lafrenière RG, Lacaille JC, Rouleau GA, Michaud JL | title = Mutations in SYNGAP1 in autosomal nonsyndromic mental retardation | journal = The New England Journal of Medicine | volume = 360 | issue = 6 | pages = 599–605 | date = Feb 2009 | pmid = 19196676 | pmc = 2925262 | doi = 10.1056/NEJMoa0805392 }}</ref>
*{{cite journal | author=Kroll J, Waltenberger J |title=The vascular endothelial growth factor receptor KDR activates multiple signal transduction pathways in porcine aortic endothelial cells. |journal=J. Biol. Chem. |volume=272 |issue= 51 |pages= 32521-7 |year= 1998 |pmid= 9405464 |doi= }}
 
*{{cite journal  | author=Kim JH, Liao D, Lau LF, Huganir RL |title=SynGAP: a synaptic RasGAP that associates with the PSD-95/SAP90 protein family. |journal=Neuron |volume=20 |issue= 4 |pages= 683-91 |year= 1998 |pmid= 9581761 |doi=  }}
Mutations in this gene have also been found associated to cases of epileptic encephalopathies. (doi: 10.1038/ng.2646)
*{{cite journal  | author=Chen HJ, Rojas-Soto M, Oguni A, Kennedy MB |title=A synaptic Ras-GTPase activating protein (p135 SynGAP) inhibited by CaM kinase II. |journal=Neuron |volume=20 |issue= 5 |pages= 895-904 |year= 1998 |pmid= 9620694 |doi=  }}
 
*{{cite journal  | author=Husi H, Ward MA, Choudhary JS, ''et al.'' |title=Proteomic analysis of NMDA receptor-adhesion protein signaling complexes. |journal=Nat. Neurosci. |volume=3 |issue= 7 |pages= 661-9 |year= 2000 |pmid= 10862698 |doi= 10.1038/76615 }}
== Interactions ==
*{{cite journal  | author=Li W, Okano A, Tian QB, ''et al.'' |title=Characterization of a novel synGAP isoform, synGAP-beta. |journal=J. Biol. Chem. |volume=276 |issue= 24 |pages= 21417-24 |year= 2001 |pmid= 11278737 |doi= 10.1074/jbc.M010744200 }}
 
*{{cite journal | author=Pei L, Teves RL, Wallace MC, Gurd JW |title=Transient cerebral ischemia increases tyrosine phosphorylation of the synaptic RAS-GTPase activating protein, SynGAP. |journal=J. Cereb. Blood Flow Metab. |volume=21 |issue= 8 |pages= 955-63 |year= 2001 |pmid= 11487731 |doi= 10.1097/00004647-200108000-00008 }}
SYNGAP1 has been shown to [[Protein-protein interaction|interact]] with [[DLG3]]<ref name="pmid9581761" /> and [[ULK1]].<ref name="pmid15014045"/>
*{{cite journal | author=Nagase T, Kikuno R, Ohara O |title=Prediction of the coding sequences of unidentified human genes. XXI. The complete sequences of 60 new cDNA clones from brain which code for large proteins. |journal=DNA Res. |volume=8 |issue= 4 |pages= 179-87 |year= 2002 |pmid= 11572484 |doi= }}
 
*{{cite journal | author=Yi J, Kloeker S, Jensen CC, ''et al.'' |title=Members of the Zyxin family of LIM proteins interact with members of the p130Cas family of signal transducers. |journal=J. Biol. Chem. |volume=277 |issue= 11 |pages= 9580-9 |year= 2002 |pmid= 11782456 |doi= 10.1074/jbc.M106922200 }}
== References ==
*{{cite journal | author=Kim JH, Lee HK, Takamiya K, Huganir RL |title=The role of synaptic GTPase-activating protein in neuronal development and synaptic plasticity. |journal=J. Neurosci. |volume=23 |issue= 4 |pages= 1119-24 |year= 2003 |pmid= 12598599 |doi= }}
{{reflist|33em}}
*{{cite journal | author=Song B, Meng F, Yan X, ''et al.'' |title=Cerebral ischemia immediately increases serine phosphorylation of the synaptic RAS-GTPase activating protein SynGAP by calcium/calmodulin-dependent protein kinase II alpha in hippocampus of rats. |journal=Neurosci. Lett. |volume=349 |issue= 3 |pages= 183-6 |year= 2003 |pmid= 12951199 |doi= }}
 
*{{cite journal | author=Mungall AJ, Palmer SA, Sims SK, ''et al.'' |title=The DNA sequence and analysis of human chromosome 6. |journal=Nature |volume=425 |issue= 6960 |pages= 805-11 |year= 2003 |pmid= 14574404 |doi= 10.1038/nature02055 }}
== Further reading ==
*{{cite journal | author=Ota T, Suzuki Y, Nishikawa T, ''et al.'' |title=Complete sequencing and characterization of 21,243 full-length human cDNAs. |journal=Nat. Genet. |volume=36 |issue= 1 |pages= 40-5 |year= 2004 |pmid= 14702039 |doi= 10.1038/ng1285 }}
{{refbegin|33em}}
*{{cite journal | author=Oh JS, Manzerra P, Kennedy MB |title=Regulation of the neuron-specific Ras GTPase-activating protein, synGAP, by Ca2+/calmodulin-dependent protein kinase II. |journal=J. Biol. Chem. |volume=279 |issue= 17 |pages= 17980-8 |year= 2004 |pmid= 14970204 |doi= 10.1074/jbc.M314109200 }}
* {{cite journal | vauthors = Fantl WJ, Escobedo JA, Martin GA, Turck CW, del Rosario M, McCormick F, Williams LT | title = Distinct phosphotyrosines on a growth factor receptor bind to specific molecules that mediate different signaling pathways | journal = Cell | volume = 69 | issue = 3 | pages = 413–23 | date = May 1992 | pmid = 1374684 | doi = 10.1016/0092-8674(92)90444-H }}
*{{cite journal | author=Tomoda T, Kim JH, Zhan C, Hatten ME |title=Role of Unc51.1 and its binding partners in CNS axon outgrowth. |journal=Genes Dev. |volume=18 |issue= 5 |pages= 541-58 |year= 2004 |pmid= 15014045 |doi= 10.1101/gad.1151204 }}
* {{cite journal | vauthors = Kroll J, Waltenberger J | title = The vascular endothelial growth factor receptor KDR activates multiple signal transduction pathways in porcine aortic endothelial cells | journal = The Journal of Biological Chemistry | volume = 272 | issue = 51 | pages = 32521–7 | date = Dec 1997 | pmid = 9405464 | doi = 10.1074/jbc.272.51.32521 }}
*{{cite journal | author=Song B, Yan XB, Zhang GY |title=PSD-95 promotes CaMKII-catalyzed serine phosphorylation of the synaptic RAS-GTPase activating protein SynGAP after transient brain ischemia in rat hippocampus. |journal=Brain Res. |volume=1005 |issue= 1-2 |pages= 44-50 |year= 2004 |pmid= 15044063 |doi= 10.1016/j.brainres.2004.01.032 }}
* {{cite journal | vauthors = Kim JH, Liao D, Lau LF, Huganir RL | title = SynGAP: a synaptic RasGAP that associates with the PSD-95/SAP90 protein family | journal = Neuron | volume = 20 | issue = 4 | pages = 683–91 | date = Apr 1998 | pmid = 9581761 | doi = 10.1016/S0896-6273(00)81008-9 }}
*{{cite journal | author=Brandenberger R, Wei H, Zhang S, ''et al.'' |title=Transcriptome characterization elucidates signaling networks that control human ES cell growth and differentiation. |journal=Nat. Biotechnol. |volume=22 |issue= 6 |pages= 707-16 |year= 2005 |pmid= 15146197 |doi= 10.1038/nbt971 }}
* {{cite journal | vauthors = Chen HJ, Rojas-Soto M, Oguni A, Kennedy MB | title = A synaptic Ras-GTPase activating protein (p135 SynGAP) inhibited by CaM kinase II | journal = Neuron | volume = 20 | issue = 5 | pages = 895–904 | date = May 1998 | pmid = 9620694 | doi = 10.1016/S0896-6273(00)80471-7 }}
*{{cite journal | author=Krapivinsky G, Medina I, Krapivinsky L, ''et al.'' |title=SynGAP-MUPP1-CaMKII synaptic complexes regulate p38 MAP kinase activity and NMDA receptor-dependent synaptic AMPA receptor potentiation. |journal=Neuron |volume=43 |issue= 4 |pages= 563-74 |year= 2004 |pmid= 15312654 |doi= 10.1016/j.neuron.2004.08.003 }}
* {{cite journal | vauthors = Husi H, Ward MA, Choudhary JS, Blackstock WP, Grant SG | title = Proteomic analysis of NMDA receptor-adhesion protein signaling complexes | journal = Nature Neuroscience | volume = 3 | issue = 7 | pages = 661–9 | date = Jul 2000 | pmid = 10862698 | doi = 10.1038/76615 }}
*{{cite journal | author=Jaffe H, Vinade L, Dosemeci A |title=Identification of novel phosphorylation sites on postsynaptic density proteins. |journal=Biochem. Biophys. Res. Commun. |volume=321 |issue= 1 |pages= 210-8 |year= 2004 |pmid= 15358237 |doi= 10.1016/j.bbrc.2004.06.122 }}
* {{cite journal | vauthors = Li W, Okano A, Tian QB, Nakayama K, Furihata T, Nawa H, Suzuki T | title = Characterization of a novel synGAP isoform, synGAP-beta | journal = The Journal of Biological Chemistry | volume = 276 | issue = 24 | pages = 21417–24 | date = Jun 2001 | pmid = 11278737 | doi = 10.1074/jbc.M010744200 }}
}}
* {{cite journal | vauthors = Pei L, Teves RL, Wallace MC, Gurd JW | title = Transient cerebral ischemia increases tyrosine phosphorylation of the synaptic RAS-GTPase activating protein, SynGAP | journal = Journal of Cerebral Blood Flow and Metabolism | volume = 21 | issue = 8 | pages = 955–63 | date = Aug 2001 | pmid = 11487731 | doi = 10.1097/00004647-200108000-00008 }}
* {{cite journal | vauthors = Nagase T, Kikuno R, Ohara O | title = Prediction of the coding sequences of unidentified human genes. XXI. The complete sequences of 60 new cDNA clones from brain which code for large proteins | journal = DNA Research | volume = 8 | issue = 4 | pages = 179–87 | date = Aug 2001 | pmid = 11572484 | doi = 10.1093/dnares/8.4.179 }}
* {{cite journal | vauthors = Yi J, Kloeker S, Jensen CC, Bockholt S, Honda H, Hirai H, Beckerle MC | title = Members of the Zyxin family of LIM proteins interact with members of the p130Cas family of signal transducers | journal = The Journal of Biological Chemistry | volume = 277 | issue = 11 | pages = 9580–9 | date = Mar 2002 | pmid = 11782456 | doi = 10.1074/jbc.M106922200 }}
* {{cite journal | vauthors = Song B, Meng F, Yan X, Guo J, Zhang G | title = Cerebral ischemia immediately increases serine phosphorylation of the synaptic RAS-GTPase activating protein SynGAP by calcium/calmodulin-dependent protein kinase II alpha in hippocampus of rats | journal = Neuroscience Letters | volume = 349 | issue = 3 | pages = 183–6 | date = Oct 2003 | pmid = 12951199 | doi = 10.1016/S0304-3940(03)00830-9 }}
* {{cite journal | vauthors = Oh JS, Manzerra P, Kennedy MB | title = Regulation of the neuron-specific Ras GTPase-activating protein, synGAP, by Ca2+/calmodulin-dependent protein kinase II | journal = The Journal of Biological Chemistry | volume = 279 | issue = 17 | pages = 17980–8 | date = Apr 2004 | pmid = 14970204 | doi = 10.1074/jbc.M314109200 }}
* {{cite journal | vauthors = Tomoda T, Kim JH, Zhan C, Hatten ME | title = Role of Unc51.1 and its binding partners in CNS axon outgrowth | journal = Genes & Development | volume = 18 | issue = 5 | pages = 541–58 | date = Mar 2004 | pmid = 15014045 | pmc = 374236 | doi = 10.1101/gad.1151204 }}
* {{cite journal | vauthors = Song B, Yan XB, Zhang GY | title = PSD-95 promotes CaMKII-catalyzed serine phosphorylation of the synaptic RAS-GTPase activating protein SynGAP after transient brain ischemia in rat hippocampus | journal = Brain Research | volume = 1005 | issue = 1–2 | pages = 44–50 | date = Apr 2004 | pmid = 15044063 | doi = 10.1016/j.brainres.2004.01.032 }}
* {{cite journal | vauthors = Brandenberger R, Wei H, Zhang S, Lei S, Murage J, Fisk GJ, Li Y, Xu C, Fang R, Guegler K, Rao MS, Mandalam R, Lebkowski J, Stanton LW | title = Transcriptome characterization elucidates signaling networks that control human ES cell growth and differentiation | journal = Nature Biotechnology | volume = 22 | issue = 6 | pages = 707–16 | date = Jun 2004 | pmid = 15146197 | doi = 10.1038/nbt971 }}
* {{cite journal | vauthors = Krapivinsky G, Medina I, Krapivinsky L, Gapon S, Clapham DE | title = SynGAP-MUPP1-CaMKII synaptic complexes regulate p38 MAP kinase activity and NMDA receptor-dependent synaptic AMPA receptor potentiation | journal = Neuron | volume = 43 | issue = 4 | pages = 563–74 | date = Aug 2004 | pmid = 15312654 | doi = 10.1016/j.neuron.2004.08.003 }}
* {{cite journal | vauthors = Jaffe H, Vinade L, Dosemeci A | title = Identification of novel phosphorylation sites on postsynaptic density proteins | journal = Biochemical and Biophysical Research Communications | volume = 321 | issue = 1 | pages = 210–8 | date = Aug 2004 | pmid = 15358237 | doi = 10.1016/j.bbrc.2004.06.122 }}
* {{cite journal | vauthors = Rumbaugh G, Adams JP, Kim JH, Huganir RL | title = SynGAP regulates synaptic strength and mitogen-activated protein kinases in cultured neurons | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 103 | issue = 12 | pages = 4344–51 | date = Mar 2006 | pmid = 16537406 | pmc = 1450173 | doi = 10.1073/pnas.0600084103 }}
{{refend}}
{{refend}}
{{protein-stub}}
{{WikiDoc Sources}}

Revision as of 20:34, 26 November 2017

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Identifiers
Aliases
External IDsGeneCards: [1]
Orthologs
SpeciesHumanMouse
Entrez

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Ensembl

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UniProt

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RefSeq (mRNA)

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RefSeq (protein)

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Location (UCSC)n/an/a
PubMed searchn/an/a
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Synaptic Ras GTPase-activating protein 1, also known as synaptic Ras-GAP 1 or SYNGAP1, is a protein that in humans is encoded by the SYNGAP1 gene.[1][2][3] SYNGAP1 is a ras GTPase-activating protein that is critical for the development of cognition and proper synapse function. Mutations in humans can cause intellectual disability or epilepsy.

Function

SynGAP1 is a complex protein with several functions that may be regulated temporally via complex isoforms.[4] A well-documented function of SynGAP1 involves NMDA receptor-mediated synaptic plasticity and membrane insertion of AMPA receptors through the suppression of upstream signaling pathways.[5] However, SynGAP1 has also been shown to function cooperatively with Unc51.1 in axon formation.[6] One way SynGAP1 affects these processes is through the MAP kinase signaling pathway by attenuation of Ras signalling.[7] However, alternative splicing and multiple translational start sites have been shown to cause opposing effects, illustrating the importance of multiple functional domains that reside within the c- and n-termini. For example, the expression of an α1 or α2 c-terminal variant of SynGAP1 will either increase or decrease synaptic strength, respectively.[4] Overall, SynGAP1 is essential for development and survival, which is evident as knockout mice die perinatally.[8]

Dendritic spine development and maturation

SynGAP1 is shown to localize at the postsynaptic density on the dendritic spines of excitatory synapses.[2] Cultured neurons of SynGAP heterozygotic and homozygotic knockout mice display accelerated maturation of dendritic spines, including an increase in overall spine size, which produces more mushroom shaped and less stubby spines.[5][7][9] Spine heads are enlarged due to the increased phosphorylation of cofilin, leading to a decrease in F-actin severing and turnover.[10] The increased size of the dendritic spines also corresponded to an increase in membrane bound AMPARs or a decrease in silent synapses. These neurons displayed a higher frequency and larger amplitudes of miniature excitatory postsynaptic potentials (mEPSP).[9] Mice models with domain specific mutations led to neonatal hyperactivity of the hippocampal trisynaptic circuit. Mutations had the greatest impact during the first 3 weeks of development, and reversal of mutations in adults did not improve behavior and cognition.[5]

Clinical significance

Several mutations in the SYNGAP1 gene were identified as the cause of intellectual disability. Intellectual disability is sometimes associated with syndromes of other defects caused by the same gene, but SYNGAP1-associated intellectual disability is not; it is therefore called non-syndromic intellectual disability. Since neither of the parents of children with this condition have the mutation, this means it was a sporadic mutation that occurred during division of the parents' gametes (meiosis) or fertilization of the egg. It is a dominant mutation, which means that the individual will be developmentally disabled even if only one allele is mutated.[11]

Mutations in this gene have also been found associated to cases of epileptic encephalopathies. (doi: 10.1038/ng.2646)

Interactions

SYNGAP1 has been shown to interact with DLG3[2] and ULK1.[6]

References

  1. ↑ "Entrez Gene: SYNGAP1 synaptic Ras GTPase activating protein 1 homolog (rat)".
  2. ↑ 2.0 2.1 2.2 Kim JH, Liao D, Lau LF, Huganir RL (Apr 1998). "SynGAP: a synaptic RasGAP that associates with the PSD-95/SAP90 protein family". Neuron. 20 (4): 683–91. doi:10.1016/S0896-6273(00)81008-9. PMID 9581761.
  3. ↑ Chen HJ, Rojas-Soto M, Oguni A, Kennedy MB (May 1998). "A synaptic Ras-GTPase activating protein (p135 SynGAP) inhibited by CaM kinase II". Neuron. 20 (5): 895–904. doi:10.1016/S0896-6273(00)80471-7. PMID 9620694.
  4. ↑ 4.0 4.1 McMahon AC, Barnett MW, O'Leary TS, Stoney PN, Collins MO, Papadia S, Choudhary JS, Komiyama NH, Grant SG, Hardingham GE, Wyllie DJ, Kind PC (June 2012). "SynGAP isoforms exert opposing effects on synaptic strength". Nature Communications. 3: 900. doi:10.1038/ncomms1900. PMC 3621422. PMID 22692543.
  5. ↑ 5.0 5.1 5.2 Clement JP, Aceti M, Creson TK, Ozkan ED, Shi Y, Reish NJ, Almonte AG, Miller BH, Wiltgen BJ, Miller CA, Xu X, Rumbaugh G (Nov 2012). "Pathogenic SYNGAP1 mutations impair cognitive development by disrupting maturation of dendritic spine synapses". Cell. 151 (4): 709–23. doi:10.1016/j.cell.2012.08.045. PMC 3500766. PMID 23141534.
  6. ↑ 6.0 6.1 Tomoda T, Kim JH, Zhan C, Hatten ME (Mar 2004). "Role of Unc51.1 and its binding partners in CNS axon outgrowth". Genes & Development. 18 (5): 541–58. doi:10.1101/gad.1151204. PMC 374236. PMID 15014045.
  7. ↑ 7.0 7.1 Rumbaugh G, Adams JP, Kim JH, Huganir RL (Mar 2006). "SynGAP regulates synaptic strength and mitogen-activated protein kinases in cultured neurons". Proceedings of the National Academy of Sciences of the United States of America. 103 (12): 4344–51. doi:10.1073/pnas.0600084103. PMC 1450173. PMID 16537406.
  8. ↑ Kim JH, Lee HK, Takamiya K, Huganir RL (Feb 2003). "The role of synaptic GTPase-activating protein in neuronal development and synaptic plasticity". The Journal of Neuroscience. 23 (4): 1119–24. PMID 12598599.
  9. ↑ 9.0 9.1 Vazquez LE, Chen HJ, Sokolova I, Knuesel I, Kennedy MB (Oct 2004). "SynGAP regulates spine formation". The Journal of Neuroscience. 24 (40): 8862–72. doi:10.1523/jneurosci.3213-04.2004. PMID 15470153.
  10. ↑ Lin YC, Koleske AJ (July 2010). "Mechanisms of synapse and dendrite maintenance and their disruption in psychiatric and neurodegenerative disorders". Annual Review of Neuroscience. 33: 349–78. doi:10.1146/annurev-neuro-060909-153204. PMC 3063389. PMID 20367247.
  11. ↑ Hamdan FF, Gauthier J, Spiegelman D, Noreau A, Yang Y, Pellerin S, Dobrzeniecka S, Côté M, Perreau-Linck E, Perreault-Linck E, Carmant L, D'Anjou G, Fombonne E, Addington AM, Rapoport JL, Delisi LE, Krebs MO, Mouaffak F, Joober R, Mottron L, Drapeau P, Marineau C, Lafrenière RG, Lacaille JC, Rouleau GA, Michaud JL (Feb 2009). "Mutations in SYNGAP1 in autosomal nonsyndromic mental retardation". The New England Journal of Medicine. 360 (6): 599–605. doi:10.1056/NEJMoa0805392. PMC 2925262. PMID 19196676.

Further reading

  • Fantl WJ, Escobedo JA, Martin GA, Turck CW, del Rosario M, McCormick F, Williams LT (May 1992). "Distinct phosphotyrosines on a growth factor receptor bind to specific molecules that mediate different signaling pathways". Cell. 69 (3): 413–23. doi:10.1016/0092-8674(92)90444-H. PMID 1374684.
  • Kroll J, Waltenberger J (Dec 1997). "The vascular endothelial growth factor receptor KDR activates multiple signal transduction pathways in porcine aortic endothelial cells". The Journal of Biological Chemistry. 272 (51): 32521–7. doi:10.1074/jbc.272.51.32521. PMID 9405464.
  • Kim JH, Liao D, Lau LF, Huganir RL (Apr 1998). "SynGAP: a synaptic RasGAP that associates with the PSD-95/SAP90 protein family". Neuron. 20 (4): 683–91. doi:10.1016/S0896-6273(00)81008-9. PMID 9581761.
  • Chen HJ, Rojas-Soto M, Oguni A, Kennedy MB (May 1998). "A synaptic Ras-GTPase activating protein (p135 SynGAP) inhibited by CaM kinase II". Neuron. 20 (5): 895–904. doi:10.1016/S0896-6273(00)80471-7. PMID 9620694.
  • Husi H, Ward MA, Choudhary JS, Blackstock WP, Grant SG (Jul 2000). "Proteomic analysis of NMDA receptor-adhesion protein signaling complexes". Nature Neuroscience. 3 (7): 661–9. doi:10.1038/76615. PMID 10862698.
  • Li W, Okano A, Tian QB, Nakayama K, Furihata T, Nawa H, Suzuki T (Jun 2001). "Characterization of a novel synGAP isoform, synGAP-beta". The Journal of Biological Chemistry. 276 (24): 21417–24. doi:10.1074/jbc.M010744200. PMID 11278737.
  • Pei L, Teves RL, Wallace MC, Gurd JW (Aug 2001). "Transient cerebral ischemia increases tyrosine phosphorylation of the synaptic RAS-GTPase activating protein, SynGAP". Journal of Cerebral Blood Flow and Metabolism. 21 (8): 955–63. doi:10.1097/00004647-200108000-00008. PMID 11487731.
  • Nagase T, Kikuno R, Ohara O (Aug 2001). "Prediction of the coding sequences of unidentified human genes. XXI. The complete sequences of 60 new cDNA clones from brain which code for large proteins". DNA Research. 8 (4): 179–87. doi:10.1093/dnares/8.4.179. PMID 11572484.
  • Yi J, Kloeker S, Jensen CC, Bockholt S, Honda H, Hirai H, Beckerle MC (Mar 2002). "Members of the Zyxin family of LIM proteins interact with members of the p130Cas family of signal transducers". The Journal of Biological Chemistry. 277 (11): 9580–9. doi:10.1074/jbc.M106922200. PMID 11782456.
  • Song B, Meng F, Yan X, Guo J, Zhang G (Oct 2003). "Cerebral ischemia immediately increases serine phosphorylation of the synaptic RAS-GTPase activating protein SynGAP by calcium/calmodulin-dependent protein kinase II alpha in hippocampus of rats". Neuroscience Letters. 349 (3): 183–6. doi:10.1016/S0304-3940(03)00830-9. PMID 12951199.
  • Oh JS, Manzerra P, Kennedy MB (Apr 2004). "Regulation of the neuron-specific Ras GTPase-activating protein, synGAP, by Ca2+/calmodulin-dependent protein kinase II". The Journal of Biological Chemistry. 279 (17): 17980–8. doi:10.1074/jbc.M314109200. PMID 14970204.
  • Tomoda T, Kim JH, Zhan C, Hatten ME (Mar 2004). "Role of Unc51.1 and its binding partners in CNS axon outgrowth". Genes & Development. 18 (5): 541–58. doi:10.1101/gad.1151204. PMC 374236. PMID 15014045.
  • Song B, Yan XB, Zhang GY (Apr 2004). "PSD-95 promotes CaMKII-catalyzed serine phosphorylation of the synaptic RAS-GTPase activating protein SynGAP after transient brain ischemia in rat hippocampus". Brain Research. 1005 (1–2): 44–50. doi:10.1016/j.brainres.2004.01.032. PMID 15044063.
  • Brandenberger R, Wei H, Zhang S, Lei S, Murage J, Fisk GJ, Li Y, Xu C, Fang R, Guegler K, Rao MS, Mandalam R, Lebkowski J, Stanton LW (Jun 2004). "Transcriptome characterization elucidates signaling networks that control human ES cell growth and differentiation". Nature Biotechnology. 22 (6): 707–16. doi:10.1038/nbt971. PMID 15146197.
  • Krapivinsky G, Medina I, Krapivinsky L, Gapon S, Clapham DE (Aug 2004). "SynGAP-MUPP1-CaMKII synaptic complexes regulate p38 MAP kinase activity and NMDA receptor-dependent synaptic AMPA receptor potentiation". Neuron. 43 (4): 563–74. doi:10.1016/j.neuron.2004.08.003. PMID 15312654.
  • Jaffe H, Vinade L, Dosemeci A (Aug 2004). "Identification of novel phosphorylation sites on postsynaptic density proteins". Biochemical and Biophysical Research Communications. 321 (1): 210–8. doi:10.1016/j.bbrc.2004.06.122. PMID 15358237.
  • Rumbaugh G, Adams JP, Kim JH, Huganir RL (Mar 2006). "SynGAP regulates synaptic strength and mitogen-activated protein kinases in cultured neurons". Proceedings of the National Academy of Sciences of the United States of America. 103 (12): 4344–51. doi:10.1073/pnas.0600084103. PMC 1450173. PMID 16537406.
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