SYNGAP1

Synaptic Ras GTPase activating protein 1
Identifiers
Symbols SYNGAP1 ; MRD5; RASA1; RASA5; SYNGAP
External IDs OMIM: 603384 MGI: 3039785 HomoloGene: 84739 GeneCards: SYNGAP1 Gene
Orthologs
Species Human Mouse
Entrez 8831 240057
Ensembl ENSG00000197283 ENSMUSG00000067629
UniProt Q96PV0 F6SEU4
RefSeq (mRNA) NM_001130066 NM_001281491
RefSeq (protein) NP_006763 NP_001268420
Location (UCSC) Chr 6:
33.42 – 33.46 Mb		 Chr 17:
26.94 – 26.97 Mb
PubMed search

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. 1 2 3 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. 1 2 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. PMID 22692543.
  5. 1 2 3 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. 1 2 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. 1 2 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. 1 2 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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