Synaptojanin

Synaptojanin is a protein involved in vesicle uncoating in neurons. This is an important regulatory lipid phosphatase. It dephosphorylates the D-5 position phosphate from phosphatidylinositol (3,4,5)-trisphosphate (PIP3) and Phosphatidylinositol (4,5)-bisphosphate(PIP2). It belongs to family of 5-phosphatases, which are structurally unrelated to D-3 inositol phosphatases like PTEN. Other members of the family of 5'phosphoinositide phosphatases include OCRL, SHIP1, SHIP2, INPP5J, INPP5E, INPP5B, INPP5A and SKIP.

synaptojanin 1
Identifiers
SymbolSYNJ1
NCBI gene8867
HGNC11503
OMIM604297
RefSeqNM_003895
UniProtO43426
Other data
LocusChr. 21 q22.2
synaptojanin 2
Identifiers
SymbolSYNJ2
NCBI gene8871
HGNC11504
OMIM609410
RefSeqNM_003898
UniProtO15056
Other data
LocusChr. 6 q25.3

Synaptojanin Family

The synaptojanin family comprises proteins that are key players in the synaptic vesicle recovery at the synapse.[1] In general, vesicles containing neurotransmitters fuse with the presynaptic cell in order to release neurotransmitter into the synaptic cleft. It is the release of neurotransmitters that allows neuron to neuron communication in the nervous system. The recovery of the vesicle is referred to as endocytosis and is important to reset the presynaptic cell with new neurotransmitter.

Synaptojanin 1 and Synaptojanin 2 are the two main proteins in the synaptojanin family. Synaptojanin 2 can be further subdivided into synaptojanin 2a and synaptojanin 2b.[2]

The mechanism by which vesicles are recovered is thought to involve the synaptojanin attracting the protein clathrin, which coats the vesicle and initiates vesicle endocytosis.

Synaptojanins are composed to three domains. The first is a central inositol 5-phosphatase domain, which can act on both PIP2 and PIP3. The second is an N-terminal Sac1-like inositol phosphatase domain, which, in vitro, can hydrolyze PIP and PIP2 to PI. The third is a C-terminal domain that is rich in the amino acid proline and interacts with several proteins also involved in vesicle endocytosis.[1] Specifically, the c-terminal domain interacts with amphiphysin, endophilin, DAP160/intersectin, syndapin and Eps15. The function of endophilin appears to be a binding partner for synaptojanin such that it can interact with other proteins and is involved in the initiation of shallow clathrin coated pits. Dap160 is a molecular scaffolding protein and functions in actin recruitment. Dynamin is a GTPase involved in vesicle budding, specifically modulating the severance of the vesicle from the neuronal membrane.[3] Dynamin appears to be playing a larger role in neurite formation because its vesicle pinching role and the possibility of it recycling plasma membrane and growth factor receptor proteins.[4]

Mutations in Synaptojanin 1 have been associated with autosomal recessive, early-onset parkinsonism.[5]

Role in Development

Synaptojanin, through its interactions with a variety of proteins and molecules is thought to play a role in the development of nervous systems.

Ephrin

Synaptojanin 1 has been found to be influenced by the protein ephrin.[6] Ephrin is a chemorepellent meaning that its interactions with proteins results in an inactivation or retraction of processes when referring to neuronal migration. Ephrin's receptor is called Eph and is a receptor tyrosine kinase.[6] Upon activation of the Eph receptor, synaptojanin 1 becomes phosphorylated at the proline rich domain and is inhibited from binding with any of its natural binding partners.[7] Therefore, the presence of ephrin inactivates vesicle endocytosis.

Calcium

The influx of calcium in the neuron has been shown to activate a variety of molecules including some calcium dependent phosphatases that activate synaptojanin.[8]

Membranes

Neuronal migration during development involves the extension of a neurite along the extracellular matrix. This extension is guided by the growth cone. However the actual extension of the neurite involves the insertion of membrane lipids immediately behind the growth one.[9] In fact, membranes can be trafficked from degenerating extensions to elongating ones.[10] Synaptojanin has been proposed as the mechanism by which membrane lipids can be trafficked around the developing neuron.[9]

Receptors

During development, receptors are trafficked around the growth cone. This trafficking involves vesicle endocytosis. In the presence of nerve growth factor (NGF), TrkA receptors are trafficked to the stimulated side of the growth cone.[8] Additionally, calcium and glutamate stimulate the trafficking of AMPA receptors to the stimulated side of the growth cone.[11] Both of these receptors are trafficked via synaptojanin.

Model organisms

Model organisms have been used in the study of Synaptojanin function. A conditional knockout mouse line of synaptojanin 2, called Synj2tm1a(EUCOMM)Wtsi[16][17] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists — at the Wellcome Trust Sanger Institute.[18][19][20]

Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[14][21] Twenty two tests were carried out on mutant mice, but no significant abnormalities were observed.[14]

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References
  1. Montesinos ML, Castellano-Muñoz M, García-Junco-Clemente P, Fernández-Chacón R (September 2005). "Recycling and EH domain proteins at the synapse". Brain Res. Brain Res. Rev. 49 (2): 416–28. doi:10.1016/j.brainresrev.2005.06.002. PMID 16054223.
  2. Nemoto Y, Wenk MR, Watanabe M, Daniell L, Murakami T, Ringstad N, Yamada H, Takei K, De Camilli P (November 2001). "Identification and characterization of a synaptojanin 2 splice isoform predominantly expressed in nerve terminals". J. Biol. Chem. 276 (44): 41133–42. doi:10.1074/jbc.M106404200. PMID 11498538.
  3. Verstreken P, Koh TW, Schulze KL, Zhai RG, Hiesinger PR, Zhou Y, Mehta SQ, Cao Y, Roos J, Bellen HJ (November 2003). "Synaptojanin is recruited by endophilin to promote synaptic vesicle uncoating". Neuron. 40 (4): 733–48. doi:10.1016/S0896-6273(03)00644-5. PMID 14622578.
  4. Torre E, McNiven MA, Urrutia R (December 1994). "Dynamin 1 antisense oligonucleotide treatment prevents neurite formation in cultured hippocampal neurons". J. Biol. Chem. 269 (51): 32411–7. PMID 7798241.
  5. Quadri M, Fang M, Picillo M, Olgiati S, Breedveld GJ, Graafland J, Wu B, Xu F, Erro R, Amboni M, Pappatà S, Quarantelli M, Annesi G, Quattrone A, Chien HF, Barbosa ER, Oostra BA, Barone P, Wang J, Bonifati V (2013). "Mutation in the SYNJ1 gene associated with autosomal recessive, early-onset Parkinsonism". Hum. Mutat. 34: 1208–15. doi:10.1002/humu.22373. PMID 23804577.
  6. Hopper NA, O'Connor V (May 2005). "Ephrin tempers two-faced synaptojanin 1". Nat. Cell Biol. 7 (5): 454–6. doi:10.1038/ncb0505-454. PMID 15867929.
  7. Irie F, Okuno M, Pasquale EB, Yamaguchi Y (May 2005). "EphrinB-EphB signalling regulates clathrin-mediated endocytosis through tyrosine phosphorylation of synaptojanin 1". Nat. Cell Biol. 7 (5): 501–9. doi:10.1038/ncb1252. PMC 1473167. PMID 15821731.
  8. Tojima T, Akiyama H, Itofusa R, Li Y, Katayama H, Miyawaki A, Kamiguchi H (January 2007). "Attractive axon guidance involves asymmetric membrane transport and exocytosis in the growth cone". Nat. Neurosci. 10 (1): 58–66. doi:10.1038/nn1814. PMID 17159991.
  9. Bonanomi D, Fornasiero EF, Valdez G, Halegoua S, Benfenati F, Menegon A, Valtorta F (November 2008). "Identification of a developmentally regulated pathway of membrane retrieval in neuronal growth cones". J. Cell Sci. 121 (Pt 22): 3757–69. doi:10.1242/jcs.033803. PMC 2731302. PMID 18940911.
  10. Shankland M, Bentley D, Goodman CS (August 1982). "Afferent innervation shapes the dendritic branching pattern of the medial giant interneuron in grasshopper embryos raised in culture". Dev. Biol. 92 (2): 507–20. doi:10.1016/0012-1606(82)90195-6. PMID 7117697.
  11. Gong LW, De Camilli P (November 2008). "Regulation of postsynaptic AMPA responses by synaptojanin 1". Proc. Natl. Acad. Sci. U.S.A. 105 (45): 17561–6. doi:10.1073/pnas.0809221105. PMC 2579885. PMID 18987319.
  12. "Salmonella infection data for Synj2". Wellcome Trust Sanger Institute.
  13. "Citrobacter infection data for Synj2". Wellcome Trust Sanger Institute.
  14. Gerdin AK (2010). "The Sanger Mouse Genetics Programme: High throughput characterisation of knockout mice". Acta Ophthalmologica. 88 (S248). doi:10.1111/j.1755-3768.2010.4142.x.
  15. Mouse Resources Portal, Wellcome Trust Sanger Institute.
  16. "International Knockout Mouse Consortium".
  17. "Mouse Genome Informatics".
  18. Skarnes, W. C.; Rosen, B.; West, A. P.; Koutsourakis, M.; Bushell, W.; Iyer, V.; Mujica, A. O.; Thomas, M.; Harrow, J.; Cox, T.; Jackson, D.; Severin, J.; Biggs, P.; Fu, J.; Nefedov, M.; De Jong, P. J.; Stewart, A. F.; Bradley, A. (2011). "A conditional knockout resource for the genome-wide study of mouse gene function". Nature. 474 (7351): 337–342. doi:10.1038/nature10163. PMC 3572410. PMID 21677750.
  19. Dolgin E (June 2011). "Mouse library set to be knockout". Nature. 474 (7351): 262–3. doi:10.1038/474262a. PMID 21677718.
  20. Collins FS, Rossant J, Wurst W (January 2007). "A mouse for all reasons". Cell. 128 (1): 9–13. doi:10.1016/j.cell.2006.12.018. PMID 17218247.
  21. van der Weyden L, White JK, Adams DJ, Logan DW (2011). "The mouse genetics toolkit: revealing function and mechanism". Genome Biol. 12 (6): 224. doi:10.1186/gb-2011-12-6-224. PMC 3218837. PMID 21722353.
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