Synaptojanin

The synaptojanin family comprises proteins that are key players in the synaptic vesicle recovery at the synapse.{{cite journal |vauthors=Montesinos ML, Castellano-Muñoz M, García-Junco-Clemente P, Fernández-Chacón R | title = Recycling and EH domain proteins at the synapse | journal = Brain Res. Brain Res. Rev. | volume = 49 | issue = 2 | pages = 416–28 |date=September 2005 | pmid = 16054223 | doi = 10.1016/j.brainresrev.2005.06.002 | s2cid = 20738882 }} 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.{{cite journal |vauthors=Nemoto Y, Wenk MR, Watanabe M, Daniell L, Murakami T, Ringstad N, Yamada H, Takei K, De Camilli P | title = Identification and characterization of a synaptojanin 2 splice isoform predominantly expressed in nerve terminals | journal = J. Biol. Chem. | volume = 276 | issue = 44 | pages = 41133–42 |date=November 2001 | pmid = 11498538 | doi = 10.1074/jbc.M106404200 | doi-access = free }}

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. 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.{{cite journal |vauthors=Verstreken P, Koh TW, Schulze KL, Zhai RG, Hiesinger PR, Zhou Y, Mehta SQ, Cao Y, Roos J, Bellen HJ | title = Synaptojanin is recruited by endophilin to promote synaptic vesicle uncoating | journal = Neuron | volume = 40 | issue = 4 | pages = 733–48 |date=November 2003 | pmid = 14622578 | doi = 10.1016/S0896-6273(03)00644-5| s2cid = 14150492 | doi-access = free }} 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.{{cite journal |vauthors=Torre E, McNiven MA, Urrutia R | title = Dynamin 1 antisense oligonucleotide treatment prevents neurite formation in cultured hippocampal neurons | journal = J. Biol. Chem. | volume = 269 | issue = 51 | pages = 32411–7 |date=December 1994 | doi = 10.1016/S0021-9258(18)31650-8 | pmid = 7798241 | doi-access = free }}

Mutations in Synaptojanin 1 have been associated with autosomal recessive, early-onset parkinsonism.{{cite journal |pmid=23804577 | doi=10.1002/humu.22373 | volume=34 | title=Mutation in the SYNJ1 gene associated with autosomal recessive, early-onset Parkinsonism | year=2013 | journal=Hum. Mutat. | pages=1208–15 |vauthors=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 | issue=9 | s2cid=5715092 | doi-access=free }}

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

Synaptojanin 1 has been found to be influenced by the protein ephrin.{{cite journal |vauthors=Hopper NA, O'Connor V | title = Ephrin tempers two-faced synaptojanin 1 | journal = Nat. Cell Biol. | volume = 7 | issue = 5 | pages = 454–6 |date=May 2005 | pmid = 15867929 | doi = 10.1038/ncb0505-454 | s2cid = 19812387 }} 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. 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.{{cite journal |vauthors=Irie F, Okuno M, Pasquale EB, Yamaguchi Y | title = EphrinB-EphB signalling regulates clathrin-mediated endocytosis through tyrosine phosphorylation of synaptojanin 1 | journal = Nat. Cell Biol. | volume = 7 | issue = 5 | pages = 501–9 |date=May 2005 | pmid = 15821731 | pmc = 1473167 | doi = 10.1038/ncb1252 }} Therefore, the presence of ephrin inactivates vesicle endocytosis.

The influx of calcium in the neuron has been shown to activate a variety of molecules including some calcium dependent phosphatases that activate synaptojanin.{{cite journal |vauthors=Tojima T, Akiyama H, Itofusa R, Li Y, Katayama H, Miyawaki A, Kamiguchi H | title = Attractive axon guidance involves asymmetric membrane transport and exocytosis in the growth cone | journal = Nat. Neurosci. | volume = 10 | issue = 1 | pages = 58–66 |date=January 2007 | pmid = 17159991 | doi = 10.1038/nn1814 | s2cid = 10762264 }}

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.{{cite journal |vauthors=Bonanomi D, Fornasiero EF, Valdez G, Halegoua S, Benfenati F, Menegon A, Valtorta F | title = Identification of a developmentally regulated pathway of membrane retrieval in neuronal growth cones | journal = J. Cell Sci. | volume = 121 | issue = Pt 22 | pages = 3757–69 |date=November 2008 | pmid = 18940911 | pmc = 2731302 | doi = 10.1242/jcs.033803 }} In fact, membranes can be trafficked from degenerating extensions to elongating ones.{{cite journal |vauthors=Shankland M, Bentley D, Goodman CS | title = Afferent innervation shapes the dendritic branching pattern of the medial giant interneuron in grasshopper embryos raised in culture | journal = Dev. Biol. | volume = 92 | issue = 2 | pages = 507–20 |date=August 1982 | pmid = 7117697 | doi = 10.1016/0012-1606(82)90195-6}} Synaptojanin has been proposed as the mechanism by which membrane lipids can be trafficked around the developing neuron.

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. Additionally, calcium and glutamate stimulate the trafficking of AMPA receptors to the stimulated side of the growth cone.{{cite journal |vauthors=Gong LW, De Camilli P | title = Regulation of postsynaptic AMPA responses by synaptojanin 1 | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 105 | issue = 45 | pages = 17561–6 |date=November 2008 | pmid = 18987319 | pmc = 2579885 | doi = 10.1073/pnas.0809221105 | bibcode = 2008PNAS..10517561G | doi-access = free }} Both of these receptors are trafficked via synaptojanin.

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Category:Peripheral membrane proteins

Category:EC 3.1.3

Category:Genes mutated in mice