Synaptojanin

Last updated
synaptojanin 1
Identifiers
SymbolSYNJ1
NCBI gene 8867
HGNC 11503
OMIM 604297
RefSeq NM_003895
UniProt O43426
Other data
Locus Chr. 21 q22.2
Search for
Structures Swiss-model
Domains InterPro
synaptojanin 2
Identifiers
SymbolSYNJ2
NCBI gene 8871
HGNC 11504
OMIM 609410
RefSeq NM_003898
UniProt O15056
Other data
Locus Chr. 6 q25.3
Search for
Structures Swiss-model
Domains InterPro

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.

Contents

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]

Related Research Articles

Axon guidance is a subfield of neural development concerning the process by which neurons send out axons to reach their correct targets. Axons often follow very precise paths in the nervous system, and how they manage to find their way so accurately is an area of ongoing research.

<span class="mw-page-title-main">Phosphatidylinositol 4,5-bisphosphate</span> Chemical compound

Phosphatidylinositol 4,5-bisphosphate or PtdIns(4,5)P2, also known simply as PIP2 or PI(4,5)P2, is a minor phospholipid component of cell membranes. PtdIns(4,5)P2 is enriched at the plasma membrane where it is a substrate for a number of important signaling proteins. PIP2 also forms lipid clusters that sort proteins.

<span class="mw-page-title-main">Phosphatidylinositol 3,4-bisphosphate</span>

Phosphatidylinositol (3,4)-bisphosphate is a minor phospholipid component of cell membranes, yet an important second messenger. The generation of PtdIns(3,4)P2 at the plasma membrane activates a number of important cell signaling pathways.

<span class="mw-page-title-main">Dynamin</span> Family of GTP-binding proteins

Dynamin is a GTPase responsible for endocytosis in the eukaryotic cell. Dynamin is part of the "dynamin superfamily", which includes classical dynamins, dynamin-like proteins, Mx proteins, OPA1, mitofusins, and GBPs. Members of the dynamin family are principally involved in the scission of newly formed vesicles from the membrane of one cellular compartment and their targeting to, and fusion with, another compartment, both at the cell surface as well as at the Golgi apparatus. Dynamin family members also play a role in many processes including division of organelles, cytokinesis and microbial pathogen resistance.

<span class="mw-page-title-main">Lipid signaling</span> Biological signaling using lipid molecules

Lipid signaling, broadly defined, refers to any biological signaling event involving a lipid messenger that binds a protein target, such as a receptor, kinase or phosphatase, which in turn mediate the effects of these lipids on specific cellular responses. Lipid signaling is thought to be qualitatively different from other classical signaling paradigms because lipids can freely diffuse through membranes. One consequence of this is that lipid messengers cannot be stored in vesicles prior to release and so are often biosynthesized "on demand" at their intended site of action. As such, many lipid signaling molecules cannot circulate freely in solution but, rather, exist bound to special carrier proteins in serum.

<span class="mw-page-title-main">Ephrin receptor</span> Protein family

Eph receptors are a group of receptors that are activated in response to binding with Eph receptor-interacting proteins (Ephrins). Ephs form the largest known subfamily of receptor tyrosine kinases (RTKs). Both Eph receptors and their corresponding ephrin ligands are membrane-bound proteins that require direct cell-cell interactions for Eph receptor activation. Eph/ephrin signaling has been implicated in the regulation of a host of processes critical to embryonic development including axon guidance, formation of tissue boundaries, cell migration, and segmentation. Additionally, Eph/ephrin signaling has been identified to play a critical role in the maintenance of several processes during adulthood including long-term potentiation, angiogenesis, and stem cell differentiation and cancer.

<span class="mw-page-title-main">Synapse</span> Structure connecting neurons in the nervous system

In the nervous system, a synapse is a structure that permits a neuron to pass an electrical or chemical signal to another neuron or to the target effector cell.

<span class="mw-page-title-main">Cortactin</span>

Cortactin is a monomeric protein located in the cytoplasm of cells that can be activated by external stimuli to promote polymerization and rearrangement of the actin cytoskeleton, especially the actin cortex around the cellular periphery. It is present in all cell types. When activated, it will recruit Arp2/3 complex proteins to existing actin microfilaments, facilitating and stabilizing nucleation sites for actin branching. Cortactin is important in promoting lamellipodia formation, invadopodia formation, cell migration, and endocytosis.

<span class="mw-page-title-main">Ephrin</span>

Ephrins are a family of proteins that serve as the ligands of the Eph receptor. Eph receptors in turn compose the largest known subfamily of receptor protein-tyrosine kinases (RTKs).

<span class="mw-page-title-main">EPS15</span> Protein-coding gene in the species Homo sapiens

Epidermal growth factor receptor substrate 15 is a protein that in humans is encoded by the EPS15 gene.

<span class="mw-page-title-main">Ephrin B1</span> Protein-coding gene in the species Homo sapiens

Ephrin B1 is a protein that in humans is encoded by the EFNB1 gene. It is a member of the ephrin family. The encoded protein is a type I membrane protein and a ligand of Eph-related receptor tyrosine kinases. It may play a role in cell adhesion and function in the development or maintenance of the nervous system.

<span class="mw-page-title-main">DNM1</span> Protein-coding gene in the species Homo sapiens

Dynamin-1 is a protein that in humans is encoded by the DNM1 gene.

<span class="mw-page-title-main">Signal-regulatory protein alpha</span>

Signal regulatory protein α (SIRPα) is a regulatory membrane glycoprotein from SIRP family expressed mainly by myeloid cells and also by stem cells or neurons.

<span class="mw-page-title-main">SH3GL2</span> Protein-coding gene in the species Homo sapiens

Endophilin-A1 is a protein that in humans is encoded by the SH3GL2 gene.

<span class="mw-page-title-main">PTPRM</span> Protein-coding gene in the species Homo sapiens

Receptor-type tyrosine-protein phosphatase mu is an enzyme that in humans is encoded by the PTPRM gene.

<span class="mw-page-title-main">SNX9</span>

Sorting nexin-9 is a protein that in humans is encoded by the SNX9 gene.

<span class="mw-page-title-main">Active zone</span>

The active zone or synaptic active zone is a term first used by Couteaux and Pecot-Dechavassinein in 1970 to define the site of neurotransmitter release. Two neurons make near contact through structures called synapses allowing them to communicate with each other. As shown in the adjacent diagram, a synapse consists of the presynaptic bouton of one neuron which stores vesicles containing neurotransmitter, and a second, postsynaptic neuron which bears receptors for the neurotransmitter, together with a gap between the two called the synaptic cleft. When an action potential reaches the presynaptic bouton, the contents of the vesicles are released into the synaptic cleft and the released neurotransmitter travels across the cleft to the postsynaptic neuron and activates the receptors on the postsynaptic membrane.

<span class="mw-page-title-main">Ephrin A5</span> Protein-coding gene in the species Homo sapiens

Ephrin A5 is a protein that in humans is encoded by the EFNA5 gene.

Phosphatidylinositol-4-phosphate 5-kinases are a class of enzymes that phosphorylate phosphatidylinositol 4-phosphate. They perform this reaction on the fifth hydroxyl of the myo-inositol ring to form phosphatidylinositol 4,5-bisphosphate.

<span class="mw-page-title-main">Synaptic stabilization</span> Modifying synaptic strength via cell adhesion molecules

Synaptic stabilization is crucial in the developing and adult nervous systems and is considered a result of the late phase of long-term potentiation (LTP). The mechanism involves strengthening and maintaining active synapses through increased expression of cytoskeletal and extracellular matrix elements and postsynaptic scaffold proteins, while pruning less active ones. For example, cell adhesion molecules (CAMs) play a large role in synaptic maintenance and stabilization. Gerald Edelman discovered CAMs and studied their function during development, which showed CAMs are required for cell migration and the formation of the entire nervous system. In the adult nervous system, CAMs play an integral role in synaptic plasticity relating to learning and memory.

References

  1. 1 2 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. S2CID   20738882.
  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. S2CID   14150492.
  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. doi: 10.1016/S0021-9258(18)31650-8 . 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 (9): 1208–15. doi: 10.1002/humu.22373 . PMID   23804577. S2CID   5715092.
  6. 1 2 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. S2CID   19812387.
  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. 1 2 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. S2CID   10762264.
  9. 1 2 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. Bibcode:2008PNAS..10517561G. 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. 1 2 3 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. S2CID   85911512.
  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. S2CID   18872015.
  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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