Munc13 1

Summary

Gene Symbol: Munc13 1
Description: unc-13 homolog A
Alias: Munc13-1, Unc13h1, protein unc-13 homolog A
Species: rat
Products:     Munc13 1

Top Publications

  1. Augustin I, Rosenmund C, Sudhof T, Brose N. Munc13-1 is essential for fusion competence of glutamatergic synaptic vesicles. Nature. 1999;400:457-61 pubmed
  2. Betz A, Thakur P, Junge H, Ashery U, Rhee J, Scheuss V, et al. Functional interaction of the active zone proteins Munc13-1 and RIM1 in synaptic vesicle priming. Neuron. 2001;30:183-96 pubmed
    ..The Munc13-1/RIM1 interaction may create a functional link between synaptic vesicle tethering and priming, or it may regulate the priming reaction itself, thereby determining the number of fusion-competent vesicles. ..
  3. Rosenmund C, Sigler A, Augustin I, Reim K, Brose N, Rhee J. Differential control of vesicle priming and short-term plasticity by Munc13 isoforms. Neuron. 2002;33:411-24 pubmed
    ..Thus, differential expression of Munc13 isoforms at individual synapses represents a general mechanism that controls short-term plasticity and contributes to the heterogeneity of synaptic information coding. ..
  4. Ohtsuka T, Takao Rikitsu E, Inoue E, Inoue M, Takeuchi M, Matsubara K, et al. Cast: a novel protein of the cytomatrix at the active zone of synapses that forms a ternary complex with RIM1 and munc13-1. J Cell Biol. 2002;158:577-90 pubmed
    ..These results suggest that these CAZ proteins are at least partly transported on the same vesicles during synapse formation. ..
  5. Betz A, Okamoto M, Benseler F, Brose N. Direct interaction of the rat unc-13 homologue Munc13-1 with the N terminus of syntaxin. J Biol Chem. 1997;272:2520-6 pubmed
    ..It is possible that the phenotype of unc-13 and unc-18 mutations is caused by the inability of the respective mutated gene products to bind to syntaxin. ..
  6. Brose N, Hofmann K, Hata Y, Sudhof T. Mammalian homologues of Caenorhabditis elegans unc-13 gene define novel family of C2-domain proteins. J Biol Chem. 1995;270:25273-80 pubmed
    ..The presence of C1- and C2-domains in these proteins and the phenotype of the C. elegans mutants raise the possibility that Munc13s may have an essential signaling role during neurotransmitter release. ..
  7. Betz A, Ashery U, Rickmann M, Augustin I, Neher E, Sudhof T, et al. Munc13-1 is a presynaptic phorbol ester receptor that enhances neurotransmitter release. Neuron. 1998;21:123-36 pubmed
    ..These observations establish Munc13-1 as a novel presynaptic target of the diacylglycerol second messenger pathway that acts in parallel with protein kinase C to regulate neurotransmitter secretion. ..
  8. Mochida S, Orita S, Sakaguchi G, Sasaki T, Takai Y. Role of the Doc2 alpha-Munc13-1 interaction in the neurotransmitter release process. Proc Natl Acad Sci U S A. 1998;95:11418-22 pubmed
    ..1 mM Ca2+. These results suggest that the Doc2alpha-Munc13-1 interaction plays a role in a step before the final fusion step of synaptic vesicles with the presynaptic plasma membrane in the evoked neurotransmitter release process. ..
  9. Rhee J, Betz A, Pyott S, Reim K, Varoqueaux F, Augustin I, et al. Beta phorbol ester- and diacylglycerol-induced augmentation of transmitter release is mediated by Munc13s and not by PKCs. Cell. 2002;108:121-33 pubmed
    ..Modulation of Munc13-1 activity by second messengers via the DAG/beta phorbol ester binding C(1) domain is essential for use-dependent alterations of synaptic efficacy and survival. ..
  10. Guan R, Dai H, Rizo J. Binding of the Munc13-1 MUN domain to membrane-anchored SNARE complexes. Biochemistry. 2008;47:1474-81 pubmed publisher

Detail Information

Publications51

  1. Augustin I, Rosenmund C, Sudhof T, Brose N. Munc13-1 is essential for fusion competence of glutamatergic synaptic vesicles. Nature. 1999;400:457-61 pubmed
  2. Betz A, Thakur P, Junge H, Ashery U, Rhee J, Scheuss V, et al. Functional interaction of the active zone proteins Munc13-1 and RIM1 in synaptic vesicle priming. Neuron. 2001;30:183-96 pubmed
    ..The Munc13-1/RIM1 interaction may create a functional link between synaptic vesicle tethering and priming, or it may regulate the priming reaction itself, thereby determining the number of fusion-competent vesicles. ..
  3. Rosenmund C, Sigler A, Augustin I, Reim K, Brose N, Rhee J. Differential control of vesicle priming and short-term plasticity by Munc13 isoforms. Neuron. 2002;33:411-24 pubmed
    ..Thus, differential expression of Munc13 isoforms at individual synapses represents a general mechanism that controls short-term plasticity and contributes to the heterogeneity of synaptic information coding. ..
  4. Ohtsuka T, Takao Rikitsu E, Inoue E, Inoue M, Takeuchi M, Matsubara K, et al. Cast: a novel protein of the cytomatrix at the active zone of synapses that forms a ternary complex with RIM1 and munc13-1. J Cell Biol. 2002;158:577-90 pubmed
    ..These results suggest that these CAZ proteins are at least partly transported on the same vesicles during synapse formation. ..
  5. Betz A, Okamoto M, Benseler F, Brose N. Direct interaction of the rat unc-13 homologue Munc13-1 with the N terminus of syntaxin. J Biol Chem. 1997;272:2520-6 pubmed
    ..It is possible that the phenotype of unc-13 and unc-18 mutations is caused by the inability of the respective mutated gene products to bind to syntaxin. ..
  6. Brose N, Hofmann K, Hata Y, Sudhof T. Mammalian homologues of Caenorhabditis elegans unc-13 gene define novel family of C2-domain proteins. J Biol Chem. 1995;270:25273-80 pubmed
    ..The presence of C1- and C2-domains in these proteins and the phenotype of the C. elegans mutants raise the possibility that Munc13s may have an essential signaling role during neurotransmitter release. ..
  7. Betz A, Ashery U, Rickmann M, Augustin I, Neher E, Sudhof T, et al. Munc13-1 is a presynaptic phorbol ester receptor that enhances neurotransmitter release. Neuron. 1998;21:123-36 pubmed
    ..These observations establish Munc13-1 as a novel presynaptic target of the diacylglycerol second messenger pathway that acts in parallel with protein kinase C to regulate neurotransmitter secretion. ..
  8. Mochida S, Orita S, Sakaguchi G, Sasaki T, Takai Y. Role of the Doc2 alpha-Munc13-1 interaction in the neurotransmitter release process. Proc Natl Acad Sci U S A. 1998;95:11418-22 pubmed
    ..1 mM Ca2+. These results suggest that the Doc2alpha-Munc13-1 interaction plays a role in a step before the final fusion step of synaptic vesicles with the presynaptic plasma membrane in the evoked neurotransmitter release process. ..
  9. Rhee J, Betz A, Pyott S, Reim K, Varoqueaux F, Augustin I, et al. Beta phorbol ester- and diacylglycerol-induced augmentation of transmitter release is mediated by Munc13s and not by PKCs. Cell. 2002;108:121-33 pubmed
    ..Modulation of Munc13-1 activity by second messengers via the DAG/beta phorbol ester binding C(1) domain is essential for use-dependent alterations of synaptic efficacy and survival. ..
  10. Guan R, Dai H, Rizo J. Binding of the Munc13-1 MUN domain to membrane-anchored SNARE complexes. Biochemistry. 2008;47:1474-81 pubmed publisher
  11. Lu J, Machius M, Dulubova I, Dai H, Sudhof T, Tomchick D, et al. Structural basis for a Munc13-1 homodimer to Munc13-1/RIM heterodimer switch. PLoS Biol. 2006;4:e192 pubmed
  12. Orita S, Naito A, Sakaguchi G, Maeda M, Igarashi H, Sasaki T, et al. Physical and functional interactions of Doc2 and Munc13 in Ca2+-dependent exocytotic machinery. J Biol Chem. 1997;272:16081-4 pubmed
    ..These results, together with the earlier findings that secretagogues produce DAG and elevate cytoplasmic Ca2+, suggest that the DAG-induced Doc2-Munc13 interactions play an important role in Ca2+-dependent exocytotic machinery. ..
  13. Junge H, Rhee J, Jahn O, Varoqueaux F, Spiess J, Waxham M, et al. Calmodulin and Munc13 form a Ca2+ sensor/effector complex that controls short-term synaptic plasticity. Cell. 2004;118:389-401 pubmed
  14. van Es M, Veldink J, Saris C, Blauw H, Van Vught P, Birve A, et al. Genome-wide association study identifies 19p13.3 (UNC13A) and 9p21.2 as susceptibility loci for sporadic amyotrophic lateral sclerosis. Nat Genet. 2009;41:1083-7 pubmed publisher
    ..01 x 10(-8)) in the combined analysis of both stages. These SNPs are located at chromosome 9p21.2, in a linkage region for familial ALS with frontotemporal dementia found previously in several large pedigrees. ..
  15. Sitarska E, Xu J, Park S, Liu X, Quade B, Stepien K, et al. Autoinhibition of Munc18-1 modulates synaptobrevin binding and helps to enable Munc13-dependent regulation of membrane fusion. elife. 2017;6: pubmed publisher
  16. Varoqueaux F, Sons M, Plomp J, Brose N. Aberrant morphology and residual transmitter release at the Munc13-deficient mouse neuromuscular synapse. Mol Cell Biol. 2005;25:5973-84 pubmed
    ..Thus, non-Munc13 priming proteins exist at this synapse or vesicle priming occurs in part spontaneously: i.e., without dedicated priming proteins in the release machinery. ..
  17. Xu J, Camacho M, Xu Y, Esser V, Liu X, Trimbuch T, et al. Mechanistic insights into neurotransmitter release and presynaptic plasticity from the crystal structure of Munc13-1 C1C2BMUN. elife. 2017;6: pubmed publisher
    ..The structure imposes key constraints for models of neurotransmitter release and suggests that Munc13-1 bridges the vesicle and plasma membranes from the periphery of the membrane-membrane interface. ..
  18. Rodriguez Castaneda F, Maestre Martínez M, Coudevylle N, Dimova K, Junge H, Lipstein N, et al. Modular architecture of Munc13/calmodulin complexes: dual regulation by Ca2+ and possible function in short-term synaptic plasticity. EMBO J. 2010;29:680-91 pubmed publisher
    ..This Ca(2+)/CaM-binding mode of Munc13 likely constitutes a key molecular correlate of the characteristic Ca(2+)-dependent modulation of short-term synaptic plasticity. ..
  19. Dimova K, Kalkhof S, Pottratz I, Ihling C, Rodriguez Castaneda F, Liepold T, et al. Structural insights into the calmodulin-Munc13 interaction obtained by cross-linking and mass spectrometry. Biochemistry. 2009;48:5908-21 pubmed publisher
  20. Rossner S, Fuchsbrunner K, Lange Dohna C, Hartlage Rübsamen M, Bigl V, Betz A, et al. Munc13-1-mediated vesicle priming contributes to secretory amyloid precursor protein processing. J Biol Chem. 2004;279:27841-4 pubmed
    ..We establish that, in addition to PKC, Munc13-1 significantly contributes to the regulation of secretory APP metabolism. ..
  21. Sakaguchi G, Orita S, Naito A, Maeda M, Igarashi H, Sasaki T, et al. A novel brain-specific isoform of beta spectrin: isolation and its interaction with Munc13. Biochem Biophys Res Commun. 1998;248:846-51 pubmed
    ..Because spectrin has been shown to interact with the actin cytoskeleton which is involved in the exocytotic process, the present results suggest that the Munc13-beta SpIII sigma 1 interactions play a role in neurotransmitter release. ..
  22. Wang S, Choi U, Gong J, Yang X, Li Y, Wang A, et al. Conformational change of syntaxin linker region induced by Munc13s initiates SNARE complex formation in synaptic exocytosis. EMBO J. 2017;36:816-829 pubmed publisher
    ..We suggest that the conformational change of the syntaxin-1 linker region induced by Munc13-1 initiates ternary SNARE complex formation in the neuronal system. ..
  23. Li W, Ma C, Guan R, Xu Y, Tomchick D, Rizo J. The crystal structure of a Munc13 C-terminal module exhibits a remarkable similarity to vesicle tethering factors. Structure. 2011;19:1443-55 pubmed publisher
    ..We propose a model whereby the MUN-CD module is central for Munc13 function but full activity requires adjacent sequences. ..
  24. Ma C, Hou H, Tian W, Xu T. Expression, purification and characterization of critical domains of Munc13-1. Acta Biochim Biophys Sin (Shanghai). 2007;39:617-23 pubmed
    ..In addition, these purified recombinant proteins provide ideal starting materials for further biochemical, biophysical, and structural studies on mammalian Munc13 proteins. ..
  25. Ma C, Li W, Xu Y, Rizo J. Munc13 mediates the transition from the closed syntaxin-Munc18 complex to the SNARE complex. Nat Struct Mol Biol. 2011;18:542-9 pubmed publisher
  26. Yang X, Wang S, Sheng Y, Zhang M, Zou W, Wu L, et al. Syntaxin opening by the MUN domain underlies the function of Munc13 in synaptic-vesicle priming. Nat Struct Mol Biol. 2015;22:547-54 pubmed publisher
    ..These results support the notion that orchestration of syntaxin-1 opening and SNARE-complex assembly underlies the central role of UNC-13-Munc13s in synaptic-vesicle priming. ..
  27. Khodthong C, Kabachinski G, James D, Martin T. Munc13 homology domain-1 in CAPS/UNC31 mediates SNARE binding required for priming vesicle exocytosis. Cell Metab. 2011;14:254-63 pubmed publisher
    ..The results show that MHD1 is a SNARE-binding domain and that SNARE protein binding is essential for CAPS function in dense-core vesicle exocytosis. ..
  28. Takao Rikitsu E, Mochida S, Inoue E, Deguchi Tawarada M, Inoue M, Ohtsuka T, et al. Physical and functional interaction of the active zone proteins, CAST, RIM1, and Bassoon, in neurotransmitter release. J Cell Biol. 2004;164:301-11 pubmed
    ..These results indicate that CAST serves as a key component of the CAZ structure and is involved in neurotransmitter release by binding these CAZ proteins. ..
  29. Vogl C, Cooper B, Neef J, Wojcik S, Reim K, Reisinger E, et al. Unconventional molecular regulation of synaptic vesicle replenishment in cochlear inner hair cells. J Cell Sci. 2015;128:638-44 pubmed publisher
    ..We conclude that IHCs use an unconventional priming machinery that involves otoferlin...
  30. Martín R, Durroux T, Ciruela F, Torres M, Pin J, Sánchez Prieto J. The metabotropic glutamate receptor mGlu7 activates phospholipase C, translocates munc-13-1 protein, and potentiates glutamate release at cerebrocortical nerve terminals. J Biol Chem. 2010;285:17907-17 pubmed publisher
    ..We propose that the mGlu7 receptor can facilitate or inhibit glutamate release through multiple pathways, thereby exerting homeostatic control of presynaptic function. ..
  31. Imig C, Min S, Krinner S, Arancillo M, Rosenmund C, Sudhof T, et al. The morphological and molecular nature of synaptic vesicle priming at presynaptic active zones. Neuron. 2014;84:416-31 pubmed publisher
  32. Wang Z, Thurmond D. Mechanisms of biphasic insulin-granule exocytosis - roles of the cytoskeleton, small GTPases and SNARE proteins. J Cell Sci. 2009;122:893-903 pubmed publisher
  33. Siksou L, Varoqueaux F, Pascual O, Triller A, Brose N, Marty S. A common molecular basis for membrane docking and functional priming of synaptic vesicles. Eur J Neurosci. 2009;30:49-56 pubmed publisher
    ..These results indicate that SV docking at the plasma membrane and functional priming are respective morphological and physiological manifestations of the same molecular process mediated by SNARE complexes and Munc13s. ..
  34. Ma C, Su L, Seven A, Xu Y, Rizo J. Reconstitution of the vital functions of Munc18 and Munc13 in neurotransmitter release. Science. 2013;339:421-5 pubmed publisher
  35. Augustin I, Betz A, Herrmann C, Jo T, Brose N. Differential expression of two novel Munc13 proteins in rat brain. Biochem J. 1999;337 ( Pt 3):363-71 pubmed
    ..Munc13-2 and Munc13-3 are expressed in a complementary fashion and might act in concert with Munc13-1 to modulate neurotransmitter release. ..
  36. Sheu L, Pasyk E, Ji J, Huang X, Gao X, Varoqueaux F, et al. Regulation of insulin exocytosis by Munc13-1. J Biol Chem. 2003;278:27556-63 pubmed
    ..In view of our findings, Munc13-1 is a potential drug target for therapeutic optimization of insulin secretion in diabetes. ..
  37. Jiang X, Litkowski P, Taylor A, Lin Y, Snider B, Moulder K. A role for the ubiquitin-proteasome system in activity-dependent presynaptic silencing. J Neurosci. 2010;30:1798-809 pubmed publisher
    ..These results suggest that modulation of the UPS by electrical activity contributes to persistent presynaptic silencing by promoting the degradation of key presynaptic proteins...
  38. Shin O, Lu J, Rhee J, Tomchick D, Pang Z, Wojcik S, et al. Munc13 C2B domain is an activity-dependent Ca2+ regulator of synaptic exocytosis. Nat Struct Mol Biol. 2010;17:280-8 pubmed publisher
  39. Daoud H, Belzil V, Desjarlais A, Camu W, Dion P, Rouleau G. Analysis of the UNC13A gene as a risk factor for sporadic amyotrophic lateral sclerosis. Arch Neurol. 2010;67:516-7 pubmed publisher
  40. Limbach C, Laue M, Wang X, Hu B, Thiede N, Hultqvist G, et al. Molecular in situ topology of Aczonin/Piccolo and associated proteins at the mammalian neurotransmitter release site. Proc Natl Acad Sci U S A. 2011;108:E392-401 pubmed publisher
    ..At both conventional and ribbon synapses, CAST, Munc13, and RIM are segregated from Aczonin, closer to the PM, and Aczonin is positioned such that it may control the access of neurotransmitter vesicles to the fusion site. ..
  41. Hartlage Rübsamen M, Waniek A, Roßner S. Munc13 genotype regulates secretory amyloid precursor protein processing via postsynaptic glutamate receptors. Int J Dev Neurosci. 2013;31:36-45 pubmed publisher
    ..We conclude that organotypic brain slices cultures are a valuable tool for studying APP processing pathways in intact neuronal circuits and that neuronal activity is important for maintenance of the non-amyloidogenic APP processing. ..
  42. Man K, Imig C, Walter A, Pinheiro P, Stevens D, Rettig J, et al. Identification of a Munc13-sensitive step in chromaffin cell large dense-core vesicle exocytosis. elife. 2015;4: pubmed publisher
    ..Our data demonstrate that the molecular steps of SV and LDCV priming are very similar while SV and LDCV docking mechanisms are distinct. ..
  43. Liu X, Seven A, Camacho M, Esser V, Xu J, Trimbuch T, et al. Functional synergy between the Munc13 C-terminal C1 and C2 domains. elife. 2016;5: pubmed publisher
    ..Overall, our results support a model whereby the multiple domains of Munc13s cooperate to coordinate synaptic vesicle docking, priming and fusion. ..
  44. Yang Y, Calakos N. Munc13-1 is required for presynaptic long-term potentiation. J Neurosci. 2011;31:12053-7 pubmed publisher
    ..These results advance our understanding of the molecular mechanisms of presynaptic plasticity and suggest that modulation of vesicle priming may provide the cellular substrate for expression of LTP at mossy fiber synapses. ..
  45. Shen N, Guryev O, Rizo J. Intramolecular occlusion of the diacylglycerol-binding site in the C1 domain of munc13-1. Biochemistry. 2005;44:1089-96 pubmed
  46. Parsaud L, Li L, Jung C, Park S, Saw N, Park S, et al. Calcium-dependent activator protein for secretion 1 (CAPS1) binds to syntaxin-1 in a distinct mode from Munc13-1. J Biol Chem. 2013;288:23050-63 pubmed publisher
    ..We also propose that the preferential binding of CAPS1 to open syntaxin-1 can contribute to the stabilization of the open state of syntaxin-1 during its transition from "closed" state to the SNARE complex formation. ..
  47. Chen Z, Cooper B, Kalla S, Varoqueaux F, Young S. The Munc13 proteins differentially regulate readily releasable pool dynamics and calcium-dependent recovery at a central synapse. J Neurosci. 2013;33:8336-51 pubmed publisher
    ..Based on these data, we conclude that Munc13-2 and Munc13-3 isoforms limit the ability of Munc13-1 to regulate calcium-dependent replenishment of readily releasable pool and slow pool to fast pool conversion in central synapses. ..
  48. Huang C, Yang D, Lin C, Kao L. Involvement of Rab3A in vesicle priming during exocytosis: interaction with Munc13-1 and Munc18-1. Traffic. 2011;12:1356-70 pubmed publisher
    ..Munc18-1 acts downstream of Munc13-1/RIM/Rab3A and interacts with syntaxin 1a allowing vesicle priming. Furthermore, Munc18-1 promotes Rab3A dissociation from vesicles, which then results in fusion. ..
  49. Yuan Q, Teng L, Zhou J, Liu C, Guo J, Liu L, et al. Characterization of Munc13-1 and insulin secretion during pancreatic development in rats. J Endocrinol Invest. 2008;31:630-5 pubmed
    ..Munc13-1 may play an essential role in insulin exocytosis. ..
  50. Ko J, Zhang C, Arac D, Boucard A, Brunger A, Sudhof T. Neuroligin-1 performs neurexin-dependent and neurexin-independent functions in synapse validation. EMBO J. 2009;28:3244-55 pubmed publisher
    ..Thus, neuroligin-1 performs diverse synaptic functions by mechanisms that include as essential components of alpha-neurexin binding and neuroligin dimerization, but extend beyond these activities. ..
  51. Andrews Zwilling Y, Kawabe H, Reim K, Varoqueaux F, Brose N. Binding to Rab3A-interacting molecule RIM regulates the presynaptic recruitment of Munc13-1 and ubMunc13-2. J Biol Chem. 2006;281:19720-31 pubmed
    ..We conclude that one function of the Munc13/RIM1alpha interaction is the active zone recruitment of Munc13-1 and ubMunc13-2. ..