Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Science 2 February 2001:
Vol. 291. no. 5505, pp. 875 - 878
DOI: 10.1126/science.291.5505.875
Prev | Table of Contents | Next

Reports

Control of Fusion Pore Dynamics During Exocytosis by Munc18

Richard J. Fisher,1 Jonathan Pevsner,2 Robert D. Burgoyne1*

Intracellular membrane fusion is mediated by the SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) proteins. All vesicle transport steps also have an essential requirement for a member of the Sec1 protein family, including the neuronal Munc18-1 (also known as nSec1) in regulated exocytosis. Here, in adrenal chromaffin cells, we expressed a Munc18 mutant with reduced affinity for syntaxin, which specifically modified the kinetics of single-granule exocytotic release events, consistent with an acceleration of fusion pore expansion. Thus, Munc18 functions in a late stage in the fusion process, where its dissociation from syntaxin determines the kinetics of postfusion events.

1 Physiological Laboratory, University of Liverpool, Crown Street, Liverpool, L69 3BX, UK.
2 Department of Neurology, Kennedy Krieger Institute; and Department of Neuroscience, Johns Hopkins School of Medicine, 707 North Broadway, Baltimore, MD 21205, USA.
*   To whom correspondence should be addressed. E-mail: Burgoyne{at}liverpool.ac.uk

Read the Full Text


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Abrogating Munc18-1-SNARE Complex Interaction Has Limited Impact on Exocytosis in PC12 Cells.
N. T. Malintan, T. H. Nguyen, L. Han, C. F. Latham, S. L. Osborne, P. J. Wen, S. J. T. Lim, S. Sugita, B. M. Collins, and F. A. Meunier (2009)
J. Biol. Chem. 284, 21637-21646
   Abstract »    Full Text »    PDF »
UNC-18 Modulates Ethanol Sensitivity in Caenorhabditis elegans.
M. E. Graham, M. R. Edwards, L. Holden-Dye, A. Morgan, R. D. Burgoyne, and J. W. Barclay (2009)
Mol. Biol. Cell 20, 43-55
   Abstract »    Full Text »    PDF »
Munc18a Scaffolds SNARE Assembly to Promote Membrane Fusion.
T. L. Rodkey, S. Liu, M. Barry, and J. A. McNew (2008)
Mol. Biol. Cell 19, 5422-5434
   Abstract »    Full Text »    PDF »
DTNBP1, a schizophrenia susceptibility gene, affects kinetics of transmitter release.
X.-W. Chen, Y.-Q. Feng, C.-J. Hao, X.-L. Guo, X. He, Z.-Y. Zhou, N. Guo, H.-P. Huang, W. Xiong, H. Zheng, et al. (2008)
J. Cell Biol. 181, 791-801
   Abstract »    Full Text »    PDF »
A Random Mutagenesis Approach to Isolate Dominant-Negative Yeast sec1 Mutants Reveals a Functional Role for Domain 3a in Yeast and Mammalian Sec1/Munc18 Proteins.
A. Boyd, L. F. Ciufo, J. W. Barclay, M. E. Graham, L. P. Haynes, M. K. Doherty, M. Riesen, R. D. Burgoyne, and A. Morgan (2008)
Genetics 180, 165-178
   Abstract »    Full Text »    PDF »
Munc18-1 Is Critical for Plasma Membrane Localization of Syntaxin1 but Not of SNAP-25 in PC12 Cells.
L. Arunachalam, L. Han, N. G. Tassew, Y. He, L. Wang, L. Xie, Y. Fujita, E. Kwan, B. Davletov, P. P. Monnier, et al. (2008)
Mol. Biol. Cell 19, 722-734
   Abstract »    Full Text »    PDF »
Temperature Dependence of Fusion Kinetics and Fusion Pores in Ca2+-triggered Exocytosis from PC12 Cells.
Z. Zhang and M. B. Jackson (2008)
J. Gen. Physiol. 131, 117-124
   Abstract »    Full Text »    PDF »
Munc18-1: Sequential Interactions with the Fusion Machinery Stimulate Vesicle Docking and Priming.
A. Gulyas-Kovacs, H. de Wit, I. Milosevic, O. Kochubey, R. Toonen, J. Klingauf, M. Verhage, and J. B. Sorensen (2007)
J. Neurosci. 27, 8676-8686
   Abstract »    Full Text »    PDF »
A Cytosolic Splice Variant of Cab45 Interacts with Munc18b and Impacts on Amylase Secretion by Pancreatic Acini.
P. P.L. Lam, K. Hyvarinen, M. Kauppi, L. Cosen-Binker, S. Laitinen, S. Keranen, H. Y. Gaisano, and V. M. Olkkonen (2007)
Mol. Biol. Cell 18, 2473-2480
   Abstract »    Full Text »    PDF »
Functionally and Spatially Distinct Modes of munc18-Syntaxin 1 Interaction.
C. Rickman, C. N. Medine, A. Bergmann, and R. R. Duncan (2007)
J. Biol. Chem. 282, 12097-12103
   Abstract »    Full Text »    PDF »
Calcium signaling and exocytosis in adrenal chromaffin cells..
A. G. Garcia, A. M. Garcia-De-Diego, L. Gandia, R. Borges, and J. Garcia-Sancho (2006)
Physiol Rev 86, 1093-1131
   Abstract »    Full Text »    PDF »
The Slp4-a Linker Domain Controls Exocytosis through Interaction with Munc18-1{middle dot}Syntaxin-1a Complex.
T. Tsuboi and M. Fukuda (2006)
Mol. Biol. Cell 17, 2101-2112
   Abstract »    Full Text »    PDF »
FUS1 Regulates the Opening and Expansion of Fusion Pores between Mating Yeast.
S. Nolan, A. E. Cowan, D. E. Koppel, H. Jin, and E. Grote (2006)
Mol. Biol. Cell 17, 2439-2450
   Abstract »    Full Text »    PDF »
Myosin-Va Regulates Exocytosis through the Submicromolar Ca2+-dependent Binding of Syntaxin-1A.
M. Watanabe, K. Nomura, A. Ohyama, R. Ishikawa, Y. Komiya, K. Hosaka, E. Yamauchi, H. Taniguchi, N. Sasakawa, K. Kumakura, et al. (2005)
Mol. Biol. Cell 16, 4519-4530
   Abstract »    Full Text »    PDF »
Amisyn Regulates Exocytosis and Fusion Pore Stability by Both Syntaxin-dependent and Syntaxin-independent Mechanisms.
J. R. L. Constable, M. E. Graham, A. Morgan, and R. D. Burgoyne (2005)
J. Biol. Chem. 280, 31615-31623
   Abstract »    Full Text »    PDF »
SNAREs can promote complete fusion and hemifusion as alternative outcomes.
C. G. Giraudo, C. Hu, D. You, A. M. Slovic, E. V. Mosharov, D. Sulzer, T. J. Melia, and J. E. Rothman (2005)
J. Cell Biol. 170, 249-260
   Abstract »    Full Text »    PDF »
Munc18-1 Regulates Early and Late Stages of Exocytosis via Syntaxin-independent Protein Interactions.
L. F. Ciufo, J. W. Barclay, R. D. Burgoyne, and A. Morgan (2005)
Mol. Biol. Cell 16, 470-482
   Abstract »    Full Text »    PDF »
Fluorescence Resonance Energy Transfer Reports Properties of Syntaxin1A Interaction with Munc18-1 in Vivo.
J. Liu, S. A. Ernst, S. E. Gladycheva, Y. Y. F. Lee, S. I. Lentz, C. S. Ho, Q. Li, and E. L. Stuenkel (2004)
J. Biol. Chem. 279, 55924-55936
   Abstract »    Full Text »    PDF »
Cycling of Synaptic Vesicles: How Far? How Fast!.
T. Galli and V. Haucke (2004)
Sci. STKE 2004, re19
   Abstract »    Full Text »    PDF »
Munc-18-2 regulates exocytosis of H+-ATPase in rat inner medullary collecting duct cells.
J. A. Nicoletta, J. J. Ross, G. Li, Q. Cheng, J. Schwartz, E. A. Alexander, and J. H. Schwartz (2004)
Am J Physiol Cell Physiol 287, C1366-C1374
   Abstract »    Full Text »    PDF »
Regulation of the Fusion Pore Conductance during Exocytosis by Cyclin-dependent Kinase 5.
J. W. Barclay, M. Aldea, T. J. Craig, A. Morgan, and R. D. Burgoyne (2004)
J. Biol. Chem. 279, 41495-41503
   Abstract »    Full Text »    PDF »
Syntaxin/Munc18 Interactions in the Late Events during Vesicle Fusion and Release in Exocytosis.
M. E. Graham, J. W. Barclay, and R. D. Burgoyne (2004)
J. Biol. Chem. 279, 32751-32760
   Abstract »    Full Text »    PDF »
rsly1 Binding to Syntaxin 5 Is Required for Endoplasmic Reticulum-to-Golgi Transport but Does Not Promote SNARE Motif Accessibility.
A. L. Williams, S. Ehm, N. C. Jacobson, D. Xu, and J. C. Hay (2004)
Mol. Biol. Cell 15, 162-175
   Abstract »    Full Text »    PDF »
Controversies in synaptic vesicle exocytosis.
R. M. Weimer and E. M. Jorgensen (2003)
J. Cell Sci. 116, 3661-3666
   Full Text »    PDF »
Munc18-Syntaxin Complexes and Exocytosis in Human Platelets.
A. Houng, J. Polgar, and G. L. Reed (2003)
J. Biol. Chem. 278, 19627-19633
   Abstract »    Full Text »    PDF »
Secretory Granule Exocytosis.
R. D. Burgoyne and A. Morgan (2003)
Physiol Rev 83, 581-632
   Abstract »    Full Text »    PDF »
Phosphorylation of Munc18 by Protein Kinase C Regulates the Kinetics of Exocytosis.
J. W. Barclay, T. J. Craig, R. J. Fisher, L. F. Ciufo, G. J. O. Evans, A. Morgan, and R. D. Burgoyne (2003)
J. Biol. Chem. 278, 10538-10545
   Abstract »    Full Text »    PDF »
Secretory granules are recaptured largely intact after stimulated exocytosis in cultured endocrine cells.
J. W. Taraska, D. Perrais, M. Ohara-Imaizumi, S. Nagamatsu, and W. Almers (2003)
PNAS 100, 2070-2075
   Abstract »    Full Text »    PDF »
Evidence of a role for Munc18-2 and microtubules in mast cell granule exocytosis.
S. Martin-Verdeaux, I. Pombo, B. Iannascoli, M. Roa, N. Varin-Blank, J. Rivera, and U. Blank (2003)
J. Cell Sci. 116, 325-334
   Abstract »    Full Text »    PDF »
Role of Secretory Carrier Membrane Protein SCAMP2 in Granule Exocytosis.
L. Liu, Z. Guo, Q. Tieu, A. Castle, and D. Castle (2002)
Mol. Biol. Cell 13, 4266-4278
   Abstract »    Full Text »    PDF »
Perturbation of a Very Late Step of Regulated Exocytosis by a Secretory Carrier Membrane Protein (SCAMP2)-derived Peptide.
Z. Guo, L. Liu, D. Cafiso, and D. Castle (2002)
J. Biol. Chem. 277, 35357-35363
   Abstract »    Full Text »    PDF »
Calcium-independent stimulation of membrane fusion and SNAREpin formation by synaptotagmin I.
L. K. Mahal, S. M. Sequeira, J. M. Gureasko, and T. H. Sollner (2002)
J. Cell Biol. 158, 273-282
   Abstract »    Full Text »    PDF »
Sequential SNARE disassembly and GATE-16-GOS-28 complex assembly mediated by distinct NSF activities drives Golgi membrane fusion.
J. M.M. Muller, J. Shorter, R. Newman, K. Deinhardt, Y. Sagiv, Z. Elazar, G. Warren, and D. T. Shima (2002)
J. Cell Biol. 157, 1161-1173
   Abstract »    Full Text »    PDF »
Complexin Regulates the Closure of the Fusion Pore during Regulated Vesicle Exocytosis.
D. A. Archer, M. E. Graham, and R. D. Burgoyne (2002)
J. Biol. Chem. 277, 18249-18252
   Abstract »    Full Text »    PDF »
Dynamin-dependent and dynamin-independent processes contribute to the regulation of single vesicle release kinetics and quantal size.
M. E. Graham, D. W. O'Callaghan, H. T. McMahon, and R. D. Burgoyne (2002)
PNAS 99, 7124-7129
   Abstract »    Full Text »    PDF »
SNAP-25 with mutations in the zero layer supports normal membrane fusion kinetics.
M. E. Graham, P. Washbourne, M. C. Wilson, and R. D. Burgoyne (2002)
J. Cell Sci. 114, 4397-4405
   Abstract »    Full Text »    PDF »
A common molecular machinery for exocytosis and the kiss-and-run' mechanism in chromaffin cells is controlled by phosphorylation.
A. W. Henkel, G. Kang, and J. Kornhuber (2002)
J. Cell Sci. 114, 4613-4620
   Abstract »    Full Text »    PDF »
Phosphorylation of Cysteine String Protein by Protein Kinase A. IMPLICATIONS FOR THE MODULATION OF EXOCYTOSIS.
G. J. O. Evans, M. C. Wilkinson, M. E. Graham, K. M. Turner, L. H. Chamberlain, R. D. Burgoyne, and A. Morgan (2001)
J. Biol. Chem. 276, 47877-47885
   Abstract »    Full Text »    PDF »
Synaptotagmin Modulation of Fusion Pore Kinetics in Regulated Exocytosis of Dense-Core Vesicles.
C.-T. Wang, R. Grishanin, C. A. Earles, P. Y. Chang, T. F. J. Martin, E. R. Chapman, and M. B. Jackson (2001)
Science 294, 1111-1115
   Abstract »    Full Text »    PDF »
Neuronal Glutamate Transporters Limit Activation of NMDA Receptors by Neurotransmitter Spillover on CA1 Pyramidal Cells.
J. S. Diamond (2001)
J. Neurosci. 21, 8328-8338
   Abstract »    Full Text »    PDF »
Spring, a Novel RING Finger Protein That Regulates Synaptic Vesicle Exocytosis.
Y. Li, L.-S. Chin, C. Weigel, and L. Li (2001)
J. Biol. Chem. 276, 40824-40833
   Abstract »    Full Text »    PDF »
SNARE proteins are highly enriched in lipid rafts in PC12 cells: Implications for the spatial control of exocytosis.
L. H. Chamberlain, R. D. Burgoyne, and G. W. Gould (2001)
PNAS 98, 5619-5624
   Abstract »    Full Text »    PDF »
Three SNARE complexes cooperate to mediate membrane fusion.
Y. Hua and R. H. Scheller (2001)
PNAS 98, 8065-8070
   Abstract »    Full Text »    PDF »


To Advertise     Find Products

Science. ISSN 0036-8075 (print), 1095-9203 (online)