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.
Subscribe

Logo for

Science 327 (5973): 1614-1618

Copyright © 2010 by the American Association for the Advancement of Science

Doc2b Is a High-Affinity Ca2+ Sensor for Spontaneous Neurotransmitter Release

Alexander J. Groffen,1,*,§ Sascha Martens,2,*,{dagger},§ Rocío Díez Arazola,1 L. Niels Cornelisse,1 Natalia Lozovaya,1,3,4 Arthur P. H. de Jong,1 Natalia A. Goriounova,1,3 Ron L. P. Habets,5,{ddagger} Yoshimi Takai,5 J. Gerard Borst,4 Nils Brose,6 Harvey T. McMahon,2,* Matthijs Verhage1,*

Abstract: Synaptic vesicle fusion in brain synapses occurs in phases that are either tightly coupled to action potentials (synchronous), immediately following action potentials (asynchronous), or as stochastic events in the absence of action potentials (spontaneous). Synaptotagmin-1, -2, and -9 are vesicle-associated Ca2+ sensors for synchronous release. Here we found that double C2 domain (Doc2) proteins act as Ca2+ sensors to trigger spontaneous release. Although Doc2 proteins are cytosolic, they function analogously to synaptotagmin-1 but with a higher Ca2+ sensitivity. Doc2 proteins bound to N-ethylmaleimide–sensitive factor attachment receptor (SNARE) complexes in competition with synaptotagmin-1. Thus, different classes of multiple C2 domain–containing molecules trigger synchronous versus spontaneous fusion, which suggests a general mechanism for synaptic vesicle fusion triggered by the combined actions of SNAREs and multiple C2 domain–containing proteins.

1 Department of Functional Genomics, CNCR, Neuroscience Campus Amsterdam, VU University and VU Medical Center, Amsterdam, 1081 HV, Netherlands.
2 Medical Research Council (MRC) Laboratory of Molecular Biology, Hills Road, Cambridge, CB2 0QH, UK.
3 Department of Integrative Neurophysiology, CNCR, VU University, Amsterdam, 1081 HV, Netherlands.
4 Bogomoletz Institute of Physiology, Kiev, 01024, Ukraine.
5 Department of Neuroscience, Erasmus MC, University Medical Center, Rotterdam, 3000 CA, Netherlands.
6 Department of Biochemistry and Molecular Biology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.
7 Max-Planck-Institut für Experimentelle Medizin, Abteilung Molekulare Neurobiologie, 37075 Göttingen, Germany.

* These authors contributed equally to this work.

{dagger} Present address: Max F. Perutz Laboratories, University of Vienna, Dr. Bohr-Gasse 9/3, 1030 Vienna, Austria.

{ddagger} Present address: Department of Molecular and Developmental Genetics, K.U.Leuven, Center for Human Genetics, 3000 Belgium.

§ To whom correspondence should be addressed. E-mail: sander.groffen{at}cncr.vu.nl (A.J.G.) and sascha.martens{at}univie.ac.at (S.M.)

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Mitochondria and plasma membrane Ca2+-ATPase control presynaptic Ca2+ clearance in capsaicin-sensitive rat sensory neurons.
L. P. Shutov, M.-S. Kim, P. R. Houlihan, Y. V. Medvedeva, and Y. M. Usachev (2013)
J. Physiol. 591, 2443-2462
   Abstract »    Full Text »    PDF »
Doc2b promotes GLUT4 exocytosis by activating the SNARE-mediated fusion reaction in a calcium- and membrane bending-dependent manner.
H. Yu, S. S. Rathore, E. M. Davis, Y. Ouyang, and J. Shen (2013)
Mol. Biol. Cell 24, 1176-1184
   Abstract »    Full Text »    PDF »
DOC2B and Munc13-1 Differentially Regulate Neuronal Network Activity.
A. Lavi, A. Sheinin, R. Shapira, D. Zelmanoff, and U. Ashery (2013)
Cereb Cortex
   Abstract »    Full Text »    PDF »
Monomeric Synucleins Generate Membrane Curvature.
C. H. Westphal and S. S. Chandra (2013)
J. Biol. Chem. 288, 1829-1840
   Abstract »    Full Text »    PDF »
Apical vacuole formation by gastric parietal cells in primary culture: effect of low extracellular Ca2+.
S. L. Nakada, J. M. Crothers Jr., T. E. Machen, and J. G. Forte (2012)
Am J Physiol Cell Physiol 303, C1301-C1311
   Abstract »    Full Text »    PDF »
Miniature IPSCs in Hippocampal Granule Cells Are Triggered by Voltage-Gated Ca2+ Channels via Microdomain Coupling.
S. P. Goswami, I. Bucurenciu, and P. Jonas (2012)
J. Neurosci. 32, 14294-14304
   Abstract »    Full Text »    PDF »
Calcium-Dependent Isoforms of Protein Kinase C Mediate Glycine-Induced Synaptic Enhancement at the Calyx of Held.
Y. Chu, D. Fioravante, M. Thanawala, M. Leitges, and W. G. Regehr (2012)
J. Neurosci. 32, 13796-13804
   Abstract »    Full Text »    PDF »
Distinct Initial SNARE Configurations Underlying the Diversity of Exocytosis.
H. Kasai, N. Takahashi, and H. Tokumaru (2012)
Physiol Rev 92, 1915-1964
   Abstract »    Full Text »    PDF »
Doc2b Is a Key Effector of Insulin Secretion and Skeletal Muscle Insulin Sensitivity.
L. Ramalingam, E. Oh, S. M. Yoder, J. T. Brozinick, M. A. Kalwat, A. J. Groffen, M. Verhage, and D. C. Thurmond (2012)
Diabetes 61, 2424-2432
   Abstract »    Full Text »    PDF »
Tonic and Transient Endocannabinoid Regulation of AMPAergic Miniature Postsynaptic Currents and Homeostatic Plasticity in Embryonic Motor Networks.
C. Gonzalez-Islas, M. A. Garcia-Bereguiain, and P. Wenner (2012)
J. Neurosci. 32, 13597-13607
   Abstract »    Full Text »    PDF »
Early Presynaptic and Postsynaptic Calcium Signaling Abnormalities Mask Underlying Synaptic Depression in Presymptomatic Alzheimer's Disease Mice.
S. Chakroborty, J. Kim, C. Schneider, C. Jacobson, J. Molgo, and G. E. Stutzmann (2012)
J. Neurosci. 32, 8341-8353
   Abstract »    Full Text »    PDF »
Spontaneous transmitter release is critical for the induction of long-term and intermediate-term facilitation in Aplysia.
I. Jin, S. Puthanveettil, H. Udo, K. Karl, E. R. Kandel, and R. D. Hawkins (2012)
PNAS 109, 9131-9136
   Abstract »    Full Text »    PDF »
Munc13-4 reconstitutes calcium-dependent SNARE-mediated membrane fusion.
K. L. Boswell, D. J. James, J. M. Esquibel, S. Bruinsma, R. Shirakawa, H. Horiuchi, and T. F. J. Martin (2012)
J. Cell Biol. 197, 301-312
   Abstract »    Full Text »    PDF »
Cell-Cell Membrane Fusion Induced by p15 Fusion-associated Small Transmembrane (FAST) Protein Requires a Novel Fusion Peptide Motif Containing a Myristoylated Polyproline Type II Helix.
D. Top, J. A. Read, S. J. Dawe, R. T. Syvitski, and R. Duncan (2012)
J. Biol. Chem. 287, 3403-3414
   Abstract »    Full Text »    PDF »
A DOC2 Protein Identified by Mutational Profiling Is Essential for Apicomplexan Parasite Exocytosis.
A. Farrell, S. Thirugnanam, A. Lorestani, J. D. Dvorin, K. P. Eidell, D. J. P. Ferguson, B. R. Anderson-White, M. T. Duraisingh, G. T. Marth, and M.-J. Gubbels (2012)
Science 335, 218-221
   Abstract »    Full Text »    PDF »
Calcium Control of Neurotransmitter Release.
T. C. Sudhof (2012)
Cold Spring Harb Perspect Biol 4, a011353
   Abstract »    Full Text »    PDF »
Reconstituted synaptotagmin I mediates vesicle docking, priming, and fusion.
Z. Wang, H. Liu, Y. Gu, and E. R. Chapman (2011)
J. Cell Biol. 195, 1159-1170
   Abstract »    Full Text »    PDF »
Dendritic SNAREs add a new twist to the old neuron theory.
S. V. Ovsepian and J. O. Dolly (2011)
PNAS 108, 19113-19120
   Abstract »    Full Text »    PDF »
Calcium Triggers Exocytosis from Two Types of Organelles in a Single Astrocyte.
T. Liu, L. Sun, Y. Xiong, S. Shang, N. Guo, S. Teng, Y. Wang, B. Liu, C. Wang, L. Wang, et al. (2011)
J. Neurosci. 31, 10593-10601
   Abstract »    Full Text »    PDF »
Forming giant vesicles with controlled membrane composition, asymmetry, and contents.
D. L. Richmond, E. M. Schmid, S. Martens, J. C. Stachowiak, N. Liska, and D. A. Fletcher (2011)
PNAS 108, 9431-9436
   Abstract »    Full Text »    PDF »
Deciphering the Roles of C2-Domain-Containing Proteins (Synaptotagmins and Otoferlin) in the Inner Ear.
F. D. Gregory and P. M. Quinones (2011)
J. Neurosci. 31, 4765-4767
   Full Text »    PDF »
Spontaneous Glutamate Release Is Independent of Calcium Influx and Tonically Activated by the Calcium-Sensing Receptor.
N. P. Vyleta and S. M. Smith (2011)
J. Neurosci. 31, 4593-4606
   Abstract »    Full Text »    PDF »
Spontaneous Neurotransmission: An Independent Pathway for Neuronal Signaling?.
E. T. Kavalali, C. Chung, M. Khvotchev, J. Leitz, E. Nosyreva, J. Raingo, and D. M. O. Ramirez (2011)
Physiology 26, 45-53
   Abstract »    Full Text »    PDF »
Role of the synaptobrevin C terminus in fusion pore formation.
A. N. Ngatchou, K. Kisler, Q. Fang, A. M. Walter, Y. Zhao, D. Bruns, J. B. Sorensen, and M. Lindau (2010)
PNAS 107, 18463-18468
   Abstract »    Full Text »    PDF »
Distinct roles for two synaptotagmin isoforms in synchronous and asynchronous transmitter release at zebrafish neuromuscular junction.
H. Wen, M. W. Linhoff, M. J. McGinley, G.-L. Li, G. M. Corson, G. Mandel, and P. Brehm (2010)
PNAS 107, 13906-13911
   Abstract »    Full Text »    PDF »
The Diversity of Calcium Sensor Proteins in the Regulation of Neuronal Function.
H. V. McCue, L. P. Haynes, and R. D. Burgoyne (2010)
Cold Spring Harb Perspect Biol 2, a004085
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882