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Complexin II plays a positive role in Ca2+-triggered exocytosis by facilitating vesicle priming

Cai, Haijiang and Reim, Kerstin and Varoqueaux, Frederique and Tapechum, Sompol and Hill, Kerstin and Sørensen, Jakob and Brose, Nils and Chow, Robert H. (2008) Complexin II plays a positive role in Ca2+-triggered exocytosis by facilitating vesicle priming. Proceedings of the National Academy of Sciences of the United States of America, 105 (49). pp. 19537-19542. ISSN 0027-8424. http://resolver.caltech.edu/CaltechAUTHORS:CAIpnas08

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Abstract

SNARE-mediated exocytosis is a multistage process central to synaptic transmission and hormone release. Complexins (CPXs) are small proteins that bind very rapidly and with a high affinity to the SNARE core complex, where they have been proposed recently to inhibit exocytosis by clamping the complex and inhibiting membrane fusion. However, several other studies also suggest that CPXs are positive regulators of neurotransmitter release. Thus, whether CPXs are positive or negative regulators of exocytosis is not known, much less the stage in the vesicle life cycle at which they function. Here, we systematically dissect the vesicle stages leading up to exocytosis using a knockout-rescue strategy in a mammalian model system. We show that adrenal chromaffin cells from CPX II knockout mice exhibit markedly diminished releasable vesicle pools (comprising the readily and slowly releasable pools), while showing no change in the kinetics of fusion pore dilation or morphological vesicle docking. Overexpression of WT CPX II—but not of SNARE-binding-deficient mutants—restores the size of the the releasable pools in knockout cells, and in WT cells it markedly enlarges them. Our results show that CPXs regulate the size of the primed vesicle pools and have a positive role in Ca2+-triggered exocytosis.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1073/pnas.0810232105DOIUNSPECIFIED
http://www.pnas.org/content/105/49/19538.abstractPublisherUNSPECIFIED
Additional Information:© 2008 by The National Academy of Sciences of the USA. Communicated by Clay M. Armstrong, University of Pennsylvania, Philadelphia, PA, October 10, 2008 (received for review August 3, 2008). Published online before print November 25, 2008, doi: 10.1073/pnas.0810232105 We thank J. Johnson, W. Xiong, D. Michael, D. Sieburth, S. Hamm-Alvarez, A. Mircheff, L. Zhang and R. Langen for comments. This work was funded by the National Institutes of Health (R.H.C.), the American Heart Association (R.H.C.), the University of Southern California New Faculty Startup Fund (R.H.C.), the Human Frontiers Science Program (N.B. and R.H.C), and the Deutsche Forschungsgemeinschaft (N.B. and J.B.S.). Author contributions: H.C., J.B.S., N.B., and R.H.C. designed research; H.C., K.R., F.V., S.T., K.H., and J.B.S. performed research; K.R. and S.T. contributed new reagents/analytic tools; H.C., K.R., F.V., K.H., and J.B.S. analyzed data; and H.C., J.B.S., N.B., and R.H.C. wrote the paper. The authors declare no conflict of interest. This article contains supporting information online at www.pnas.org/cgi/content/full/0810232105/DCSupplemental.
Funders:
Funding AgencyGrant Number
National Institutes of HealthUNSPECIFIED
American Heart AssociationUNSPECIFIED
New Faculty Startup Fund, University of Southern CaliforniaUNSPECIFIED
Human Frontiers Science ProgramUNSPECIFIED
Deutsche Forschungsgemeinschaft (DFG)UNSPECIFIED
Subject Keywords:chromaffin cell; large dense core vesicle; SNARE complex
Issue or Number:49
Record Number:CaltechAUTHORS:CAIpnas08
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:CAIpnas08
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:12511
Collection:CaltechAUTHORS
Deposited By: Archive Administrator
Deposited On:12 Dec 2008 00:53
Last Modified:14 Nov 2014 19:20

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