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The Journal of Neuroscience, July 2, 2008, 28(27):6794-6806; doi:10.1523/JNEUROSCI.0538-08.2008

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Cellular/Molecular
DOC2B Acts as a Calcium Switch and Enhances Vesicle Fusion

Reut Friedrich,1 * Alexander J. Groffen,2 * Emma Connell,3 Jan R. T. van Weering,2 Orit Gutman,1 Yoav I. Henis,1 Bazbek Davletov,3 and Uri Ashery1

1Department of Neurobiology, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel, 2Department of Functional Genomics, Center for Neurogenomics and Cognition Research, Vrije Universiteit (VU) and VU Medical Centre, 1081 HV Amsterdam, The Netherlands, and 3Neurobiology Division, Medical Research Council–Laboratory of Molecular Biology, Cambridge CB2 0QH, United Kingdom

Correspondence should be addressed to Uri Ashery, Department of Neurobiology, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel. Email: uria{at}post.tau.ac.il

Calcium-dependent exocytosis is regulated by a vast number of proteins. DOC2B is a synaptic protein that translocates to the plasma membrane (PM) after small elevations in intracellular calcium concentration. The aim of this study was to investigate the role of DOC2B in calcium-triggered exocytosis. Using biochemical and biophysical measurements, we demonstrate that the C2A domain of DOC2B interacts directly with the PM in a calcium-dependent manner. Using a combination of electrophysiological, morphological, and total internal reflection fluorescent measurements, we found that DOC2B acts as a priming factor and increases the number of fusion-competent vesicles. Comparing secretion during repeated stimulation between wild-type DOC2B and a mutated DOC2B that is constantly at the PM showed that DOC2B enhances catecholamine secretion also during repeated stimulation and that DOC2B has to translocate to the PM to exert its facilitating effect, suggesting that its activity is dependent on calcium. The hypothesis that DOC2B exerts its effect at the PM was supported by the finding that DOC2B affects the fusion kinetics of single vesicles and interacts with the PM SNAREs (soluble NSF attachment receptors). We conclude that DOC2B is a calcium-dependent priming factor and its activity at the PM enables efficient expansion of the fusion pore, leading to increased catecholamine release.

Key words: DOC2B; priming; calcium; exocytosis; SNAREs; plasma membrane

Received Feb. 6, 2008; revised May 20, 2008; accepted May 20, 2008.

Correspondence should be addressed to Uri Ashery, Department of Neurobiology, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel. Email: uria{at}post.tau.ac.il






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