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The Journal of Neuroscience, January 7, 2009, 29(1):23-37; doi:10.1523/JNEUROSCI.3931-08.2009

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Cellular/Molecular
Matrix-Dependent Local Retention of Secretory Vesicle Cargo in Cortical Neurons

Joris de Wit, Ruud F. Toonen, and Matthijs Verhage

Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, Vrije Universiteit Amsterdam (VUA) and VUA Medical Center, 1081 HV Amsterdam, The Netherlands

Correspondence should be addressed to Prof. Matthijs Verhage, Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, Vrije Universiteit Amsterdam (VUA) and VUA Medical Center, De Boelelaan 1087, 1081 HV Amsterdam, The Netherlands. Email: matthijs.verhage{at}cncr.vu.nl

Neurons secrete many diffusible signals from synaptic and other secretory vesicles. We characterized secretion of guidance cues, neuropeptides, neurotrophins, and proteases from single secretory vesicles using pHluorin-tagged cargo in cortical neurons. Stimulation triggered transient and persistent fusion events. Transient events represented full release followed by cargo diffusion or incomplete release followed by vesicle retrieval, as previously observed in neuroendocrine cells. Unexpectedly, we also observed that certain cargo, such as Semaphorin 3A (Sema3A), was delivered at the cell surface as stable deposits. Stable deposits and transient events were observed for single cargo and both were SNARE (soluble N-ethylmaleimide-sensitive factor attachment protein receptor) and calcium dependent. The ratio between stable and transient events did not depend on cargo size, subcellular localization (synaptic vs extrasynaptic secretion), or the presence of the extracellular matrix. Instead, the ratio is cargo specific and depends on an interaction with the vesicle matrix through a basic domain in the cargo protein. Inhibition of this interaction through deletion of the basic domain in Sema3A abolished stable deposits and rendered all events transient. Strikingly, cargo favoring transient release was stably deposited after corelease with cargo favoring stable deposit. These data argue against cargo diffusion after exocytosis as a general principle. Instead, the vesicle matrix retains secreted signals, probably for focal signaling at the cell surface.

Key words: exocytosis; activity-dependent secretion; peptidergic release; neurons; synaptic plasticity; large dense-core vesicles

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Received Aug. 18, 2008; revised Nov. 21, 2008; accepted Nov. 23, 2008.

Correspondence should be addressed to Prof. Matthijs Verhage, Department of Functional Genomics, Center for Neurogenomics and Cognitive Research, Vrije Universiteit Amsterdam (VUA) and VUA Medical Center, De Boelelaan 1087, 1081 HV Amsterdam, The Netherlands. Email: matthijs.verhage{at}cncr.vu.nl

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