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The Journal of Neuroscience, November 9, 2005, 25(45):10546-10555; doi:10.1523/JNEUROSCI.3275-05.2005

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Cellular/Molecular
The Role of Snapin in Neurosecretion: Snapin Knock-Out Mice Exhibit Impaired Calcium-Dependent Exocytosis of Large Dense-Core Vesicles in Chromaffin Cells

Jin-Hua Tian,^1 * Zheng-Xing Wu,^2 * Michael Unzicker,² Li Lu,¹ Qian Cai,¹ Cuiling Li,³ Claudia Schirra,² Ulf Matti,² David Stevens,² Chuxia Deng,³ Jens Rettig,² and Zu-Hang Sheng¹

¹Synaptic Function Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892-3701, ²Physiologisches Institut, Universitaet des Saarlandes, 66424 Homburg/Saar, Germany, and ³Mammalian Genetics Section, Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892

Identification of the molecules that regulate the priming of synaptic vesicles for fusion and the structural coupling of the calcium sensor with the soluble N-ethyl maleimide sensitive factor adaptor protein receptor (SNARE)-based fusion machinery is critical for understanding the mechanisms underlying calcium-dependent neurosecretion. Snapin binds to synaptosomal-associated protein 25 kDa (SNAP-25) and enhances the association of the SNARE complex with synaptotagmin. In the present study, we abolished snapin expression in mice and functionally evaluated the role of Snapin in neuroexocytosis. We found that the association of synaptotagmin-1 with SNAP-25 in brain homogenates of snapin mutant mice is impaired. Consequently, the absence of Snapin in embryonic chromaffin cells leads to a significant reduction of calcium-dependent exocytosis resulting from a decreased number of vesicles in releasable pools. Overexpression of Snapin fully rescued this inhibitory effect in the mutant cells. Furthermore, Snapin is relatively enriched in the purified large dense-core vesicles of chromaffin cells and associated with synaptotagmin-1. Thus, our biochemical and electrophysiological studies using snapin knock-out mice demonstrate that Snapin plays a critical role in modulating neurosecretion by stabilizing the release-ready vesicles.

Key words: exocytosis; neurosecretion; SNARE proteins; synaptic vesicle release; chromaffin cell; catecholamine

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Received Aug 4, 2005; revised September 26, 2005; accepted September 29, 2005.

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