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J. Biol. Chem., Vol. 284, Issue 2, 1050-1056, January 9, 2009

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Ca²⁺-dependent Activator Proteins of Secretion Promote Vesicular Monoamine Uptake^*

Irene Brunk, Christian Blex, Dina Speidel¹, Nils Brose, and Gudrun Ahnert-Hilger²

From the AG Functional Cell Biology, Institute for Integrative Neuroanatomy, Charité Center 2 for Basic Medicine, Philippstr. 12, D-10115 Berlin and the Department of Molecular Neurobiology, Max Planck Institute of Experimental Medicine, Hermann-Rein-Str. 3, D-37075 Göttingen, Germany

Ca²⁺-dependent activator proteins of secretion (CAPS) 1 and 2 are essential regulators of synaptic vesicle and large dense core vesicle priming in mammalian neurons and neuroendocrine cells. CAPS1 appears to have an additional and as yet unexplained function in vesicular catecholamine uptake or storage as CAPS1-deficient chromaffin cells exhibit strongly reduced vesicular catecholamine levels. Here we describe a role of CAPS proteins in vesicular monoamine uptake. Both CAPS1 and CAPS2 promote monoamine uptake and storage mediated by the vesicular monoamine transporters VMAT1 and VMAT2. Monoamine uptake of vesicular preparations from embryonic brains of CAPS1 deletion mutants is decreased as compared with corresponding preparations from wild type littermates, and anti-CAPS1 or anti-CAPS2 antibodies inhibit monoamine sequestration by synaptic vesicles from adult mouse brain. In addition, overexpression of CAPS1 or CAPS2 enhances vesicular monoamine uptake in Chinese hamster ovary cells that stably express VMAT1 or VMAT2. CAPS function has been linked to the heterotrimeric GTPase G_o, which modulates vesicular monoamine uptake. We found that the expression of CAPS1 is decreased in brain membrane preparations from mice lacking G_o2, which may explain the reduced monoamine uptake by G_o2-deficient synaptic vesicles. Accordingly, anti-CAPS1 antibodies do not further reduce monoamine uptake by G_o2-deficient synaptic vesicles, whereas antibodies directed against CAPS2, whose expression is not altered in G_o2-deficient brain, still reduce monoamine uptake into G_o2-deficient vesicles. We conclude that CAPS proteins are involved in optimizing vesicular monoamine uptake and storage mediated by VMAT1 and VMAT2.

Received for publication, July 14, 2008 , and in revised form, November 13, 2008.

^* This work was supported by Max Planck Society Grant AH 67/3-3 (to G. A.-H.) and German Research Foundation Grant SFB406/A1 (to N. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Present address: Lund University, Dept. of Clinical Sciences Malmö, UMAS Ing 72, CRC 91-11, S-20502 Malmö, Sweden.

² To whom correspondence should be addressed. E-mail: gudrun.ahnert{at}charite.de.

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