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          Institute: MPI für molekulare Genetik     Collection: Department of Human Molecular Genetics     Display Documents



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ID: 307334.0, MPI für molekulare Genetik / Department of Human Molecular Genetics
The first lumenal domain of vesicular monoamine transporters mediates G-protein-dependent regulation of transmitter uptake
Authors:Brunk, Irene; Blex, Christian; Rachakonda, Sivaramakrishna; Höltje, Markus; Winter, Sandra; Pahner, Ingrid; Walther, Diego J.; Ahnert-Hilger, Gudrun
Language:English
Date of Publication (YYYY-MM-DD):2006-11-03
Title of Journal:Journal of Biological Chemistry
Journal Abbrev.:J. Biol. Chem
Volume:281
Issue / Number:44
Start Page:33373
End Page:33385
Copyright:Copyright © 2006 by the American Society for Biochemistry and Molecular Biology.
Review Status:not specified
Audience:Experts Only
Abstract / Description:The activity of vesicular monoamine transporters (VMATs) is down-regulated by the G-protein {alpha}-subunits of Go2 and Gq, but the signaling pathways are not known. We show here that no such regulation is observed when VMAT1 or VMAT2 are expressed in Chinese hamster ovary (CHO) cells. However, when the intracellular compartments of VMAT-expressing CHO cells are preloaded with different monoamines, transport becomes susceptible to G-protein-dependent regulation, with differences between the two transporter isoforms. Epinephrine induces G-protein-mediated inhibition of transmitter uptake in CHOVMAT1 cells but prevents inhibition induced by dopamine in CHOVMAT2 cells. Epinephrine also antagonizes G-protein-mediated inhibition of monoamine uptake by VMAT2 expressing platelets or synaptic vesicles. In CHOVMAT2 cells G-protein-mediated inhibition of monoamine uptake can be induced by 5-hydroxytryptamine (serotonin) 1B receptor agonists, whereas {alpha}1 receptor agonists modulate uptake into CHOVMAT1 cells. Accordingly, 5-hydroxytryptamine 1B receptor antagonists prevent G-proteinmediated inhibition of uptake in partially filled platelets and synaptic vesicles expressing VMAT2. CHO cells expressing VMAT mutants with a shortened first vesicular loop transport monoamines. However, no or a reduced G-protein regulation of uptake can be initiated. In conclusion, vesicular content is involved in the activation of vesicle associated G-proteins via a structure sensing the luminal monoamine content. The first luminal loop of VMATs may represent a G-protein-coupled receptor that adapts vesicular filling.
Comment of the Author/Creator:This work was supported by the Deutsche Forschungsgemeinschaft. 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.
To whom correspondence should be addressed: AG Functional Cell Biology, Centre for Anatomy, Charité-Universitätsmedizin, Philippstr. 12, D-10115 Berlin, Germany. Tel.: 49-30-450-528276; Fax: 49-30-450-528912; E-mail: gudrun.ahnert@charite.de.
External Publication Status:published
Document Type:Article
Communicated by:Hans-Hilger Ropers
Affiliations:MPI für molekulare Genetik
External Affiliations:1.Functional Cell Biology, Centre for Anatomy, Charité-Universitätsmedizin Berlin, Philippstrasse 12 D-10115 Berlin, Germany.
Identifiers:ISSN:0021-9258
DOI:10.1074/jbc.M603204200
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