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The Journal of Neuroscience, May 4, 2005, 25(18):4672-4680; doi:10.1523/JNEUROSCI.0549-05.2005

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Cellular/Molecular
G_o2 Regulates Vesicular Glutamate Transporter Activity by Changing Its Chloride Dependence

Sandra Winter,^1 * Irene Brunk,^1 * Diego J. Walther,² Markus Höltje,¹ Meisheng Jiang,³ Jens-Uwe Peter,² Shigeo Takamori,⁴ Reinhard Jahn,⁴ Lutz Birnbaumer,³ and Gudrun Ahnert-Hilger¹

¹AG Funktionelle Zellbiologie, Centrum für Anatomie, Charité Universitätsmedizin Berlin, D-10115 Berlin, Germany, ²Max-Planck-Institut für Molekulare Genetik, D-14195 Berlin, Germany, ³National Institute of Environmental Health Sciences, Triangle Park, North Carolina 27709, and ⁴Max-Planck-Institut für Biophysikalische Chemie, D-37707 Göttingen, Germany

Classical neurotransmitters, including monoamines, acetylcholine, glutamate, GABA, and glycine, are loaded into synaptic vesicles by means of specific transporters. Vesicular monoamine transporters are under negative regulation by subunits of trimeric G-proteins, including G_o2 and G_q. Furthermore, glutamate uptake, mediated by vesicular glutamate transporters (VGLUTs), is decreased by the nonhydrolysable GTP-analog guanylylimidodiphosphate. Using mutant mice lacking various G subunits, including G_o1, G_o2, G_q, and G₁₁, and a G_o2-specific monoclonal antibody, we now show that VGLUTs are exclusively regulated by G_o2. G-protein activation does not affect the electrochemical proton gradient serving as driving force for neurotransmitter uptake; rather, G_o2 exerts its action by specifically affecting the chloride dependence of VGLUTs. All VGLUTs show maximal activity at 5 mM chloride. Activated G_o2 shifts this maximum to lower chloride concentrations. In contrast, glutamate uptake by vesicles isolated from G_o2^-/- mice have completely lost chloride activation. Thus, G_o2 acts on a putative regulatory chloride binding domain that appears to modulate transport activity of vesicular glutamate transporters.

Key words: G_o2; VGLUT; regulation; vesicular transmitter transporter; presynaptic; plasticity; chloride dependence

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Received July 20, 2004; revised March 21, 2005; accepted March 29, 2005.

This article has been cited by other articles:

				I. Brunk, C. Blex, C. Sanchis-Segura, J. Sternberg, S. Perreau-Lenz, A. Bilbao, H. Hortnagl, J. Baron, J. Juranek, G. Laube, et al. Deletion of Go2{alpha} abolishes cocaine-induced behavioral sensitization by disturbing the striatal dopamine system FASEB J, October 1, 2008; 22(10): 3736 - 3746. [Abstract] [Full Text] [PDF]

				I. Brunk, C. Blex, S. Rachakonda, M. Holtje, S. Winter, I. Pahner, D. J. Walther, and G. Ahnert-Hilger The First Luminal Domain of Vesicular Monoamine Transporters Mediates G-protein-dependent Regulation of Transmitter Uptake J. Biol. Chem., November 3, 2006; 281(44): 33373 - 33385. [Abstract] [Full Text] [PDF]

				S. V. Yelamanchili, G. Pendyala, I. Brunk, M. Darna, U. Albrecht, and G. Ahnert-Hilger Differential Sorting of the Vesicular Glutamate Transporter 1 into a Defined Vesicular Pool Is Regulated by Light Signaling Involving the Clock Gene Period2 J. Biol. Chem., June 9, 2006; 281(23): 15671 - 15679. [Abstract] [Full Text] [PDF]

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