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Galphao2 regulates vesicular glutamate transporter activity by changing its chloride dependence.
- Source :
-
The Journal of neuroscience : the official journal of the Society for Neuroscience [J Neurosci] 2005 May 04; Vol. 25 (18), pp. 4672-80. - Publication Year :
- 2005
-
Abstract
- 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 alpha subunits of trimeric G-proteins, including Galpha(o2) and Galpha(q). Furthermore, glutamate uptake, mediated by vesicular glutamate transporters (VGLUTs), is decreased by the nonhydrolysable GTP-analog guanylylimidodiphosphate. Using mutant mice lacking various Galpha subunits, including Galpha(o1), Galpha(o2), Galpha(q), and Galpha11, and a Galpha(o2)-specific monoclonal antibody, we now show that VGLUTs are exclusively regulated by Galpha(o2). G-protein activation does not affect the electrochemical proton gradient serving as driving force for neurotransmitter uptake; rather, Galpha(o2) exerts its action by specifically affecting the chloride dependence of VGLUTs. All VGLUTs show maximal activity at approximately 5 mm chloride. Activated Galpha(o2) shifts this maximum to lower chloride concentrations. In contrast, glutamate uptake by vesicles isolated from Galpha(o2-/-) mice have completely lost chloride activation. Thus, Galpha(o2) acts on a putative regulatory chloride binding domain that appears to modulate transport activity of vesicular glutamate transporters.
- Subjects :
- Adenosine Triphosphate pharmacology
Animals
Antibodies pharmacology
Blotting, Western methods
Dose-Response Relationship, Drug
Drug Interactions
GTP-Binding Protein alpha Subunits, Gi-Go deficiency
GTP-Binding Protein alpha Subunits, Gi-Go immunology
Glutamic Acid pharmacokinetics
Glutamic Acid pharmacology
Guanylyl Imidodiphosphate pharmacology
Mice
Mice, Knockout
Potassium Chloride pharmacology
R-SNARE Proteins metabolism
Rats
Synaptic Vesicles drug effects
Synaptosomal-Associated Protein 25 immunology
Tritium pharmacokinetics
Vesicular Glutamate Transport Proteins classification
Chlorides metabolism
GTP-Binding Protein alpha Subunits, Gi-Go physiology
Glutamic Acid metabolism
Synaptic Vesicles metabolism
Vesicular Glutamate Transport Proteins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1529-2401
- Volume :
- 25
- Issue :
- 18
- Database :
- MEDLINE
- Journal :
- The Journal of neuroscience : the official journal of the Society for Neuroscience
- Publication Type :
- Academic Journal
- Accession number :
- 15872115
- Full Text :
- https://doi.org/10.1523/JNEUROSCI.0549-05.2005