Demonstration of functional coupling between γ-aminobutyric acid (GABA) synthesis and vesicular GABA transport into synaptic vesicles

Jin, Hong; Wu, Heng; Osterhaus, Gregory; Wei, Jianning; Davis, Kathleen; Sha, Di; Floor, Eric; Hsu, Che-Chang; Kopke, Richard D.; Wu, Jang-Yen

doi:10.1073/pnas.0730698100

Cited by 243Neuroscience and Neuropharmacology ResearchCellular transport and secretionAmino Acid Enzymes and Metabolism

Demonstration of functional coupling between γ-aminobutyric acid (GABA) synthesis and vesicular GABA transport into synaptic vesicles

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Jin, Hong, Wu, Heng, Osterhaus, Gregory, Wei, Jianning, Davis, Kathleen, Sha, Di, Floor, Eric, Hsu, Che-Chang +2 more·2003·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.0730698100PMC PMC153086

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Abstract

l -Glutamic acid decarboxylase (GAD) exists as both membrane-associated and soluble forms in the mammalian brain. Here, we propose that there is a functional and structural coupling between the synthesis of γ-aminobutyric acid (GABA) by membrane-associated GAD and its packaging into synaptic vesicles (SVs) by vesicular GABA transporter (VGAT). This notion is supported by the following observations. First, newly synthesized [ 3 H]GABA from [ 3 H] l -glutamate by membrane-associated GAD is taken up preferentially over preexisting GABA by using immunoaffinity-purified GABAergic SVs. Second, the activity of SV-associated GAD and VGAT seems to be coupled because inhibition of GAD also decreases VGAT activity. Third, VGAT and SV-associated Ca 2+ /calmodulin-dependent kinase II have been found to form a protein complex with GAD. A model is also proposed to link the neuronal stimulation to enhanced synthesis and packaging of GABA into SVs.

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GAD67 and GAD65 form complexes with vGAT on synaptic vesicles, facilitating coupling from GABA synthesis to vesicular packaging.
“It should be noted that, in addition to mediating cytosolic GABA synthesis, which influences cellular GABA levels, GAD67 and GAD65 form complexes that directly interact with vGAT on synaptic vesicles, thereby facilitating the coupling from GABA synthesis to vesicular packaging (51,52).”
From MeCP2 regulates the timing of critical period plasticity that shapes functional connectivity in primary visual cortex (2015) · cites this paper as [51]

Identification and characterization of the vesicular GABA transporter
McIntire, S. L., Reimer, R. J., Schuske, K. R., Edwards, R. H., & Jørgensen, E. M. (1997) · Nature · doi:10.1038/39908 · Cited by 867 · see citing works
Two Forms of the γ‐Aminobutyric Acid Synthetic Enzyme Glutamate Decarboxylase Have Distinct Intraneuronal Distributions and Cofactor Interactions
Kaufman, D. L., Houser, C. R., & Tobin, A. J. (1991) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.1991.tb08211.x · Cited by 789 · see citing works
Cleft palate and decreased brain γ-aminobutyric acid in mice lacking the 67-kDa isoform of glutamic acid decarboxylase
Asada, H., Kawamura, Y., Maruyama, K., Kume, H., Ding, R.-G., Kanbara, N., Kuzume, H., Sanbo, M., Yagi, T., & Obata, K. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.12.6496 · Cited by 556 · see citing works
The structural and functional heterogeneity of glutamic acid decarboxylase: A review
Erlander, M. G., & Tobin, A. J. (1991) · Neurochemical Research · doi:10.1007/bf00966084 · Cited by 462 · see citing works
Characterization of the proteins purified with monoclonal antibodies to glutamic acid decarboxylase
Chang, Y., & Gottlieb, D. I. (1988) · Journal of Neuroscience · doi:10.1523/jneurosci.08-06-02123.1988 · Cited by 329 · see citing works
The distribution of glutamate decarboxylase and aspartate transaminase in subcellular fractions of rat and guinea-pig brain
Fonnum, F. (1968) · Biochemical Journal · doi:10.1042/bj1060401 · Cited by 253 · see citing works
Increased anxiety and altered responses to anxiolytics in mice deficient in the 65-kDa isoform of glutamic acid decarboxylase
Kash, S. F., Tecott, L. H., Hodge, C. W., & Bækkeskov, S. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.4.1698 · Cited by 216 · see citing works
Membrane anchoring of the autoantigen GAD65 to microvesicles in pancreatic beta-cells by palmitoylation in the NH2-terminal domain.
Christgau, S., Aanstoot, H., Schierbeck, H., Begley, K., Tullin, S., Hejnæs, K. R., & Bækkeskov, S. (1992) · The Journal of Cell Biology · doi:10.1083/jcb.118.2.309 · Cited by 181 · see citing works
Permissive proteolytic activity for visual cortical plasticity
Mataga, N., Nagai, N., & Hensch, T. K. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.102088899 · Cited by 179 · see citing works
Postnatal development of a GABA deficit and disturbance of neural functions in mice lacking GAD65
Stork, O., Ji, F.-Y., Kaneko, K., Stork, S., Yoshinobu, Y., Moriya, T., Shibata, S., & Obata, K. (2000) · Brain Research · doi:10.1016/s0006-8993(00)02206-x · Cited by 177 · see citing works
Immunoisolation of GABA-Specific Synaptic Vesicles Defines a Functionally Distinct Subset of Synaptic Vesicles
Takamori, S., Riedel, D., & Jahn, R. (2000) · Journal of Neuroscience · doi:10.1523/jneurosci.20-13-04904.2000 · Cited by 177 · see citing works
Cleft palate in mice with a targeted mutation in the γ-aminobutyric acid-producing enzyme glutamic acid decarboxylase 67
Condie, B. G., Bain, G., Gottlieb, D. I., & Capecchi, M. R. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.21.11451 · Cited by 136 · see citing works
Energy dependence and functional reconstitution of the gamma-aminobutyric acid carrier from synaptic vesicles.
Hell, J. W., Maycox, P. R., & Jahn, R. (1990) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)39947-8 · Cited by 120 · see citing works
Dynamic Storage of Dopamine in Rat Brain Synaptic Vesicles In Vitro
Floor, E., Leventhal, P. S., Wang, Y., Meng, L., & Chen, W. (1995) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.1995.64020689.x · Cited by 79 · see citing works
Self-citation
Absence of Long-Term Depression in the Visual Cortex of Glutamic Acid Decarboxylase-65 Knock-Out Mice
Choi, S., Morales, B., Lee, H., & Kirkwood, A. (2002) · Journal of Neuroscience · doi:10.1523/jneurosci.22-13-05271.2002 · Cited by 78 · see citing works
Association of GAD-65, but not of GAD-67, with the Golgi complex of transfected Chinese hamster ovary cells mediated by the N-terminal region.
Solimena, M., Aggujaro, D., Muntzel, C., et al. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.7.3073 · Cited by 77 · see citing works
Amino acid residues 24-31 but not palmitoylation of cysteines 30 and 45 are required for membrane anchoring of glutamic acid decarboxylase, GAD65
Shi, Y., Veit, B., & Bækkeskov, S. (1994) · The Journal of Cell Biology · doi:10.1083/jcb.124.6.927 · Cited by 76 · see citing works
Targeting of the 67-kDa Isoform of Glutamic Acid Decarboxylase to Intracellular Organelles Is Mediated by Its Interaction with the NH2-terminal Region of the 65-kDa Isoform of Glutamic Acid Decarboxylase
Dirkx, R. A., Reetz, A., Li, L., Lernmark, Å., Sherwin, R. S., Camilli, P. V. D., & Solimena, M. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.5.2241 · Cited by 76 · see citing works
Brain L-Glutamate Decarboxylase
Bao, J., Cheung, W. Y., & Wu, J. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.12.6464 · Cited by 71 · see citing works
Self-citation
Association of l-Glutamic Acid Decarboxylase to the 70-kDa Heat Shock Protein as a Potential Anchoring Mechanism to Synaptic Vesicles
Hsu, C.-C., Davis, K. M., Jin, H., Foos, T., Floor, E., Chen, W., Tyburski, J. B., Yang, C.-Y., Schloss, J. V., & Wu, J.-Y. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m001403200 · Cited by 69 · see citing works
Self-citation
Comparative study of the release of glutamate and GABA, newly synthesized from glutamine, in various regions of the central nervous system
Reubi, J. C. (1980) · Neuroscience · doi:10.1016/0306-4522(80)90130-x · Cited by 67 · see citing works
Phosphorylation of Serine Residues 3, 6, 10, and 13 Distinguishes Membrane Anchored from Soluble Glutamic Acid Decarboxylase 65 and Is Restricted to Glutamic Acid Decarboxylase 65α
Namchuk, M., Lindsay, L., Turck, C. W., Kanaani, J., & Bækkeskov, S. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.3.1548 · Cited by 65 · see citing works
The Hydrophilic Isoform of Glutamate Decarboxylase, GAD67, Is Targeted to Membranes and Nerve Terminals Independent of Dimerization with the Hydrophobic Membrane-anchored Isoform, GAD65
Kanaani, J., Lissin, D., Kash, S. F., & Bækkeskov, S. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.52.37200 · Cited by 63 · see citing works
Role of Synaptic Vesicle Proton Gradient and Protein Phosphorylation on ATP-mediated Activation of Membrane-associated Brain Glutamate Decarboxylase
Hsu, C., Thomas, C., Chen, W., Davis, K. M., Foos, T., Chen, J. L., Wu, E., Floor, E., Schloss, J. V., & Wu, J. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.34.24366 · Cited by 61 · see citing works
Self-citation
Lipid Composition and Orientation in Secretory Vesiclesa
Westhead, E. W. (1987) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.1987.tb27186.x · Cited by 57 · see citing works
Production and characterization of polyclonal and monoclonal antibodies to rat brain l-glutamate decar☐ylase
Wu, J., Denner, L. A., Wei, S., Lin, C., Song, G., Xu, Y., Liu, J. W., & Lin, H. S. (1986) · Brain Research · doi:10.1016/0006-8993(86)90309-4 · Cited by 55 · see citing works
Self-citation
Two distinct domains in hsc70 are essential for the interaction with the synaptic vesicle cysteine string protein
Stahl, B., Tobaben, S., & Südhof, T. C. (1999) · European Journal of Cell Biology · doi:10.1016/s0171-9335(99)80079-x · Cited by 40 · see citing works
Effect of Nucleotides and Other Inhibitors on the Inactivation of Glutamate Decarboxylase
Martin, D. L., & Martin, S. B. (1982) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.1982.tb11489.x · Cited by 34 · see citing works
Heteromers of Glutamate Decarboxylase Isoforms Occur in Rat Cerebellum
Sheikh, S. N., & Martin, D. L. (1996) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.1996.66052082.x · Cited by 31 · see citing works
A Novel Method for Expression and Large-Scale Production of Human Brain -Glutamate Decarboxylase
Davis, K. M., Foos, T., Bates, C. S., Tucker, E., Hsu, C., Chen, W., Jin, H., Tyburski, J. B., Schloss, J. V., Tobin, A. J., et al. (2000) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1999.2038 · Cited by 25 · see citing works
Self-citation
Tissue and regional distribution of cysteic acid decarboxylase
Wu, J., Moss, L. G., & Chen, M.-S. (1979) · Neurochemical Research · doi:10.1007/bf00964144 · Cited by 25 · see citing works
Self-citation
Dynamic storage of glutamate in rat brain synaptic vesicles
Wang, Y., & Floor, E. (1994) · Neuroscience Letters · doi:10.1016/0304-3940(94)90515-0 · Cited by 19 · see citing works
Self-citation
Synaptic vesicles from hog brain—their isolation and the coupling between synthesis and uptake of γ-aminobutyrate by glutamate decarboxylase
Angel, I., Fleissner, A., & Seifert, R. (1983) · Neurochemistry International · doi:10.1016/0197-0186(83)90095-5 · Cited by 17 · see citing works

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Giorgi, O., & Meek, J. L. (1984) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.1984.tb09720.x · Cited by 25 · see citing works

Authors: Jin, H., Wu, H., Osterhaus, G., Wei, J., Davis, K., Sha, D., Floor, E., Hsu, C.-C., Kopke, R. D., & Wu, J.-Y.
Affiliations: Scripps Research Institute (US)
Departments of Molecular Biosciences and Medicinal Chemistry, University of Kansas, Lawrence, KS 66045; Department of Biomedical Science, Florida Atlantic University, Boca Raton, FL 33431; Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037; and Department of Otolaryngology, Naval Medical Center, San Diego, CA 92134-5000
ORCID: Jin, Hong
Wu, Heng
Wei, Jianning
Kopke, Richard D.
Wu, Jang-Yen
Venue: Proceedings of the National Academy of Sciences
Publisher: National Academy of Sciences
Published: 2003-03-12
Volume: 100
Issue: 7
Pages: 4293-4298
ISSN: 0027-8424 (ISSN-L)
1091-6490
DOI: 10.1073/pnas.0730698100
PMC: PMC153086
OpenAlex: W2083327596
Cited by: 243
References: 33
Citations by year: 2026: 4 · 2025: 4 · 2024: 8 · 2023: 5 · 2022: 10 · 2021: 14 · 2020: 5 · 2019: 9 · 2018: 8 · 2017: 7 · 2016: 12 · 2015: 17 · 2014: 10 · 2013: 10 · 2012: 12
FWCI: 4.00
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Proceedings of the National Academy of Sciences (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: National Science Foundation (9723079)
Florida Atlantic University
Schmidt Family Foundation
Universidad del Atlántico
National Institutes of Health
National Institute of Neurological Disorders and Stroke (NS37851, R01NS037851)
Topics: Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
Keywords: GABA, GABA synthesis, vesicular GABA transporter, synaptic vesicles, glutamic acid decarboxylase, protein complexes, neurostimulation, GABAergic neurotransmission
MeSH terms: Animals, Biological Transport, Brain, gamma-Aminobutyric Acid, Glutamate Decarboxylase, Kinetics, Models, Neurological, Recombinant Fusion Proteins, Synaptic Vesicles, Rats, Sprague-Dawley, Glutamic Acid, Rats

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Demonstration of functional coupling between γ-aminobutyric acid (GABA) synthesis and vesicular GABA transport into synaptic vesicles

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