DOI: 10.1523/jneurosci.4011-04.2005. Distinct γ2 Subunit Domains Mediate Clustering and Synaptic Function of Postsynaptic GABA<sub>A</sub>Receptors and Gephyrin

Distinct γ2 Subunit Domains Mediate Clustering and Synaptic Function of Postsynaptic GABAAReceptors and Gephyrin

10.1523/jneurosci.4011-04.2005

Crossref journal-article

Society for Neuroscience

The Journal of Neuroscience (393)

Abstract

Modulation of the concentration of postsynaptic GABAAreceptors contributes to functional plasticity of inhibitory synapses. The γ2 subunit of GABAAreceptor is specifically required for clustering of these receptors, for recruitment of the submembrane scaffold protein gephyrin to postsynaptic sites, and for postsynaptic function of GABAergic inhibitory synapses. To elucidate this mechanism, we here have mapped the γ2 subunit domains required for restoration of postsynaptic clustering and function of GABAAreceptors in γ2 subunit mutant neurons. Transfection of γ2-/-neurons with the γ2 subunit but not the α2 subunit rescues postsynaptic clustering of GABAAreceptors, results in recruitment of gephyrin to postsynaptic sites, and restores the amplitude and frequency of miniature inhibitory postsynaptic currents to wild-type levels. Analogous analyses of chimeric γ2/α2 subunit constructs indicate, unexpectedly, that the fourth transmembrane domain of the γ2 subunit is required and sufficient for postsynaptic clustering of GABAAreceptors, whereas cytoplasmic γ2 subunit domains are dispensable. In contrast, both the major cytoplasmic loop and the fourth transmembrane domain of the γ2 subunit contribute to efficient recruitment of gephyrin to postsynaptic receptor clusters and are essential for restoration of miniature IPSCs. Our study points to a novel mechanism involved in targeting of GABAAreceptors and gephyrin to inhibitory synapses.

Bibliography

Alldred, M. J., Mulder-Rosi, J., Lingenfelter, S. E., Chen, G., & LÃ¼scher, B. (2005). Distinct Î³2 Subunit Domains Mediate Clustering and Synaptic Function of Postsynaptic GABAAReceptors and Gephyrin. The Journal of Neuroscience, 25(3), 594â603.

Authors 5

Melissa J. Alldred (first)
Jonas Mulder-Rosi (additional)
Sue E. Lingenfelter (additional)
Gong Chen (additional)
Bernhard Lüscher (additional)

References 43 Referenced 127

10.1523/JNEUROSCI.13-04-01429.1993 / J Neurosci (1993)
10.1073/pnas.96.22.12860
Banker G, Goslin K (1998) Culturing nerve cells. Cambridge, MA: MIT. (10.7551/mitpress/4913.001.0001)
10.1016/S0014-5793(98)00803-5
10.1021/bi00176a016
10.1016/S0028-3908(01)00121-6
10.1016/S0896-6273(03)00640-8
10.1523/JNEUROSCI.21-02-00504.2001 / J Neurosci (2001)
{'key': '2023041303103526000_25.3.594.9', 'first-page': '2745', 'volume': '7', 'year': '1987', 'journal-title': 'Mol Cell Biol'} / Mol Cell Biol (1987)
10.1074/jbc.271.1.89
10.1006/mcne.1999.0746
10.1074/jbc.274.51.36565
10.1038/12207
10.1016/S0006-3495(04)74284-8 / Biophys J (2004)
10.1038/2798
10.1002/1096-9861(20001127)427:4<634::AID-CNE10>3.0.CO;2-X
10.1016/S0163-7258(03)00037-8
Graf ER, Zhang XZ, Jin S-X, Linhoff MW, Craig AM (2004) Neurexins induce differentiation of GABA and glutamate postsynaptic specializations via neuroligins. Cell, in press. (10.1016/j.cell.2004.11.035)
10.1073/pnas.92.17.7749
10.1523/JNEUROSCI.23-08-03262.2003 / J Neurosci (2003)
10.1523/JNEUROSCI.1037-04.2004
10.1523/JNEUROSCI.20-21-07972.2000 / J Neurosci (2000)
10.1006/mcne.2001.1005
10.1111/j.1469-7793.2000.t01-4-00001.x
10.1523/JNEUROSCI.19-21-09289.1999 / J Neurosci (1999)
10.1073/pnas.97.15.8594
10.1006/mcne.2001.0983
10.1523/JNEUROSCI.1661-03.2004
10.1111/j.1469-7793.2000.t01-1-00011.x
10.1016/S0896-6273(00)81150-2
10.1016/j.pharmthera.2004.04.003
10.1016/0169-328X(90)90017-8
10.1016/0896-6273(95)90145-0
10.1038/35067500
10.1046/j.1471-4159.2002.01222.x
10.1016/j.neuroscience.2004.06.007
10.1016/j.mcn.2004.01.012
10.1016/S1044-7431(03)00202-1
10.1038/sj.emboj.7600256
van Rijnsoever C, Sidler C, Fritschy JM (2005) Internalized GABAA receptor subunits are transferred to an intracellular pool associated with the postsynaptic density. Eur J Neurosci, in press. (10.1111/j.1460-9568.2005.03884.x)
10.1016/0896-6273(90)90145-6
10.1038/16264
10.1523/JNEUROSCI.23-03-00826.2003 / J Neurosci (2003)

Dates

Type	When
Created	20 years, 7 months ago (Jan. 19, 2005, 1:42 p.m.)
Deposited	2 years, 4 months ago (April 13, 2023, 12:31 p.m.)
Indexed	1 month, 1 week ago (July 25, 2025, 6:34 a.m.)
Issued	20 years, 7 months ago (Jan. 19, 2005)
Published	20 years, 7 months ago (Jan. 19, 2005)
Published Online	20 years, 7 months ago (Jan. 19, 2005)
Published Print	20 years, 7 months ago (Jan. 19, 2005)

Funders 0

None

BibTeX

@article{Alldred_2005, title={Distinct γ2 Subunit Domains Mediate Clustering and Synaptic Function of Postsynaptic GABAAReceptors and Gephyrin}, volume={25}, ISSN={1529-2401}, url={http://dx.doi.org/10.1523/jneurosci.4011-04.2005}, DOI={10.1523/jneurosci.4011-04.2005}, number={3}, journal={The Journal of Neuroscience}, publisher={Society for Neuroscience}, author={Alldred, Melissa J. and Mulder-Rosi, Jonas and Lingenfelter, Sue E. and Chen, Gong and Lüscher, Bernhard}, year={2005}, month=jan, pages={594–603} }

JSON

{
  "indexed": {
    "date-parts": [
      [
        2025,
        7,
        25
      ]
    ],
    "date-time": "2025-07-25T10:34:05Z",
    "timestamp": 1753439645745
  },
  "reference-count": 43,
  "publisher": "Society for Neuroscience",
  "issue": "3",
  "license": [
    {
      "start": {
        "date-parts": [
          [
            2005,
            7,
            19
          ]
        ],
        "date-time": "2005-07-19T00:00:00Z",
        "timestamp": 1121731200000
      },
      "content-version": "vor",
      "delay-in-days": 181,
      "URL": "https://creativecommons.org/licenses/by-nc-sa/4.0/"
    }
  ],
  "content-domain": {
    "domain": [],
    "crossmark-restriction": false
  },
  "published-print": {
    "date-parts": [
      [
        2005,
        1,
        19
      ]
    ]
  },
  "abstract": "<jats:p>Modulation of the concentration of postsynaptic GABA<jats:sub>A</jats:sub>receptors contributes to functional plasticity of inhibitory synapses. The \u03b32 subunit of GABA<jats:sub>A</jats:sub>receptor is specifically required for clustering of these receptors, for recruitment of the submembrane scaffold protein gephyrin to postsynaptic sites, and for postsynaptic function of GABAergic inhibitory synapses. To elucidate this mechanism, we here have mapped the \u03b32 subunit domains required for restoration of postsynaptic clustering and function of GABA<jats:sub>A</jats:sub>receptors in \u03b32 subunit mutant neurons. Transfection of \u03b32<jats:sup>-/-</jats:sup>neurons with the \u03b32 subunit but not the \u03b12 subunit rescues postsynaptic clustering of GABA<jats:sub>A</jats:sub>receptors, results in recruitment of gephyrin to postsynaptic sites, and restores the amplitude and frequency of miniature inhibitory postsynaptic currents to wild-type levels. Analogous analyses of chimeric \u03b32/\u03b12 subunit constructs indicate, unexpectedly, that the fourth transmembrane domain of the \u03b32 subunit is required and sufficient for postsynaptic clustering of GABA<jats:sub>A</jats:sub>receptors, whereas cytoplasmic \u03b32 subunit domains are dispensable. In contrast, both the major cytoplasmic loop and the fourth transmembrane domain of the \u03b32 subunit contribute to efficient recruitment of gephyrin to postsynaptic receptor clusters and are essential for restoration of miniature IPSCs. Our study points to a novel mechanism involved in targeting of GABA<jats:sub>A</jats:sub>receptors and gephyrin to inhibitory synapses.</jats:p>",
  "DOI": "10.1523/jneurosci.4011-04.2005",
  "type": "journal-article",
  "created": {
    "date-parts": [
      [
        2005,
        1,
        19
      ]
    ],
    "date-time": "2005-01-19T18:42:55Z",
    "timestamp": 1106160175000
  },
  "page": "594-603",
  "source": "Crossref",
  "is-referenced-by-count": 127,
  "title": "Distinct \u03b32 Subunit Domains Mediate Clustering and Synaptic Function of Postsynaptic GABA<sub>A</sub>Receptors and Gephyrin",
  "prefix": "10.1523",
  "volume": "25",
  "author": [
    {
      "given": "Melissa J.",
      "family": "Alldred",
      "sequence": "first",
      "affiliation": []
    },
    {
      "given": "Jonas",
      "family": "Mulder-Rosi",
      "sequence": "additional",
      "affiliation": []
    },
    {
      "given": "Sue E.",
      "family": "Lingenfelter",
      "sequence": "additional",
      "affiliation": []
    },
    {
      "given": "Gong",
      "family": "Chen",
      "sequence": "additional",
      "affiliation": []
    },
    {
      "given": "Bernhard",
      "family": "L\u00fcscher",
      "sequence": "additional",
      "affiliation": []
    }
  ],
  "member": "393",
  "published-online": {
    "date-parts": [
      [
        2005,
        1,
        19
      ]
    ]
  },
  "reference": [
    {
      "key": "2023041303103526000_25.3.594.1",
      "doi-asserted-by": "crossref",
      "first-page": "1429",
      "DOI": "10.1523/JNEUROSCI.13-04-01429.1993",
      "volume": "13",
      "year": "1993",
      "journal-title": "J Neurosci"
    },
    {
      "key": "2023041303103526000_25.3.594.2",
      "doi-asserted-by": "publisher",
      "DOI": "10.1073/pnas.96.22.12860"
    },
    {
      "key": "2023041303103526000_25.3.594.3",
      "doi-asserted-by": "crossref",
      "unstructured": "Banker G, Goslin K (1998) Culturing nerve cells. Cambridge, MA: MIT.",
      "DOI": "10.7551/mitpress/4913.001.0001"
    },
    {
      "key": "2023041303103526000_25.3.594.4",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/S0014-5793(98)00803-5"
    },
    {
      "key": "2023041303103526000_25.3.594.5",
      "doi-asserted-by": "publisher",
      "DOI": "10.1021/bi00176a016"
    },
    {
      "key": "2023041303103526000_25.3.594.6",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/S0028-3908(01)00121-6"
    },
    {
      "key": "2023041303103526000_25.3.594.7",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/S0896-6273(03)00640-8"
    },
    {
      "key": "2023041303103526000_25.3.594.8",
      "doi-asserted-by": "crossref",
      "first-page": "504",
      "DOI": "10.1523/JNEUROSCI.21-02-00504.2001",
      "volume": "21",
      "year": "2001",
      "journal-title": "J Neurosci"
    },
    {
      "key": "2023041303103526000_25.3.594.9",
      "first-page": "2745",
      "volume": "7",
      "year": "1987",
      "journal-title": "Mol Cell Biol"
    },
    {
      "key": "2023041303103526000_25.3.594.10",
      "doi-asserted-by": "publisher",
      "DOI": "10.1074/jbc.271.1.89"
    },
    {
      "key": "2023041303103526000_25.3.594.11",
      "doi-asserted-by": "publisher",
      "DOI": "10.1006/mcne.1999.0746"
    },
    {
      "key": "2023041303103526000_25.3.594.12",
      "doi-asserted-by": "publisher",
      "DOI": "10.1074/jbc.274.51.36565"
    },
    {
      "key": "2023041303103526000_25.3.594.13",
      "doi-asserted-by": "publisher",
      "DOI": "10.1038/12207"
    },
    {
      "key": "2023041303103526000_25.3.594.14",
      "doi-asserted-by": "crossref",
      "first-page": "2261",
      "DOI": "10.1016/S0006-3495(04)74284-8",
      "volume": "86",
      "year": "2004",
      "journal-title": "Biophys J"
    },
    {
      "key": "2023041303103526000_25.3.594.15",
      "doi-asserted-by": "publisher",
      "DOI": "10.1038/2798"
    },
    {
      "key": "2023041303103526000_25.3.594.16",
      "doi-asserted-by": "publisher",
      "DOI": "10.1002/1096-9861(20001127)427:4<634::AID-CNE10>3.0.CO;2-X"
    },
    {
      "key": "2023041303103526000_25.3.594.17",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/S0163-7258(03)00037-8"
    },
    {
      "key": "2023041303103526000_25.3.594.18",
      "doi-asserted-by": "crossref",
      "unstructured": "Graf ER, Zhang XZ, Jin S-X, Linhoff MW, Craig AM (2004) Neurexins induce differentiation of GABA and glutamate postsynaptic specializations via neuroligins. Cell, in press.",
      "DOI": "10.1016/j.cell.2004.11.035"
    },
    {
      "key": "2023041303103526000_25.3.594.19",
      "doi-asserted-by": "publisher",
      "DOI": "10.1073/pnas.92.17.7749"
    },
    {
      "key": "2023041303103526000_25.3.594.20",
      "doi-asserted-by": "crossref",
      "first-page": "3262",
      "DOI": "10.1523/JNEUROSCI.23-08-03262.2003",
      "volume": "23",
      "year": "2003",
      "journal-title": "J Neurosci"
    },
    {
      "key": "2023041303103526000_25.3.594.21",
      "doi-asserted-by": "publisher",
      "DOI": "10.1523/JNEUROSCI.1037-04.2004"
    },
    {
      "key": "2023041303103526000_25.3.594.22",
      "doi-asserted-by": "crossref",
      "first-page": "7972",
      "DOI": "10.1523/JNEUROSCI.20-21-07972.2000",
      "volume": "20",
      "year": "2000",
      "journal-title": "J Neurosci"
    },
    {
      "key": "2023041303103526000_25.3.594.23",
      "doi-asserted-by": "publisher",
      "DOI": "10.1006/mcne.2001.1005"
    },
    {
      "key": "2023041303103526000_25.3.594.24",
      "doi-asserted-by": "publisher",
      "DOI": "10.1111/j.1469-7793.2000.t01-4-00001.x"
    },
    {
      "key": "2023041303103526000_25.3.594.25",
      "doi-asserted-by": "crossref",
      "first-page": "9289",
      "DOI": "10.1523/JNEUROSCI.19-21-09289.1999",
      "volume": "19",
      "year": "1999",
      "journal-title": "J Neurosci"
    },
    {
      "key": "2023041303103526000_25.3.594.26",
      "doi-asserted-by": "publisher",
      "DOI": "10.1073/pnas.97.15.8594"
    },
    {
      "key": "2023041303103526000_25.3.594.27",
      "doi-asserted-by": "publisher",
      "DOI": "10.1006/mcne.2001.0983"
    },
    {
      "key": "2023041303103526000_25.3.594.28",
      "doi-asserted-by": "publisher",
      "DOI": "10.1523/JNEUROSCI.1661-03.2004"
    },
    {
      "key": "2023041303103526000_25.3.594.29",
      "doi-asserted-by": "publisher",
      "DOI": "10.1111/j.1469-7793.2000.t01-1-00011.x"
    },
    {
      "key": "2023041303103526000_25.3.594.30",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/S0896-6273(00)81150-2"
    },
    {
      "key": "2023041303103526000_25.3.594.31",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/j.pharmthera.2004.04.003"
    },
    {
      "key": "2023041303103526000_25.3.594.32",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/0169-328X(90)90017-8"
    },
    {
      "key": "2023041303103526000_25.3.594.33",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/0896-6273(95)90145-0"
    },
    {
      "key": "2023041303103526000_25.3.594.34",
      "doi-asserted-by": "publisher",
      "DOI": "10.1038/35067500"
    },
    {
      "key": "2023041303103526000_25.3.594.35",
      "doi-asserted-by": "publisher",
      "DOI": "10.1046/j.1471-4159.2002.01222.x"
    },
    {
      "key": "2023041303103526000_25.3.594.36",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/j.neuroscience.2004.06.007"
    },
    {
      "key": "2023041303103526000_25.3.594.37",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/j.mcn.2004.01.012"
    },
    {
      "key": "2023041303103526000_25.3.594.38",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/S1044-7431(03)00202-1"
    },
    {
      "key": "2023041303103526000_25.3.594.39",
      "doi-asserted-by": "publisher",
      "DOI": "10.1038/sj.emboj.7600256"
    },
    {
      "key": "2023041303103526000_25.3.594.40",
      "doi-asserted-by": "crossref",
      "unstructured": "van Rijnsoever C, Sidler C, Fritschy JM (2005) Internalized GABAA receptor subunits are transferred to an intracellular pool associated with the postsynaptic density. Eur J Neurosci, in press.",
      "DOI": "10.1111/j.1460-9568.2005.03884.x"
    },
    {
      "key": "2023041303103526000_25.3.594.41",
      "doi-asserted-by": "publisher",
      "DOI": "10.1016/0896-6273(90)90145-6"
    },
    {
      "key": "2023041303103526000_25.3.594.42",
      "doi-asserted-by": "publisher",
      "DOI": "10.1038/16264"
    },
    {
      "key": "2023041303103526000_25.3.594.43",
      "doi-asserted-by": "crossref",
      "first-page": "826",
      "DOI": "10.1523/JNEUROSCI.23-03-00826.2003",
      "volume": "23",
      "year": "2003",
      "journal-title": "J Neurosci"
    }
  ],
  "container-title": "The Journal of Neuroscience",
  "original-title": [],
  "language": "en",
  "link": [
    {
      "URL": "https://syndication.highwire.org/content/doi/10.1523/JNEUROSCI.4011-04.2005",
      "content-type": "unspecified",
      "content-version": "vor",
      "intended-application": "similarity-checking"
    }
  ],
  "deposited": {
    "date-parts": [
      [
        2023,
        4,
        13
      ]
    ],
    "date-time": "2023-04-13T16:31:08Z",
    "timestamp": 1681403468000
  },
  "score": 1,
  "resource": {
    "primary": {
      "URL": "https://www.jneurosci.org/lookup/doi/10.1523/JNEUROSCI.4011-04.2005"
    }
  },
  "subtitle": [],
  "short-title": [],
  "issued": {
    "date-parts": [
      [
        2005,
        1,
        19
      ]
    ]
  },
  "references-count": 43,
  "journal-issue": {
    "issue": "3",
    "published-online": {
      "date-parts": [
        [
          2005,
          1,
          19
        ]
      ]
    },
    "published-print": {
      "date-parts": [
        [
          2005,
          1,
          19
        ]
      ]
    }
  },
  "alternative-id": [
    "10.1523/JNEUROSCI.4011-04.2005"
  ],
  "URL": "http://dx.doi.org/10.1523/JNEUROSCI.4011-04.2005",
  "relation": {},
  "ISSN": [
    "0270-6474",
    "1529-2401"
  ],
  "subject": [],
  "container-title-short": "J. Neurosci.",
  "published": {
    "date-parts": [
      [
        2005,
        1,
        19
      ]
    ]
  }
}