GABAA receptor trafficking and its role in the dynamic modulation of neuronal inhibition (original) (raw)

• Sieghart, W. & Sperk, G. Subunit composition, distribution and function of GABAA receptor subtypes. Curr. Top. Med. Chem. 2, 795–816 (2002).
  Article CAS PubMed Google Scholar
• Rudolph, U. & Mohler, H. Analysis of GABAA receptor function and dissection of the pharmacology of benzodiazepines and general anesthetics through mouse genetics. Annu. Rev. Pharmacol. Toxicol. 44, 475–498 (2004).
  Article CAS PubMed Google Scholar
• Bormann, J. & Feigenspan, A. GABAC receptors. Trends Neurosci. 18, 515–519 (1995).
  Article CAS PubMed Google Scholar
• Couve, A., Moss, S. J. & Pangalos, M. N. GABAB receptors: a new paradigm in G protein signaling. Mol. Cell. Neurosci. 16, 296–312 (2000).
  Article CAS PubMed Google Scholar
• Bettler, B. & Tiao, J. Y. Molecular diversity, trafficking and subcellular localization of GABAB receptors. Pharmacol. Ther. 110, 533–543 (2006).
  Article CAS PubMed Google Scholar
• Barnard, E. A. et al. International Union of Pharmacology. XV. Subtypes of γ-aminobutyric acidA receptors: classification on the basis of subunit structure and receptor function. Pharmacol. Rev. 50, 291–313 (1998).
  CAS PubMed Google Scholar
• Unwin, N. The structure of ion channels in membranes of excitable cells. Neuron 3, 665–676 (1989).
  Article CAS PubMed Google Scholar
• Fritschy, J. M., Johnson, D. K., Mohler, H. & Rudolph, U. Independent assembly and subcellular targeting of GABAA-receptor subtypes demonstrated in mouse hippocampal and olfactory neurons in vivo. Neurosci. Lett. 249, 99–102 (1998).
  Article CAS PubMed Google Scholar
• Brunig, I., Scotti, E., Sidler, C. & Fritschy, J. M. Intact sorting, targeting, and clustering of γ-aminobutyric acidA receptor subtypes in hippocampal neurons in vitro. J. Comp. Neurol. 443, 43–55 (2002).
  Article CAS PubMed Google Scholar
• Draguhn, A., Axmacher, N. & Kolbaev, S. Presynaptic ionotropic GABA receptors. Results Probl. Cell Differ. 44, 69–85 (2008).
  Article CAS PubMed Google Scholar
• McKernan, R. M. & Whiting, P. J. Which GABAA-receptor subtypes really occur in the brain? Trends Neurosci. 19, 139–143 (1996).
  Article CAS PubMed Google Scholar
• Kittler, J. T., McAinsh, K. & Moss, S. J. Mechanisms of GABAA receptor assembly and trafficking: implications for the modulation of inhibitory neurotransmission. Mol. Neurobiol. 26, 251–268 (2002).
  Article CAS PubMed Google Scholar
• Connolly, C. N., Krishek, B. J., McDonald, B. J., Smart, T. G. & Moss, S. J. Assembly and cell surface expression of heteromeric and homomeric γ-aminobutyric acidA receptors. J. Biol. Chem. 271, 89–96 (1996).
  Article CAS PubMed Google Scholar
• Gorrie, G. H. et al. Assembly of GABAA receptors composed of α1 and β2 subunits in both cultured neurons and fibroblasts. J. Neurosci. 17, 6587–6596 (1997).
  Article CAS PubMed PubMed Central Google Scholar
• Nusser, Z. et al. Alterations in the expression of GABAA receptor subunits in cerebellar granule cells after the disruption of the α6 subunit gene. Eur. J. Neurosci. 11, 1685–1697 (1999).
  Article CAS PubMed Google Scholar
• Peng, Z. et al. GABAA receptor changes in δ subunit-deficient mice: altered expression of α4 and γ2 subunits in the forebrain. J. Comp. Neurol. 446, 179–197 (2002).
  Article CAS PubMed Google Scholar
• Korpi, E. R. et al. Altered receptor subtypes in the forebrain of GABAA receptor δ subunit-deficient mice: recruitment of γ2 subunits. Neuroscience 109, 733–743 (2002).
  Article CAS PubMed Google Scholar
• Bedford, F. K. et al. GABAA receptor cell surface number and subunit stability are regulated by the ubiquitin-like protein Plic-1. Nature Neurosci. 4, 908–916 (2001). This was the first report to demonstrate that GABA A Rs are stabilized by a direct interaction with the ubiquitin-like protein PLIC1.
  Article CAS PubMed Google Scholar
• Yi, J. J. & Ehlers, M. D. Emerging roles for ubiquitin and protein degradation in neuronal function. Pharmacol. Rev. 59, 14–39 (2007).
  Article CAS PubMed Google Scholar
• Saliba, R. S., Michels, G., Jacob, T. C., Pangalos, M. N. & Moss, S. J. Activity-dependent ubiquitination of GABAA receptors regulates their accumulation at synaptic sites. J. Neurosci. 27, 13341–13351 (2007). This paper reported activity-dependent ubiquitylation of GABA A Rs and subsequent degradation by the proteasome as a mechanism that regulates GABA A R accumulation at synaptic sites.
  Article CAS PubMed PubMed Central Google Scholar
• Kleijnen, M. F. et al. The hPLIC proteins may provide a link between the ubiquitination machinery and the proteasome. Mol. Cell 6, 409–419 (2000).
  Article CAS PubMed Google Scholar
• Wang, H., Bedford, F. K., Brandon, N. J., Moss, S. J. & Olsen, R. W. GABAA receptor-associated protein links GABAA receptors and the cytoskeleton. Nature 397, 69–72 (1999). This was the first identification of GABARAP as a protein that interacts with the γ 2 subunit of GABA A Rs.
  Article CAS PubMed Google Scholar
• Wang, H. & Olsen, R. W. Binding of the GABAA receptor-associated protein (GABARAP) to microtubules and microfilaments suggests involvement of the cytoskeleton in GABARAP-GABAA receptor interaction. J. Neurochem. 75, 644–655 (2000).
  Article CAS PubMed Google Scholar
• Kittler, J. T. et al. The subcellular distribution of GABARAP and its ability to interact with NSF suggest a role for this protein in the intracellular transport of GABAA receptors. Mol. Cell. Neurosci. 18, 13–25 (2001).
  Article CAS PubMed Google Scholar
• Zhao, C., Slevin, J. T. & Whiteheart, S. W. Cellular functions of NSF: not just SNAPs and SNAREs. FEBS Lett. 581, 2140–2149 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Kneussel, M. et al. The γ-aminobutyric acidA receptor (GABAAR)-associated protein GABARAP interacts with gephyrin but is not involved in receptor anchoring at the synapse. Proc. Natl Acad. Sci. USA 97, 8594–8599 (2000).
  Article CAS PubMed PubMed Central Google Scholar
• Chen, L., Wang, H., Vicini, S. & Olsen, R. W. The γ-aminobutyric acid type A (GABAA) receptor-associated protein (GABARAP) promotes GABAA receptor clustering and modulates the channel kinetics. Proc. Natl Acad. Sci. USA 97, 11557–11562 (2000).
  Article CAS PubMed PubMed Central Google Scholar
• Chen, Z. W., Chang, C. S., Leil, T. A., Olcese, R. & Olsen, R. W. GABAA receptor-associated protein regulates GABAA receptor cell-surface number in Xenopus laevis oocytes. Mol. Pharmacol. 68, 152–159 (2005).
  Article CAS PubMed Google Scholar
• Leil, T. A., Chen, Z. W., Chang, C. S. & Olsen, R. W. GABAA receptor-associated protein traffics GABAA receptors to the plasma membrane in neurons. J. Neurosci. 24, 11429–11438 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Chen, Z. W., Chang, C. S., Leil, T. A. & Olsen, R. W. C-terminal modification is required for GABARAP-mediated GABAA receptor trafficking. J. Neurosci. 27, 6655–6663 (2007). This paper demonstrated that a post-translational lipid modification of GABARAP is essential for the proper localization of GABARAP and for its function as a trafficking protein of GABA A Rs.
  Article CAS PubMed PubMed Central Google Scholar
• O'Sullivan, G. A., Kneussel, M., Elazar, Z. & Betz, H. GABARAP is not essential for GABAA receptor targeting to the synapse. Eur. J. Neurosci. 22, 2644–2648 (2005).
  Article PubMed Google Scholar
• Mansuy, V. et al. GEC1, a protein related to GABARAP, interacts with tubulin and GABAA receptor. Biochem. Biophys. Res. Commun. 325, 639–648 (2004).
  Article CAS PubMed Google Scholar
• Marsden, K. C., Beattie, J. B., Friedenthal, J. & Carroll, R. C. NMDA receptor activation potentiates inhibitory transmission through GABAA receptor-associated protein-dependent exocytosis of GABAA receptors. J. Neurosci. 27, 14326–14337 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Goto, H. et al. Direct interaction of _N_-ethylmaleimide-sensitive factor with GABAA receptor β subunits. Mol. Cell. Neurosci. 30, 197–206 (2005).
  Article CAS PubMed Google Scholar
• Nishimune, A. et al. NSF binding to GluR2 regulates synaptic transmission. Neuron 21, 87–97 (1998).
  Article CAS PubMed Google Scholar
• Song, I. et al. Interaction of the _N_-ethylmaleimide-sensitive factor with AMPA receptors. Neuron 21, 393–400 (1998).
  Article CAS PubMed Google Scholar
• Kanematsu, T. et al. Domain organization of p130, PLC-related catalytically inactive protein, and structural basis for the lack of enzyme activity. Eur. J. Biochem. 267, 2731–2737 (2000).
  Article CAS PubMed Google Scholar
• Uji, A. et al. Molecules interacting with PRIP-2, a novel Ins(1,4,5)P3 binding protein type 2: comparison with PRIP-1. Life Sci. 72, 443–453 (2002).
  Article CAS PubMed Google Scholar
• Kanematsu, T. et al. Role of the PLC-related, catalytically inactive protein p130 in GABAA receptor function. Embo J. 21, 1004–1011 (2002). This study was the first to identify PRIP1 as a protein that interacts with GABA A R subunits. It also reported electrophysiological and behavioural studies on PRIP1-knockout mice that demonstrated an essential role for PRIP1 in the normal functioning of GABA A Rs.
  Article CAS PubMed PubMed Central Google Scholar
• Mizokami, A. et al. Phospholipase C-related inactive protein is involved in trafficking of γ2 subunit-containing GABAA receptors to the cell surface. J. Neurosci. 27, 1692–1701 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Kittler, J. T. & Moss, S. J. Modulation of GABAA receptor activity by phosphorylation and receptor trafficking: implications for the efficacy of synaptic inhibition. Curr. Opin. Neurobiol. 13, 341–347 (2003).
  Article CAS PubMed Google Scholar
• Terunuma, M. et al. GABAA receptor phospho-dependent modulation is regulated by phospholipase C-related inactive protein type 1, a novel protein phosphatase 1 anchoring protein. J. Neurosci. 24, 7074–7084 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Yoshimura, K. et al. Interaction of p130 with, and consequent inhibition of, the catalytic subunit of protein phosphatase 1α. J. Biol. Chem. 276, 17908–17913 (2001).
  Article CAS PubMed Google Scholar
• Kanematsu, T. et al. Phospholipase C-related inactive protein is implicated in the constitutive internalization of GABAA receptors mediated by clathrin and AP2 adaptor complex. J. Neurochem. 101, 898–905 (2007).
  Article CAS PubMed Google Scholar
• Huang, K. & El-Husseini, A. Modulation of neuronal protein trafficking and function by palmitoylation. Curr. Opin. Neurobiol. 15, 527–535 (2005).
  Article CAS PubMed Google Scholar
• Keller, C. A. et al. The γ2 subunit of GABAA receptors is a substrate for palmitoylation by GODZ. J. Neurosci. 24, 5881–5891 (2004). This paper provided the first identification of GODZ as a palmitoyltransferase that interacts with and palmitoylates the γ 2 subunit of GABA A Rs.
  Article CAS PubMed PubMed Central Google Scholar
• Rathenberg, J., Kittler, J. T. & Moss, S. J. Palmitoylation regulates the clustering and cell surface stability of GABAA receptors. Mol. Cell. Neurosci. 26, 251–257 (2004).
  Article CAS PubMed Google Scholar
• Fang, C. et al. GODZ-mediated palmitoylation of GABAA receptors is required for normal assembly and function of GABAergic inhibitory synapses. J. Neurosci. 26, 12758–12768 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Charych, E. I. et al. The brefeldin A-inhibited GDP/GTP exchange factor 2, a protein involved in vesicular trafficking, interacts with the β subunits of the GABAA receptors. J. Neurochem. 90, 173–189 (2004).
  Article CAS PubMed Google Scholar
• Moss, J. & Vaughan, M. Structure and function of ARF proteins: activators of cholera toxin and critical components of intracellular vesicular transport processes. J. Biol. Chem. 270, 12327–12330 (1995).
  Article CAS PubMed Google Scholar
• Beck, M. et al. Identification, molecular cloning, and characterization of a novel GABAA receptor-associated protein, GRIF-1. J. Biol. Chem. 277, 30079–30090 (2002).
  Article CAS PubMed Google Scholar
• Brickley, K., Smith, M. J., Beck, M. & Stephenson, F. A. GRIF-1 and OIP106, members of a novel gene family of coiled-coil domain proteins: association in vivo and in vitro with kinesin. J. Biol. Chem. 280, 14723–14732 (2005).
  Article CAS PubMed Google Scholar
• Smith, M. J., Pozo, K., Brickley, K. & Stephenson, F. A. Mapping the GRIF-1 binding domain of the kinesin, KIF5C, substantiates a role for GRIF-1 as an adaptor protein in the anterograde trafficking of cargoes. J. Biol. Chem. 281, 27216–27228 (2006).
  Article CAS PubMed Google Scholar
• Gilbert, S. L. et al. Trak1 mutation disrupts GABAA receptor homeostasis in hypertonic mice. Nature Genet. 38, 245–250 (2006).
  Article CAS PubMed Google Scholar
• Jacob, T. C. et al. Gephyrin regulates the cell surface dynamics of synaptic GABAA receptors. J. Neurosci. 25, 10469–10478 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Thomas, P., Mortensen, M., Hosie, A. M. & Smart, T. G. Dynamic mobility of functional GABAA receptors at inhibitory synapses. Nature Neurosci. 8, 889–897 (2005). The authors of this paper developed a novel electrophysiological tracking method to show that GABA A R lateral diffusion in the plasma membrane — not receptor insertion — results in rapid recovery from selective inhibition.
  Article CAS PubMed Google Scholar
• Bogdanov, Y. et al. Synaptic GABAA receptors are directly recruited from their extrasynaptic counterparts. Embo J. 25, 4381–4389 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Danglot, L., Triller, A. & Bessis, A. Association of gephyrin with synaptic and extrasynaptic GABAA receptors varies during development in cultured hippocampal neurons. Mol. Cell. Neurosci. 23, 264–278 (2003).
  Article CAS PubMed Google Scholar
• Sun, C., Sieghart, W. & Kapur, J. Distribution of α1, α4, γ2, and δ subunits of GABAA receptors in hippocampal granule cells. Brain Res. 1029, 207–216 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Mangan, P. S. et al. Cultured hippocampal pyramidal neurons express two kinds of GABAA receptors. Mol. Pharmacol. 67, 775–788 (2005).
  Article CAS PubMed Google Scholar
• Wei, W., Zhang, N., Peng, Z., Houser, C. R. & Mody, I. Perisynaptic localization of δ subunit-containing GABAA receptors and their activation by GABA spillover in the mouse dentate gyrus. J. Neurosci. 23, 10650–10661 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Pfeiffer, F., Graham, D. & Betz, H. Purification by affinity chromatography of the glycine receptor of rat spinal cord. J. Biol. Chem. 257, 9389–9393 (1982).
  Article CAS PubMed Google Scholar
• Meyer, G., Kirsch, J., Betz, H. & Langosch, D. Identification of a gephyrin binding motif on the glycine receptor β subunit. Neuron 15, 563–572 (1995).
  Article CAS PubMed Google Scholar
• Kneussel, M., Hermann, A., Kirsch, J. & Betz, H. Hydrophobic interactions mediate binding of the glycine receptor β subunit to gephyrin. J. Neurochem. 72, 1323–1326 (1999).
  Article CAS PubMed Google Scholar
• Feng, G. et al. Dual requirement for gephyrin in glycine receptor clustering and molybdoenzyme activity. Science 282, 1321–1324 (1998).
  Article CAS PubMed Google Scholar
• Levi, S., Logan, S. M., Tovar, K. R. & Craig, A. M. Gephyrin is critical for glycine receptor clustering but not for the formation of functional GABAergic synapses in hippocampal neurons. J. Neurosci. 24, 207–217 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Kirsch, J., Wolters, I., Triller, A. & Betz, H. Gephyrin antisense oligonucleotides prevent glycine receptor clustering in spinal neurons. Nature 366, 745–748 (1993).
  Article CAS PubMed Google Scholar
• Fritschy, J. M. & Brunig, I. Formation and plasticity of GABAergic synapses: physiological mechanisms and pathophysiological implications. Pharmacol. Ther. 98, 299–323 (2003).
  Article CAS PubMed Google Scholar
• Essrich, C., Lorez, M., Benson, J. A., Fritschy, J. M. & Luscher, B. Postsynaptic clustering of major GABAA receptor subtypes requires the γ2 subunit and gephyrin. Nature Neurosci. 1, 563–571 (1998). In this study, an analysis of mice that lacked GABA A R γ 2 subunits showed significant reductions in synaptic GABA A R and gephyrin clusters, indicating that a γ 2-dependent mechanism is involved in the formation of inhibitory synapses. More recently, γ 2 was also demonstrated to be required for the maintenance of mature synapses (see reference 75).
  Article CAS PubMed Google Scholar
• Kneussel, M. et al. Gephyrin-independent clustering of postsynaptic GABAA receptor subtypes. Mol. Cell. Neurosci. 17, 973–982 (2001).
  Article CAS PubMed Google Scholar
• Kneussel, M. et al. Loss of postsynaptic GABAA receptor clustering in gephyrin-deficient mice. J. Neurosci. 19, 9289–9297 (1999).
  Article CAS PubMed PubMed Central Google Scholar
• Kins, S., Betz, H. & Kirsch, J. Collybistin, a newly identified brain-specific GEF, induces submembrane clustering of gephyrin. Nature Neurosci. 3, 22–29 (2000).
  Article CAS PubMed Google Scholar
• Harvey, K. et al. The GDP-GTP exchange factor collybistin: an essential determinant of neuronal gephyrin clustering. J. Neurosci. 24, 5816–5826 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Papadopoulos, T. et al. Impaired GABAergic transmission and altered hippocampal synaptic plasticity in collybistin-deficient mice. Embo J. 26, 3888–3899 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Schweizer, C. et al. The γ2 subunit of GABAA receptors is required for maintenance of receptors at mature synapses. Mol. Cell. Neurosci. 24, 442–450 (2003).
  Article CAS PubMed Google Scholar
• Alldred, M. J., Mulder-Rosi, J., Lingenfelter, S. E., Chen, G. & Luscher, B. Distinct γ2 subunit domains mediate clustering and synaptic function of postsynaptic GABAA receptors and gephyrin. J. Neurosci. 25, 594–603 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Christie, S. B., Li, R. W., Miralles, C. P., Yang, B. Y. & De Blas, A. L. Clustered and non-clustered GABAA receptors in cultured hippocampal neurons. Mol. Cell. Neurosci. 31, 1–14 (2006).
  Article CAS PubMed Google Scholar
• Kirsch, J., Kuhse, J. & Betz, H. Targeting of glycine receptor subunits to gephyrin-rich domains in transfected human embryonic kidney cells. Mol. Cell. Neurosci. 6, 450–461 (1995).
  Article CAS PubMed Google Scholar
• Tretter, V. et al. The clustering of GABAA receptor subtypes at inhibitory synapses is facilitated via the direct binding of receptor α2 subunits to gephyrin. J. Neurosci. 28, 1356–1365 (2008). This paper described the first evidence that GABA A Rs bind directly to gephyrin and that disruption of this binding alters the synaptic targeting of receptor subtypes containing α 2 subunits.
  Article CAS PubMed PubMed Central Google Scholar
• Prior, P. et al. Primary structure and alternative splice variants of gephyrin, a putative glycine receptor-tubulin linker protein. Neuron 8, 1161–1170 (1992).
  Article CAS PubMed Google Scholar
• Maas, C. et al. Neuronal cotransport of glycine receptor and the scaffold protein gephyrin. J. Cell Biol. 172, 441–451 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Hanus, C., Ehrensperger, M. V. & Triller, A. Activity-dependent movements of postsynaptic scaffolds at inhibitory synapses. J. Neurosci. 26, 4586–4595 (2006). This paper, along with reference 81, used live imaging of fluorescently tagged gephyrin to reveal constant synaptic movements of gephyrin that could be controlled by activity. This showed that gephyrin is a significant dynamic force at inhibitory synapses.
  Article CAS PubMed PubMed Central Google Scholar
• Zita, M. M. et al. Post-phosphorylation prolyl isomerisation of gephyrin represents a mechanism to modulate glycine receptors function. Embo J. 26, 1761–1771 (2007).
  Article CAS PubMed Google Scholar
• Loebrich, S., Bahring, R., Katsuno, T., Tsukita, S. & Kneussel, M. Activated radixin is essential for GABAA receptor α5 subunit anchoring at the actin cytoskeleton. Embo J. 25, 987–999 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Bretscher, A., Edwards, K. & Fehon, R. G. ERM proteins and merlin: integrators at the cell cortex. Nature Rev. Mol. Cell Biol. 3, 586–599 (2002).
  Article CAS Google Scholar
• Cinar, H. & Barnes, E. M. Jr. Clathrin-independent endocytosis of GABAA receptors in HEK 293 cells. Biochemistry 40, 14030–14036 (2001).
  Article CAS PubMed Google Scholar
• Kittler, J. T. et al. Constitutive endocytosis of GABAA receptors by an association with the adaptin AP2 complex modulates inhibitory synaptic currents in hippocampal neurons. J. Neurosci. 20, 7972–7977 (2000). This paper provided the first evidence that GABA A Rs undergo constitutive endocytosis and described the role that this process has in regulating the efficacy of synaptic inhibition.
  Article CAS PubMed PubMed Central Google Scholar
• Kittler, J. T. et al. Huntingtin-associated protein 1 regulates inhibitory synaptic transmission by modulating γ-aminobutyric acidA receptor membrane trafficking. Proc. Natl Acad. Sci. USA 101, 12736–12741 (2004). This study demonstrated that GABA A Rs are internalized and either rapidly recycled to the cell-surface membrane or targeted for lysosomal degradation. It also demonstrated that this sorting decision can be regulated by a direct interaction of GABA A Rs with HAP1.
  Article CAS PubMed PubMed Central Google Scholar
• Herring, D. et al. Constitutive GABAA receptor endocytosis is dynamin-mediated and dependent on a dileucine AP2 adaptin-binding motif within the β2 subunit of the receptor. J. Biol. Chem. 278, 24046–24052 (2003).
  Article CAS PubMed Google Scholar
• van Rijnsoever, C., Sidler, C. & Fritschy, J. M. Internalized GABAA receptor subunits are transferred to an intracellular pool associated with the postsynaptic density. Eur. J. Neurosci. 21, 327–338 (2005).
  Article PubMed Google Scholar
• Pearse, B. M. F., Smith, C. J. & Owen, D. J. Clathrin coat construction in endocytosis. Curr. Opin. Struct. Biol. 10, 220–228 (2000).
  Article CAS PubMed Google Scholar
• Kittler, J. T. et al. Phospho-dependent binding of the clathrin AP2 adaptor complex to GABAA receptors regulates the efficacy of inhibitory synaptic transmission. Proc. Natl Acad. Sci. USA 102, 14871–14876 (2005). This paper identified a novel AP2 binding motif in β 3 GABA A R subunits. Furthermore, phosphorylation of this motif was demonstrated to decrease AP2 binding, showing that phospho-dependent modulation of AP2 binding to GABA A Rs can regulate endocytosis and receptor cell-surface levels.
  Article CAS PubMed PubMed Central Google Scholar
• Kittler, J. T. et al. Regulation of synaptic inhibition by phospho-dependent binding of the AP2 complex to a YECL motif in the GABAA receptor γ2 subunit. Proc. Natl Acad. Sci. USA 105, 3616–3621 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Moss, S. J., Gorrie, G. H., Amato, A. & Smart, T. G. Modulation of GABAA receptors by tyrosine phosphorylation. Nature 377, 344–348 (1995).
  Article CAS PubMed Google Scholar
• Chen, G., Kittler, J. T., Moss, S. J. & Yan, Z. Dopamine D3 receptors regulate GABAA receptor function through a phospho-dependent endocytosis mechanism in nucleus accumbens. J. Neurosci. 26, 2513–2521 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Feng, J., Cai, X., Zhao, J. & Yan, Z. Serotonin receptors modulate GABAA receptor channels through activation of anchored protein kinase C in prefrontal cortical neurons. J. Neurosci. 21, 6502–6511 (2001).
  Article CAS PubMed PubMed Central Google Scholar
• Yan, Z. & Surmeier, D. J. D5 dopamine receptors enhance Zn2+-sensitive GABAA currents in striatal cholinergic interneurons through a PKA/PP1 cascade. Neuron 19, 1115–1126 (1997).
  Article CAS PubMed Google Scholar
• Li, X.-J. et al. A huntingtin-associated protein enriched in brain with implications for pathology. Nature 378, 398–402 (1995).
  Article CAS PubMed Google Scholar
• Sheng, G. et al. Hypothalamic huntingtin-associated protein 1 as a mediator of feeding behavior. Nature Med. 12, 526–533 (2006). This elegant study demonstrated that decreases in HAP1 affect the activity of GABA A Rs in the hypothalamus and result in a functional change in food intake and body weight in rodents.
  Article CAS PubMed Google Scholar
• Benarroch, E. E. GABAA receptor heterogeneity, function, and implications for epilepsy. Neurology 68, 612–614 (2007).
  Article CAS PubMed Google Scholar
• Thompson-Vest, N. M., Waldvogel, H. J., Rees, M. I. & Faull, R. L. GABAA receptor subunit and gephyrin protein changes differ in the globus pallidus in Huntington's diseased brain. Brain Res. 994, 265–270 (2003).
  Article CAS PubMed Google Scholar
• DeLorey, T. M. & Olsen, R. W. GABA and epileptogenesis: comparing gabrb3 gene-deficient mice with Angelman syndrome in man. Epilepsy Res. 36, 123–132 (1999).
  Article CAS PubMed Google Scholar
• D'Hulst, C. & Kooy, R. F. The GABAA receptor: a novel target for treatment of fragile X? Trends Neurosci. 30, 425–431 (2007).
  Article CAS PubMed Google Scholar
• Lewis, D. A. & Gonzalez-Burgos, G. Pathophysiologically based treatment interventions in schizophrenia. Nature Med. 12, 1016–1022 (2006).
  Article CAS PubMed Google Scholar
• Krystal, J. H. et al. γ-aminobutyric acidA receptors and alcoholism: intoxication, dependence, vulnerability, and treatment. Arch. Gen. Psychiatry 63, 957–968 (2006).
  Article CAS PubMed Google Scholar
• Coulter, D. A. Epilepsy-associated plasticity in γ-aminobutyric acid receptor expression, function, and inhibitory synaptic properties. Int. Rev. Neurobiol. 45, 237–252 (2001).
  Article CAS PubMed Google Scholar
• Chen, J. W., Naylor, D. E. & Wasterlain, C. G. Advances in the pathophysiology of status epilepticus. Acta Neurol. Scand. Suppl. 186, 7–15 (2007).
  Article CAS PubMed Google Scholar
• Naylor, D. E., Liu, H. & Wasterlain, C. G. Trafficking of GABAA receptors, loss of inhibition, and a mechanism for pharmacoresistance in status epilepticus. J. Neurosci. 25, 7724–7733 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Goodkin, H. P., Yeh, J. L. & Kapur, J. Status epilepticus increases the intracellular accumulation of GABAA receptors. J. Neurosci. 25, 5511–5520 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Terunuma, M. et al. Deficits in phosphorylation of GABAA receptors by intimately associated protein kinase C activity underlies compromised synaptic inhibition during status epilepticus. J. Neurosci. 28, 37–84 (2008).
  Article CAS Google Scholar
• Bouilleret, V., Loup, F., Kiener, T., Marescaux, C. & Fritschy, J. M. Early loss of interneurons and delayed subunit-specific changes in GABAA receptor expression in a mouse model of mesial temporal lobe epilepsy. Hippocampus 10, 305–324 (2000).
  Article CAS PubMed Google Scholar
• Knuesel, I., Zuellig, R. A., Schaub, M. C. & Fritschy, J. M. Alterations in dystrophin and utrophin expression parallel the reorganization of GABAergic synapses in a mouse model of temporal lobe epilepsy. Eur. J. Neurosci. 13, 1113–1124 (2001).
  Article CAS PubMed Google Scholar
• Fritschy, J. M., Kiener, T., Bouilleret, V. & Loup, F. GABAergic neurons and GABAA receptors in temporal lobe epilepsy. Neurochem. Int. 34, 435–445 (1999).
  Article CAS PubMed Google Scholar
• Brooks-Kayal, A. R., Shumate, M. D., Jin, H., Rikhter, T. Y. & Coulter, D. A. Selective changes in single cell GABAA receptor subunit expression and function in temporal lobe epilepsy. Nature Med. 4, 1166–1172 (1998).
  Article CAS PubMed Google Scholar
• Schwarzer, C. et al. GABAA receptor subunits in the rat hippocampus II: altered distribution in kainic acid-induced temporal lobe epilepsy. Neuroscience 80, 1001–1017 (1997).
  Article CAS PubMed Google Scholar
• Peng, Z., Huang, C. S., Stell, B. M., Mody, I. & Houser, C. R. Altered expression of the δ subunit of the GABAA receptor in a mouse model of temporal lobe epilepsy. J. Neurosci. 24, 8629–8639 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Pirker, S. et al. Increased expression of GABAA receptor β subunits in the hippocampus of patients with temporal lobe epilepsy. J. Neuropathol. Exp. Neurol. 62, 820–834 (2003).
  Article CAS PubMed Google Scholar
• Loup, F., Wieser, H. G., Yonekawa, Y., Aguzzi, A. & Fritschy, J. M. Selective alterations in GABAA receptor subtypes in human temporal lobe epilepsy. J. Neurosci. 20, 5401–5419 (2000). This paper reported that there are marked changes in the expression of major GABA A R subtypes in the hippocampus of temporal lobe epilepsy patients.
  Article CAS PubMed PubMed Central Google Scholar
• Wallace, R. H. et al. Mutant GABAA receptor γ2 subunit in childhood absence epilepsy and febrile seizures. Nature Genet. 28, 49–52 (2001).
  CAS PubMed Google Scholar
• Baulac, S. et al. First genetic evidence of GABAA receptor dysfunction in epilepsy: a mutation in the γ2 subunit gene. Nature Genet. 28, 46–48 (2001). This paper, together with reference 119, provided the first report of mutations in the genes that encode GABA A R subunits being associated with human epilepsy.
  CAS PubMed Google Scholar
• Kananura, C. et al. A splice-site mutation in GABRG2 associated with childhood absence epilepsy and febrile convulsions. Arch. Neurol. 59, 1137–1141 (2002).
  Article PubMed Google Scholar
• Cossette, P. et al. Mutation of GABRA1 in an autosomal dominant form of juvenile myoclonic epilepsy. Nature Genet. 31, 184–189 (2002).
  Article CAS PubMed Google Scholar
• Maljevic, S. et al. A mutation in the GABAA receptor α1 subunit is associated with absence epilepsy. Ann. Neurol. 59, 983–987 (2006).
  Article CAS PubMed Google Scholar
• Feng, H. J. et al. δ subunit susceptibility variants E177A and R220H associated with complex epilepsy alter channel gating and surface expression of α4β2δ GABAA receptors. J. Neurosci. 26, 1499–1506 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Hirose, S. A new paradigm of channelopathy in epilepsy syndromes: intracellular trafficking abnormality of channel molecules. Epilepsy Res. 70 (Suppl. 1), S206–S217 (2006).
  Article CAS PubMed Google Scholar
• Bianchi, M. T., Song, L., Zhang, H. & Macdonald, R. L. Two different mechanisms of disinhibition produced by GABAA receptor mutations linked to epilepsy in humans. J. Neurosci. 22, 5321–5327 (2002).
  Article CAS PubMed PubMed Central Google Scholar
• Eugene, E. et al. GABAA receptor γ2 subunit mutations linked to human epileptic syndromes differentially affect phasic and tonic inhibition. J. Neurosci. 27, 14108–14116 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Gallagher, M. J., Ding, L., Maheshwari, A. & Macdonald, R. L. The GABAA receptor α1 subunit epilepsy mutation A322D inhibits transmembrane helix formation and causes proteasomal degradation. Proc. Natl Acad. Sci. USA 104, 12999–13004 (2007). This paper presented a biochemical mechanism for how a mutation in the GABA A R α 1 subunit might result in a form of human epilepsy. The mutation was demonstrated to lead to subunit misfolding followed by ER-associated degradation, which resulted in reduced GABA A R cell-surface expression.
  Article CAS PubMed PubMed Central Google Scholar
• Kalivas, P. W. Neurobiology of cocaine addiction: implications for new pharmacotherapy. Am. J. Addict. 16, 71–78 (2007).
  Article PubMed Google Scholar
• Kumar, S., Fleming, R. L. & Morrow, A. L. Ethanol regulation of γ-aminobutyric acidA receptors: genomic and nongenomic mechanisms. Pharmacol. Ther. 101, 211–226 (2004).
  Article CAS PubMed Google Scholar
• Wafford, K. A. GABAA receptor subtypes: any clues to the mechanism of benzodiazepine dependence? Curr. Opin. Pharmacol. 5, 47–52 (2005).
  Article CAS PubMed Google Scholar
• Liang, J. et al. Mechanisms of reversible GABAA receptor plasticity after ethanol intoxication. J. Neurosci. 27, 12367–12377 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Liang, J. et al. Chronic intermittent ethanol-induced switch of ethanol actions from extrasynaptic to synaptic hippocampal GABAA receptors. J. Neurosci. 26, 1749–1758 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Kumar, S., Sieghart, W. & Morrow, A. L. Association of protein kinase C with GABAA receptors containing α1 and α4 subunits in the cerebral cortex: selective effects of chronic ethanol consumption. J. Neurochem. 82, 110–117 (2002).
  Article CAS PubMed Google Scholar
• Kumar, S., Kralic, J. E., O'Buckley, T. K., Grobin, A. C. & Morrow, A. L. Chronic ethanol consumption enhances internalization of α1 subunit-containing GABAA receptors in cerebral cortex. J. Neurochem. 86, 700–708 (2003).
  Article CAS PubMed Google Scholar
• Khanna, J. M., Kalant, H., Chau, A. & Shah, G. Rapid tolerance and crosstolerance to motor impairment effects of benzodiazepines, barbiturates, and ethanol. Pharmacol. Biochem. Behav. 59, 511–519 (1998).
  Article CAS PubMed Google Scholar
• Volk, D. W. et al. Reciprocal alterations in pre- and postsynaptic inhibitory markers at chandelier cell inputs to pyramidal neurons in schizophrenia. Cereb. Cortex 12, 1063–1070 (2002).
  Article PubMed Google Scholar
• Wassef, A., Baker, J. & Kochan, L. D. GABA and schizophrenia: a review of basic science and clinical studies. J. Clin. Psychopharmacol. 23, 601–640 (2003).
  Article CAS PubMed Google Scholar
• Yee, B. K. et al. A schizophrenia-related sensorimotor deficit links α3-containing GABAA receptors to a dopamine hyperfunction. Proc. Natl Acad. Sci. USA 102, 17154–17159 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Braff, D. L., Geyer, M. A. & Swerdlow, N. R. Human studies of prepulse inhibition of startle: normal subjects, patient groups, and pharmacological studies. Psychopharmacology (Berl.) 156, 234–258 (2001).
  Article CAS Google Scholar
• Studer, R. et al. Alteration of GABAergic synapses and gephyrin clusters in the thalamic reticular nucleus of GABAA receptor α3 subunit-null mice. Eur. J. Neurosci. 24, 1307–1315 (2006).
  Article PubMed Google Scholar
• Fritschy, J. M. & Mohler, H. GABAA receptor heterogeneity in the adult rat brain: differential regional and cellular distribution of seven major subunits. J. Comp. Neurol. 359, 154–194 (1995).
  Article CAS PubMed Google Scholar
• Hauser, J. et al. Hippocampal α5 subunit-containing GABAA receptors modulate the expression of prepulse inhibition. Mol. Psychiatry 10, 201–207 (2005).
  Article CAS PubMed Google Scholar
• Moss, S. J. & Smart, T. G. Constructing inhibitory synapses. Nature Rev. Neurosci. 2, 240–250 (2001).
  Article CAS Google Scholar
• Belelli, D. & Lambert, J. J Neurosteroids: endogenous regulators of the GABAA receptor. Nature Rev. Neurosci. 6, 565–575 (2005).
  Article CAS Google Scholar
• Arancibia-Carcamo, I. L. & Moss, S. J. Molecular organization and assembly of the central inhibitory postsynapse. Results Probl. Cell Differ. 43, 25–47 (2006).
  Article CAS PubMed Google Scholar
• Giesemann, T. et al. Complex formation between the postsynaptic scaffolding protein gephyrin, profilin, and mena: a possible link to the microfilament system. J. Neurosci. 23, 8330–8339 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Mammoto, A. et al. Interactions of drebrin and gephyrin with profilin. Biochem. Biophys. Res. Commun. 243, 86–89 (1998).
  Article CAS PubMed Google Scholar