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  • Review Article
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GABAA receptor trafficking and its role in the dynamic modulation of neuronal inhibition

Key Points

  • GABA (γ-aminobutyric acid) type A receptors (GABAARs) are GABA-gated, Cl-selective channels that are responsible for most fast synaptic inhibition in the mammalian brain. GABAARs at extrasynaptic sites also have crucial roles in mediating tonic inhibition in the brain. In addition, GABAARs are clinically relevant drug targets for many sedative–hypnotic, anxiolytic, anti-convulsant and general-anaesthetic agents.

  • GABAARs are synthesized and assembled in the endoplasmic reticulum (ER) to form select pentameric receptor populations that each have distinct physiological and pharmacological properties, as well as differential subcellular targeting and expression throughout the brain. The ER-associated degradation of GABAAR subunits by the ubiquitin–proteasome system is one mechanism that neurons use to regulate the number of GABAARs that are exported from the ER. New research suggests that synaptic activity can bidirectionally regulate this degradation process.

  • Numerous proteins have been identified that interact with GABAARs in the Golgi apparatus, to help them segregate and exit the Golgi in the appropriate transport vesicles. This helps the GABAARs traffic to the appropriate destination on the plasma membrane. Post-translational modifications, such as phosphorylation and palmitoylation, have been demonstrated to be of crucial importance in dynamically modulating these protein–protein interactions and in influencing GABAAR trafficking to the plasma membrane.

  • Lateral diffusion of GABAARs in the plasma membrane allows continual exchange between synaptic and extrasynaptic receptor populations, with inhibitory scaffold molecules tethering or corralling moving receptors. The inhibitory scaffold is also a dynamic entity that displays local lateral movements and rapid intracellular transport to or from the synapse. These mechanisms contribute to the regulation of receptor cell-surface localization and synaptic strength.

  • Clathrin-dependent endocytosis is the major internalization mechanism for neuronal GABAARs. It depends on interactions between the intracellular loops of GABAAR subunits and the clathrin-adaptor protein (AP2) complex. Phosphorylation of GABAAR subunits at distinct AP2 binding sites seems to regulate receptor stability at the cell surface and, consequently, the strength of synaptic inhibition. Once they have been endocytosed, GABAARs can be recycled to the plasma membrane or degraded in lysosomes, a complex process that is likely to be regulated at multiple points.

  • Dysregulation of GABAAR expression and trafficking has been implicated in a number of neurological and neuropsychiatric disorders, including epilepsy, drug abuse disorders and schizophrenia.

Abstract

GABA (γ-aminobutyric acid) type A receptors (GABAARs) mediate most fast synaptic inhibition in the mammalian brain, controlling activity at both the network and the cellular levels. The diverse functions of GABA in the CNS are matched not just by the heterogeneity of GABAARs, but also by the complex trafficking mechanisms and protein–protein interactions that generate and maintain an appropriate receptor cell-surface localization. In this Review, we discuss recent progress in our understanding of the dynamic regulation of GABAAR composition, trafficking to and from the neuronal surface, and lateral movement of receptors between synaptic and extrasynaptic locations. Finally, we highlight a number of neurological disorders, including epilepsy and schizophrenia, in which alterations in GABAAR trafficking occur.

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Figure 1: GABAA receptor structure and neuronal localization.
Figure 2: Trafficking of GABAA receptors.
Figure 3: Dynamic regulation of receptor lateral mobility at the GABAergic synapse.
Figure 4: Regulation of GABAA receptor endocytosis and post-endocytic sorting.
Figure 5: Dysregulation of GABAA receptor trafficking in neurological disease.

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References

  1. 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 

  2. 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 

  3. Bormann, J. & Feigenspan, A. GABAC receptors. Trends Neurosci. 18, 515–519 (1995).

    Article  CAS  PubMed  Google Scholar 

  4. 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 

  5. 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 

  6. 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 

  7. Unwin, N. The structure of ion channels in membranes of excitable cells. Neuron 3, 665–676 (1989).

    Article  CAS  PubMed  Google Scholar 

  8. 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 

  9. 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 

  10. Draguhn, A., Axmacher, N. & Kolbaev, S. Presynaptic ionotropic GABA receptors. Results Probl. Cell Differ. 44, 69–85 (2008).

    Article  CAS  PubMed  Google Scholar 

  11. 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 

  12. 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 

  13. 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 

  14. 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 

  15. 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 

  16. 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 

  17. 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 

  18. 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 

  19. 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 

  20. 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 

  21. 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 

  22. 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 

  23. 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 

  24. 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 

  25. 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 

  26. 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 

  27. 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 

  28. 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 

  29. 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 

  30. 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 

  31. 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 

  32. 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 

  33. 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 

  34. 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 

  35. Nishimune, A. et al. NSF binding to GluR2 regulates synaptic transmission. Neuron 21, 87–97 (1998).

    Article  CAS  PubMed  Google Scholar 

  36. Song, I. et al. Interaction of the N-ethylmaleimide-sensitive factor with AMPA receptors. Neuron 21, 393–400 (1998).

    Article  CAS  PubMed  Google Scholar 

  37. 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 

  38. 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 

  39. 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 

  40. 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 

  41. 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 

  42. 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 

  43. 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 

  44. 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 

  45. 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 

  46. 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 

  47. 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 

  48. 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 

  49. 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 

  50. 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 

  51. 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 

  52. 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 

  53. 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 

  54. 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 

  55. 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 

  56. 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 

  57. 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 

  58. 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 

  59. 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 

  60. 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 

  61. 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 

  62. 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 

  63. 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 

  64. 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 

  65. 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 

  66. 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 

  67. 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 

  68. 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 

  69. 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 

  70. Kneussel, M. et al. Gephyrin-independent clustering of postsynaptic GABAA receptor subtypes. Mol. Cell. Neurosci. 17, 973–982 (2001).

    Article  CAS  PubMed  Google Scholar 

  71. 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 

  72. 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 

  73. 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 

  74. 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 

  75. 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 

  76. 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 

  77. 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 

  78. 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 

  79. 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 

  80. 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 

  81. 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 

  82. 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 

  83. 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 

  84. 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 

  85. 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 

  86. 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 

  87. 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 

  88. 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 

  89. 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 

  90. 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 

  91. 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 

  92. 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 

  93. 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 

  94. 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 

  95. 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 

  96. 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 

  97. 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 

  98. 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 

  99. 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 

  100. Benarroch, E. E. GABAA receptor heterogeneity, function, and implications for epilepsy. Neurology 68, 612–614 (2007).

    Article  CAS  PubMed  Google Scholar 

  101. 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 

  102. 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 

  103. 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 

  104. Lewis, D. A. & Gonzalez-Burgos, G. Pathophysiologically based treatment interventions in schizophrenia. Nature Med. 12, 1016–1022 (2006).

    Article  CAS  PubMed  Google Scholar 

  105. 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 

  106. 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 

  107. 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 

  108. 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 

  109. 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 

  110. 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 

  111. 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 

  112. 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 

  113. 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 

  114. 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 

  115. 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 

  116. 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 

  117. 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 

  118. 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 

  119. 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 

  120. 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 

  121. 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 

  122. 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 

  123. 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 

  124. 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 

  125. 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 

  126. 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 

  127. 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 

  128. 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 

  129. Kalivas, P. W. Neurobiology of cocaine addiction: implications for new pharmacotherapy. Am. J. Addict. 16, 71–78 (2007).

    Article  PubMed  Google Scholar 

  130. 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 

  131. 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 

  132. 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 

  133. 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 

  134. 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 

  135. 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 

  136. 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 

  137. 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 

  138. 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 

  139. 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 

  140. 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 

  141. 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 

  142. 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 

  143. 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 

  144. Moss, S. J. & Smart, T. G. Constructing inhibitory synapses. Nature Rev. Neurosci. 2, 240–250 (2001).

    Article  CAS  Google Scholar 

  145. Belelli, D. & Lambert, J. J Neurosteroids: endogenous regulators of the GABAA receptor. Nature Rev. Neurosci. 6, 565–575 (2005).

    Article  CAS  Google Scholar 

  146. 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 

  147. 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 

  148. Mammoto, A. et al. Interactions of drebrin and gephyrin with profilin. Biochem. Biophys. Res. Commun. 243, 86–89 (1998).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

In memory of Professor Robert Eisenthal, the 'master enzymologist'. SJM is supported by NIH grants NS046478, NS048045, NS051195, NS056359 and P01NS054900 and by the MRC (UK) and the Wellcome Trust. The authors would like to thank R. Olsen for communication of unpublished results.

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DATABASES

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Angelman syndrome

fragile X syndrome

Huntington's disease

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Glossary

Tonic inhibition

An inhibitory response that results from the activation of extra- or perisynaptic GABAA receptors by ambient concentrations of GABA.

Benzodiazepines

Pharmacologically active molecules with sedative, anxiolytic, amnesic and anticonvulsant effects. They act by binding at the interface between the α(1, 2, 3 or 5) and γ subunits of GABAA receptors and potentiating the response elicited by GABA.

Ubiquitin–proteasome system

(UPS). Ubiquitin is a 76-amino-acid protein that, among other functions, tags proteins for degradation. Tagged proteins are targeted to the proteasome, a large, multimeric barrel-like complex that degrades proteins.

Palmitoylation

The covalent attachment of a palmitate (16-carbon saturated fatty acid) molecule to a cysteine residue through a thioester bond.

RNA interference

(RNAi). A molecular method in which small interfering RNA sequences are introduced into cells or tissues to decrease the expression of target genes.

Yeast two-hybrid screen

A system used to determine whether two proteins interact. It involves the expression of two proteins in yeast: the plasmids encoding these proteins are fused to the GAL4 DNA-binding and activation domains. If the proteins interact, the resulting complex drives the expression of a reporter gene, commonly β-galactosidase.

Miniature inhibitory postsynaptic current

(mIPSC). The postsynaptic current that results from the activation of synaptic receptors by neurotransmitters (GABA or glycine) that are usually released from a single vesicle.

Clathrin

One of the main protein components of the coat that is formed during membrane endocytosis.

Clathrin-adaptor protein 2 (AP2) complex

A heterotetrameric complex composed of subunits called adaptins that have an important role in clathrin-dependent membrane endocytosis.

GABAergic plasticity

Changes in local activity that lead to longer-term increases or decreases in inhibitory synaptic strength.

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Jacob, T., Moss, S. & Jurd, R. GABAA receptor trafficking and its role in the dynamic modulation of neuronal inhibition. Nat Rev Neurosci 9, 331–343 (2008). https://doi.org/10.1038/nrn2370

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