Dynamic Regulation of GABAA Receptor Biosynthesis and Transport

  • Yu. D. BogdanovEmail author

γ-Aminobutyric acid (GABA) receptors are the main receptors supporting inhibition in the central nervous system. These receptors are divided into the ionotropic (GABAA, ion channels) and metabotropic (GABAB, coupled with G proteins) types. Activation of GABAA receptors is the main source of rapid inhibition in the central nervous system. This review addresses dynamic regulation of the delivery of GABAA receptors on formation of inhibitory synapses. The plasticity of inhibitory synapses in regulating the attachment of receptors within them is not discussed. Impairments to the regulation of GABAA receptors has been described in diseases such as epilepsy, anxiety disorders, schizophrenia, and alcoholism. Thus, studies of the biogenesis of GABAA receptors, their dynamic regulation, and their role in the etiology of various diseases are important prerequisites for the development of novel therapeutic strategies.


GABA GABAA receptors regulation of transcription RNA editing endoplasmic reticulum Golgi apparatus 


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  1. Alam, J., Deharo, D., Redding, K. M., et al., “C-terminal processing of GABARAP is not required for trafficking of the angiotensin II type 1A receptor,” Regul. Pept., 159, No. 1–3, 78–86 (2010).Google Scholar
  2. Bedford, F. K., Kittler, J. T., Muller, E., et al., “GABA(A) receptor cell surface number and subunit stability are regulated by the ubiquitin-like protein Plic-1,” Nat. Neurosci., 4, No. 9, 908–916 (2001).Google Scholar
  3. Bogdanov, Y. D., Michels, G., Armstrong-Gold, C., et al., “Synaptic GABAA receptors are directly recruited from their extrasynaptic counterparts,” EMBO, J., 25, No. 18, 4381–4389 (2006).Google Scholar
  4. Borghese, C. M., Ruiz, C. I., Lee, U. S., et al., “Identification of an inhibitory alcohol binding site in GABAA ρ1 receptors,” ACS Chem. Neurosci., 7, No. 1, 100–108 (2016).Google Scholar
  5. Buhr, A., Bianchi, M. T., Baur, R., et al., “Functional characterization of the new human GABA(A) receptor mutation beta3(R192H),” Hum. Genet., 111, No. 2, 154–160 (2002).Google Scholar
  6. Charlton, M. E., Sweetnam, P. M., Fitzgerald, L. W., et al., “Chronic ethanol administration regulates the expression of GABAA receptor α1 and α5 subunits in the ventral tegmental area and hippocampus,” J. Neurochem., 68, No. 1, 121–127 (1997).Google Scholar
  7. Daniel, C., Veno, M. T., Ekdahl, Y., et al., “A distant cis acting intronic element induces site-selective RNA editing,” Nucl. Acids Res., 40, No. 19, 9876–9886 (2012).Google Scholar
  8. Devaud, L. L., Smith, F. D., Grayson, D. R., and Morrow, A. L., “Chronic ethanol consumption differentially alters the expression of γ-aminobutyric acid A receptor subunit mRNAs in rat cerebral cortex: competitive, quantitative reverse-transcriptase polymerase chain reaction analysis,” Mol. Pharmacol., 48, 861–868 (1995).Google Scholar
  9. Di, X.-J., Wang, Y.-J., Han, D.-Y., et al., “Grp94 protein delivers γ-aminobutyric acid type A (GABAA) receptors to Hrd1 protein-mediated endoplasmic reticulum-associated degradation,” J. Biol. Chem., 291, No. 18, 9526–9539 (2016).Google Scholar
  10. Enstero, M., Akerborg, O., Lundin, D., et al., “A computational screen for site-selective A-to-I editing detects novel sites in neuron-specific Hu proteins,” BMC Bioinformatics, 11, 6 (2010).Google Scholar
  11. Enz, R., “GABA(C) receptors: a molecular view,” Biol. Chem., 8, 1111– 1122 (2001).Google Scholar
  12. Fang, C., Deng, L., Keller, C. A., et al., “GODZ-mediated palmitoylation of GABA(A) receptors is required for normal assembly and function of GABAergic inhibitory synapses,” J. Neurosci., 26, No. 49, 12758–12768 (2006).Google Scholar
  13. Förstera, B., Castro, P. A., Moraga-Cid, G., and Aguayo, L. G., “Potentiation of gamma aminobutyric acid receptors (GABAAR) by ethanol: How are inhibitory receptors affected?” Front. Cell. Neuroscience, 10, 114 (2016).Google Scholar
  14. Fritchy, J. M. and Panzanelli, P., “GABAA receptors and plasticity of inhibitory neurotransmission in the central nervous system,” Eur. J. Neurosci., 39, No. 11, 1845–1865 (2014).Google Scholar
  15. Gemer, F. M., Trapp, T., and Hauser, C. A., “A classic cAMP responsive element in the promoter region of the alpha 1 GABAA receptor subunit has non-classical properties,” Funct. Neurology, 12, No. 2, 55–61 (1997).Google Scholar
  16. Green, W. N. and Millar, N. S., “Ion channel assembly,” Trends Neurosci., 18, 280–287 (1995).Google Scholar
  17. Green, F., O’Hare, T., Blackwell, A., and Enns, C. A., “Association of human transferrin receptor with GABARAP,” FEBS Lett., 518, No. 1–3, 101–106 (2002).Google Scholar
  18. Gulinello, M., Gong, Q. H., Li, X., and Smith, S. S., “Short-term exposure to neuroactive steroid increases alpha4 GABA(A) receptor subunit levels in association with increased anxiety in the female rat,” Brain Res., 910, 55–66 (2001).Google Scholar
  19. Han, D. Y., Di, X. J., Fu, Y. L., and Mu, T. W., “Combining valosin-containing protein (VCP) inhibition and suberaniloxydroxamic acid (SAHA) treatment additively enhances the folding, trafficking and function of epilepsy-associated γ-aminobutyric acid type A (GABAA) receptors,” J. Biol. Chem., 290, 325–337 (2015).Google Scholar
  20. Herring, D., Huang, R., Singh, M., et al., “Constitutive GABAA receptor endocytosis is dynamin-mediated and dependent on a dileucine AP2 adaptin-binding motif within the beta2 subunit of the receptor,” J. Biol. Chem., 278, 24046–24052 (2003).Google Scholar
  21. Herring, D., Huang, R., Singh, M., et al., “PKC modulation of GABAA receptor endocytosis and function is inhibited by mutation of a dileucine motif within the receptor β2 subunit,” Neuropharmacology, 48, 181–194 (2005).Google Scholar
  22. Hosie, A. M., Wilkins, M. E., da Silva, H. M., and Smart, T. G., “Endogenous neurosteroids regulate GABAA receptors through two discrete transmembrane sites,” Nature, 444, 486–489 (2006).Google Scholar
  23. Hu, Y., Lund, I. V., Gravielle, M. C., et al., “Surface expression of GABAA receptors is transcriptionally controlled by the interplay of cAMP-response element-binding protein and its binding partner inducible cAMP early repressor,” J. Biol. Chem., 283, 9328–9340 (2008).Google Scholar
  24. Jacob, T. C., Bogdanov, Y. D., Magnus, C., et al., “Gephyrin regulates the cell surface dynamics of synaptic GABAA receptors,” J. Neurosci., 25, No. 45, 10469–10478 (2005).Google Scholar
  25. Jacob, T. C., Moss, S. J., and Jurd, R., “GABAA receptor trafficking and its role in the dynamic modulation of neuronal inhibition,” Nat. Rev. Neurosci., 9, No. 5, 331–343 (2008).Google Scholar
  26. Jembrek, M. J. and Vlainic, J., “GABA receptors: pharmacological potential and pitfalls,” Curr. Pharm. Des., 21, No. 34, 4943–4959 (2015).Google Scholar
  27. Jin, H., Chiou, T. T., Serwanski, D. R., et al., “Ring finger protein 34 (RNF34) interacts with and promotes γ-aminobutyric acid type-A receptor degradation via ubiquitination of the γ2 subunit,” J. Biol. Chem., 289, 29420–29436 (2014).Google Scholar
  28. Johar, K., Priya, A., Dhar, S., et al., “Neuron-specific specificity protein 4 biogenomically regulates the transcription of all mitochondria-and nucleus-encoded cytochrome c oxidase subunit genes in neurons,” J. Neurochem., 127, 496–508 (2013).Google Scholar
  29. Johar, K., Priya, A., and Wong-Riley, M. T., “Regulation of Na(+)K(+)-ATPase by neuron-specific transcription factor Sp4: implication in the tight coupling of energy production, neuronal activity and energy consumption in neurons,” Eur. J. Neurosci., 39, 566–578 (2014).Google Scholar
  30. Kanematsu, T., Jang, I. S., Yamaguchi, T., et al., “Role of the PLC-related, catalytically inactive protein p130 in GABA(A) receptor function,” EMBO J., 21, No. 5, 1004–1111 (2002).Google Scholar
  31. Kang, I., Lindquist, D. G., Kinane, T. B., et al., “Isolation and characterization of the promoter of the human GABAA receptor alpha1 subunit gene,” J. Neurochem., 62, No. 4, 1643–1646 (1994).Google Scholar
  32. Keller, C. A., Yuan, X., Panzanelli, P., et al., “The gamma2 subunit of GABA(A) receptors is a substrate for palmitoylation by GODZ,” J. Neurosci., 24, No. 26, 5881–5891 (2004).Google Scholar
  33. Kim, Y., Glatt, H., Xie, W., et al., “Human gamma-aminobutyric acid-type A receptor alpha5 subunit gene (GABRA5, characterization and structural organization of the 5’-flanking region,” Genomics, 42, No. 3, 378–387 (1997).Google Scholar
  34. Kirkness, E. G. and Fraser, C. M., “A strong promoter element is located between alternative exons of a gene encoding the human gamma-aminobutyric acid type-A receptor beta3 subunit (GABRB3),” J. Biol. Chem., 268, No. 6, 4420–4428 (1993).Google Scholar
  35. Kittler, J. T., Delmas, P., Jovanovic, J. N., 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).Google Scholar
  36. Kittler, J. T., Rostaing, P., Schiavo, G., 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).Google Scholar
  37. Kittler, J. T., Thomas, P., Tretter, V., et al., “Huntingtin-associated protein 1 regulates inhibitory synaptic transmission by modulating gamma-aminobutyric type A receptor membrane trafficking,” Proc. Natl. Acad. Sci. USA, 101, 12736–12741 (2004).Google Scholar
  38. Kittler, J. T., Chen, G., Honing, S., 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, No. 41, 14871–14876 (2005).Google Scholar
  39. Kittler, J. T., Chen, G., Kukhtina, V., et al., “Regulation of synaptic inhibition by phospho-dependent binding of AP2 complex to a YECL motif in the GABAA receptor gamma2 subunit,” Proc. Natl. Acad. Sci. USA, 105, No. 9, 3616–3621 (2008).Google Scholar
  40. Ma, L., Song, L., Radoi, G. E., and Harrisson, N. L., “Transcriptional regulation of the mouse gene encoding the α4 subunit of the GABAA receptor,” J. Biol. Chem., 279, 40451–40461 (2004).Google Scholar
  41. Macdonald, R. L. and Kang, J.-Q., “mRNA surveillance and endoplasmic reticulum quality control processes alter biogenesis of mutant GABAA receptor subunits associated with genetic epilepsies,” Epilepsia, 53, No. 9, 59–70 (2012).Google Scholar
  42. Machuca-Parra, A. I., Miledi, R., and Martinez-Torres, A., “Identification of the minimal promoter for specific expression of the GABAρ1 receptor in retinal bipolar cells,” J. Neurochem., 124, No. 2, 175–188 (2013).Google Scholar
  43. MacKenzie, G. and Maguire, J., “Neurosteroids and GABAergic signalling in health and disease,” Biomol. Concepts, 4, No. 1, 29–42 (2013).Google Scholar
  44. Maguire, J. L., Stell, B. M., Rafizadeh, M., and Mody, I., “Ovarian cycle-linked changes in GABA(A) receptor mediating tonic inhibition alter seizure susceptibility and anxiety,” Nat. Neurosci., 8, 797–804 (2005).Google Scholar
  45. McLean, P. J., Shpektor, D., Bandyopadhyay, S., et al., “A minimal promoter for the GABA(A) receptor alpha6-subunit gene controls tissue specificity,” J. Neurochem., 74, No. 5, 1858–1869 (2000).Google Scholar
  46. Mele, M., Ribeiro, L., Inacio, A. R., et al., “GABAA receptor dephosphorylation followed by internalization is coupled to neuronal death in in vitro ischemia,” Neurobiol. Dis., 65, 220–232 (2014).Google Scholar
  47. Mhatre, M. C. and Ticku, M. K., “Chronic ethanol administration alters γ-aminobutiric acid A receptor gene expression,” Mol. Pharmacol., 42, 415–422 (1992).Google Scholar
  48. Mhatre, M. C. and Ticku, M. K., “Chronic ethanol treatment upregulates the GABA receptor β subunit expression,” Brain Res. Mol. Brain Res., 23, 246–252 (1994).Google Scholar
  49. Mhatre, M. C., Pena, G., Sieghart, W., and Ticku, M. K., “Antibodies specific for GABAA receptor α subunits reveal that chronic alcohol treatment down-regulates α-subunit expression in rat brain regions,” J. Neurochem., 61, 1620–1625 (1993).Google Scholar
  50. Miller, P. S. and Aricescu, A. R., “Crystal structure of a human GABAA receptor,” Nature, 512, No. 7514, 270–275 (2014).Google Scholar
  51. Mizokami, A., Kanematsu, T., Ishibashi, H., et al., “Phospholipase C-related inactive protein is involved in trafficking of gamma2 subunit-containing GABA(A) receptors to the cell surface,” J. Neurosci., 27, No. 7, 1692–1701 (2007).Google Scholar
  52. Mo, J., Kim, C. H., Lee, D., et al., “Early growth response 1 (Egr-1) directly regulates GABAA receptor α2, α4 and θ subunits in the hippocampus,” J. Neurochem., 133, No. 4, 489–500 (2015).Google Scholar
  53. Möhler, H., “Endogenous benzodiazepine site peptide ligands operating bidirectionally in vivo in neurogenesis and thalamic oscillations,” Neurochem. Res., 39, No. 6, 1032–1036 (2014).Google Scholar
  54. Motejlwk, K., Hauselmann, R., Leitgeb, S., and Luscher, B., “BSF1, a novel brain-specific DNA-binding protein recognizing a tandemly repeated purine DNA element in the GABAA receptor delta subunit gene,” J. Biol. Chem., 269, No. 21, 15265–15263 (1994).Google Scholar
  55. Mu, W. and Burt, D. R., “Transcriptional regulation of GABAA receptor gamma2 subunit gene,” Brain Res. Mol. Brain Res., 67, No. 1, 137–147 (1999a).Google Scholar
  56. Mu, W. and Burt, D. R., “The mouse GABA(A) receptor alpha3 subunit gene and promoter,” Brain Res. Mol. Brain Res., 73, No. 1–2, 172–180 (1999b).Google Scholar
  57. Nair, B., Johar, K., Priya, A., and Wong-Riley, M. T., “Specificity protein 4 (Sp4) transcriptionally regulates inhibitory GABAergic receptors in neurons,” Biochim. Biophys. Acta, 1863, 1–9 (2016).Google Scholar
  58. Nakajima, K., Yin, X., Takei, Y., et al., “Molecular motor KIF5A is essential for GABAA receptor transport and KIF5A deletion causes epilepsy,” Neuron, 76, 945–961 (2012).Google Scholar
  59. Nakamura, Y., Morrow, D. H., Modgil, A., et al., “Proteomic characterization of inhibitory synapses using a novel pHluorin-tagged γ-aminobutyric acid receptor type A (GABAA) α2 subunit knock-in mouse,” J. Biol. Chem., 291, No. 23, 12394–12407 (2016).Google Scholar
  60. Nusser, Z., Ahmad, Z., Tretter, V., et al., “Alterations in the expression of GABAA receptor subunits in cerebellar granule cells after the disruption of the alpha6 subunit gene,” Eur. J. Neurosci., 11, No. 5, 1685–1697 (1999).Google Scholar
  61. Ohlson, J., Pedersen, J. S., Haussler, D., and Ohman, M., “Editing modifies the GABA(A) receptor subunit alpha3,” RNA, 13, 698–703 (2007).Google Scholar
  62. Olsen, R. W. and Sieghart, W., “International Union of Pharmacology. LXX. Subtypes of gamma-aminobutyric acid(A) receptors: classification on the basis of subunit composition, pharmacology, and function. Update,” Pharmacol. Rev., 60, 243–260 (2008).Google Scholar
  63. Olsen, R. W., Hanchar, H. J., Meera, P., and Wallner, M., “GABAA receptor subtypes: the “One glass of wine” receptors,” Alcohol, 41, No. 3, 201–209 (2007).Google Scholar
  64. Olsen, R. W. and Li, G. D., “GABA(A) receptors as molecular targets of general anesthetics: identification of binding sites provides clues to allosteric modulation,” Can. J. Anaesth., 58, No. 2, 206–215 (2011).Google Scholar
  65. Osechkina, N. S., Ivanov, M. B., Nazarov, G. V., et al., “Assessment of expression of genes coding GABAA receptors during chronic and acute intoxication of laboratory rats with ethanol,” Bull. Exp. Biol. Med., 160, No. 4, 452–454 (2016).Google Scholar
  66. Ostroumov, A., Thomas, A. M., Kimmey, B. A., et al., “Stress increases ethanol self-administration via a shift toward excitatory GABA signalling in the ventral tegmental area,” Neuron, 92, No. 2, 493–504 (2016).Google Scholar
  67. Peng, Z., Hauer, B., Mihalek, R. M., et al., “GABAA receptor changes in delta-subunit-deficient mice: altered expression of α4 and γ2 subunits in the forebrain,” J. Comp. Neurol., 446, 179–197 (2002).Google Scholar
  68. Priya, A., Johar, K., and Wong-Riley, M. T., “Specificity protein 4 functionally regulates the transcription of NMDA receptors subunitsGluN1, GluN2A and GluN2B,” Biochim. Biophys. Acta, 1833, 2745–2756 (2013).Google Scholar
  69. Priya, A., Johar, K., Nair, B., and Wong-Riley, M. T., “Specificity protein 4 (Sp4) regulates the transcription of AMPA receptor subunit GluA2 (Gria2),” Biochim. Biophys. Acta, 1843, 1196–1206 (2014).Google Scholar
  70. Quadrato, G., Elnaggar, M., Duman, C., et al., “Modulation of GABAA receptor signalling increases neurogenesis and supresses anxiety through NFATc4,” J. Neurosci., 34, No. 25, 8630–8645 (2014).Google Scholar
  71. Reddy, D. S. and Estes, W. A., “Clinical potential of neurosteroids for CNS disorders,” Trends Pharmacol. Sci., 37, No. 7, 543–61 (2016).Google Scholar
  72. Roberts, D. S., Raol, Y. H., Bandyopadhyay, S., et al., “Egr3 stimulation of GABRA4 promoter activity as a mechanism for seizure-induced up-regulation of GABAA receptor α4 subunit expression,” Proc. Natl. Acad. Sci. USA, 102, No. 33, 11894–11899 (2005).Google Scholar
  73. Rula, E. Y., Lagrange, A. H., Jacobs, M. M., et al., “Developmental modulation of GABA(A) receptor function by RNA editing,” J. Neurosci., 28, 6196–6201 (2008).Google Scholar
  74. Russek, S. J., “Evolution of GABA(A) receptor diversity in the human genome,” Gene, 227, 213–222 (1999).Google Scholar
  75. Russek, S. J., Bandyopadhyay, S., and Farb, D. H., “An initiator element mediates autologous downregulation of the human type-A gamma-aminobutyric acid receptor beta1 subunit gene,” Proc. Natl. Acad. Sci. USA, 95, No. 15, 8600–8605 (2000).Google Scholar
  76. Shen, H., Gong, Q. H., Yuan, M., and Smith, S. S., “Short-term steroid treatment increases delta GABA(A) receptor subunit expression in rat CA1 hippocampus: pharmacological and behavioural effects,” Neuropharmacology, 49, 573–586 (2005).Google Scholar
  77. Simon, J., Wakimoto, H., Fujita, N., et al., “Analysis of the set of GABA(A) receptors in the human genome,” J. Biol. Chem., 279, No. 40, 41422–41435 (2004).Google Scholar
  78. Stell, B. M., Brickley, S. G., Tang, C. Y., et al., “Neuroactive steroids reduce neuronal excitability by selectively enhancing tonic inhibition mediated by delta subunit-containing GABA(A) receptors,” Proc. Natl. Acad. Sci. USA, 100, 14439–14444 (2003).Google Scholar
  79. Terunuma, M., Jang, I. S., Ha, S. H., 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, No. 32, 7074–7084 (2004).Google Scholar
  80. Tretter, V., Hauer, B., Nusser, Z., et al., “Targeted disruption of the GABAA receptor α4 subunit gene leads to an up-regulation of γ2 subunit-containing receptors in cerebellar granule cells,” J. Biol. Chem., 276, 10532–10538 (2001).Google Scholar
  81. Tsang, S.-Y., Ng, S.-K., Xu, Z., and Xue, H., “The evolution of GABAA receptor-like genes,” Mol. Biol. Evol., 24, No. 2, 599–610 (2007).Google Scholar
  82. Twelvetrees, A. E., Yuen, E. Y., Arancibia-Carcamo, I. L., et al., “Delivery of GABAARs to synapses is mediated by HAP1-KIF5 and disrupted by mutant huntingtin,” Neuron, 65, No. 1, 53–65 (2010).Google Scholar
  83. Uusi-Oukari, M., Heikkila, J., Sinkkonen, S. T., et al., “Long-range interactions in neuronal gene expression: evidence from gene targeting in the GABAA receptor β2-α6-α1-γ2 subunit gene cluster,” Mol. Cell. Neurosci., 16, 34–41 (2000).Google Scholar
  84. Wahlstedt, H., Daniel, C., Enstero, M., and Ohman, M., “Large-scale mRNA sequencing determines global regulation of RNA editing during brain development,” Genome Res., 19, 978–986 (2009).Google Scholar
  85. Wang, H., Bedford, F. K., Brandon, N. J., et al., “GABA(A)-receptor-associated protein links GABA(A) receptors and cytoskeleton,” Nature, 397, No. 6714, 69–72 (1999).Google Scholar
  86. Wang, Y. J., Han, D. Y., Tabib, T., et al., “Identification of GABA(C) receptor protein homeostasis network components from three tandem mass spectrometry proteomics approaches,” J. Proteome Res., 12, 5570–5586 (2013).Google Scholar
  87. Wang, P., Eshaq, R. S., Meshul, C. K., et al., “Neuronal gamma-aminobutyric acid (GABA) type A receptors undergo cognate ligand chaperoning in the endoplasmic reticulum by endogenous GABA,” Front. Cell. Neurosci., 9, 188 (2015).Google Scholar
  88. Wu, C. H., Frostholm, A., De Blas, A. L., and Rotter, A., “Differential expression of GABAA/benzodiazepine receptor subunit mRNAs and ligand binding sites in mouse cerebellar neurons following in vivo ethanol administration: an autoradiographic analysis,” J. Neurochem., 65, 1229–1239 (1995).Google Scholar

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Authors and Affiliations

  1. 1.Faculty of MedicineSouthampton UniversitySouthamptonUK

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