Alcohol Modulation of Extra-synaptic Gamma-aminobutyric Acid Type A Receptors

Ayla Arslan

Abstract


Development of effective treatment agents for the alcohol use disorders requires the detailed understanding of molecular targets of alcohol in the brain. The gamma-aminobutyric acid type A receptors (GABAARs) are the major molecular targets of alcohol in the central nervous system. Mediating inhibitory neurotransmission upon GABA binding in the vertebrate central nervous system, GABAARs are heteropentameric chloride channels, assembled from a large subunit pool encoded by 19 distinct genes. It is the subunit composition that determines the receptor’s biophysical properties, neurotransmitter affinity, the pharmacology, and the position on the cell i.e., synaptic or extra-synaptic. This review paper briefly presents the alcohol modulation of a specific GABAAR subtype located at the extra-synaptic sites with a subunit composition of alpha, beta and delta

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Arslan A, von Engelhardt J, Wisden W. (2014) Cytoplasmic domain of δ subunit is important for the extra-synaptic targeting of GABAA receptor subtypes. J Integr Neurosci. Dec; 13(4):617-31.

Bayard M, McIntyre J, Hill KR, Woodside J Jr. (2004) Alcohol withdrawal syndrome. Am Fam Physician. 2004 Mar 15; 69(6):1443-50.

Boehm SL 2nd, Ponomarev I, Jennings AW, Whiting PJ, Rosahl TW, Garrett EM, Blednov YA, Harris RA. (2004) gamma-Aminobutyric acid A receptor subunit mutant mice: new perspectives on alcohol actions. Biochem Pharmacol. Oct 15;68(8):1581-602.

Borghese CM, Stórustovu Sí, Ebert B, Herd MB, Belelli D, Lambert JJ, Marshall G, Wafford KA, Harris RA. (2006) The delta subunit of gamma-aminobutyric acid type A receptors does not confer sensitivity to low concentrations of ethanol. J.

Pharmacol Exp Ther. Mar; 316(3):1360-8.

Botta P, Mameli M, Floyd KL, Radcliffe RA, Valenzuela CF. (2007a) Ethanol sensitivity of GABAergic currents in cerebellar granule neurons is not increased by a single amino acid change (R100Q) in the alpha6 GABAA receptor subunit. J Pharmacol Exp

Ther. Nov; 323(2):684-91.

Botta P, Radcliffe RA, Carta M, Mameli M, Daly E, Floyd KL, Deitrich RA, Valenzuela CF. (2007b) Modulation of GABAA receptors in cerebellar granule neurons by ethanol: a review of genetic and electrophysiological studies. Alcohol. 2007 May; 41(3):187-99.

Bonnert, T.P., McKernan, R.M., Farrar, S., le Bourdelles, B., Heavens, R.P., Smith, D.W., Hewson, L., Rigby, M.R., Sirinathsinghji, D.J., Brown, N., Wafford, K.A., Whiting, P.J. (1999) A novel g-aminobutyric acid type A receptor subunit. Proc Natl Acad Sci U S A, 96:9891-9896.

Böhme I, Rabe H, Lüddens H. (2004) Four amino acids in the alpha subunits determine the gamma-aminobutyric acid sensitivities of GABAA receptor subtypes. J Biol Chem. 2004 Aug 20; 279(34):35193-200.

Brejc, K., van Dijk, W.J., Klaassen, R.V., Schuurmans, M., van Der Oost, J., Smit, A.B., Sixma, T.K. (2001) Crystal structure of an ACh-binding protein reveals the ligand-binding domain of nicotinic receptors. Nature, 411:269-276.

Brickley, S.G., Revilla, V., Cull-Candy, S.G., Wisden, W., Farrant, M. (2001) Adaptive regulation of neuronal excitability by a voltage-independent potassium conductance. Nature, 409:88-92.

Brickley SG, Mody I. (2012) Extrasynaptic GABA(A) receptors: their function in the CNS and implications for disease. Neuron. 2012 Jan 12;73(1):23-34.

Cromer BA, Morton CJ, Parker MW. Anxiety over GABA(A) receptor structure relieved by AChBP. Trends Biochem Sci. 2002 Jun; 27(6):280-7.

Caldeira JC, Wu Y, Mameli M, Purdy RH, Li PK, Akwa Y, Savage DD, Engen JR, Valenzuela CF. (2004) Fetal alcohol exposure alters neurosteroid levels in the developing rat brain. J Neurochem. Sep; 90(6):1530-9.

Carta M, Mameli M, Valenzuela CF. (2004) Alcohol enhances GABAergic transmission to cerebellar granule cells via an increase in Golgi cell excitability. J Neurosci. Apr 14; 24(15):3746-51.

Cope, D.W., Hughes, S.W., Crunelli, V. (2005) GABAA receptor-mediated tonic inhibition in thalamic neurons. J Neurosci., 25:11553-11563.

Deitrich RA, Dunwiddie TV, Harris RA, Erwin VG. Mechanism of action of ethanol: initial central nervous system actions. Pharmacol Rev. 1989 Dec;41(4):489-537.

Ernst, M., Brauchart, D., Boresch, S., Sieghart, W. (2003) Comparative modeling of GABAA receptors: limits, insights, future developments. Neuroscience, 119:933-943.

Fritschy, J.M., Mohler, H. (1995) GABAA-receptor heterogeneity in the adult rat brain: differential regional and cellular distribution of seven major subunits. J Comp Neurol., 359:154-194.

Glykys J, Peng Z, Chandra D, Homanics GE, Houser CR, Mody I. (2007) A new naturally occurring GABA(A) receptor subunit partnership with high sensitivity to ethanol. Nat Neurosci. Jan;10(1):40-8.

Goetz, T., Arslan, A., Wisden, W., Wulff, P., (2007) GABAA receptor structure and function in the basal ganglia. Prog. Brain Res. 160: 21-41.

Haas KF, Macdonald RL. (1999) GABAA receptor subunit gamma2 and delta subtypes confer unique kinetic properties on recombinant GABAA receptor currents in mouse fibroblasts. J Physiol. 1; 514 ( Pt 1): 27-45.

Hamann, M., Rossi, D.J., Attwell, D., (2002) Tonic and spillover inhibition of granule cells control information flow through cerebellar cortex. Neuron 33(4): 625-33.

Hanchar, H.J., Wallner, M., Olsen, R.W. (2004) Alcohol effects on g-aminobutyric acid type A receptors: are extra-synaptic receptors the answer? Life Sciences, 76:1–8.

Hanchar, H.J., Dodson, P.D., Olsen, R.W., Otis, T.S., Wallner, M. (2005) Alcohol-induced motor impairment caused by increased extra-synaptic GABAA receptor activity. Nat Neurosci., 8:339-345.

Hanchar HJ, Chutsrinopkun P, Meera P, Supavilai P, Sieghart W, Wallner M, Olsen RW. (2006) Ethanol potently and competitively inhibits binding of the alcohol antagonist Ro15-4513 to alpha4/6beta3delta GABAA receptors. Proc Natl Acad Sci U S A. 103(22):8546-51.

Hassaine G, Deluz C, Grasso L, Wyss R, Tol MB, Hovius R, Graff A, Stahlberg H, Tomizaki T, Desmyter A, Moreau C, Li XD, Poitevin F, Vogel H, Nury H. (2014) X-ray structure of the mouse serotonin 5-HT3 receptor. Nature, 21; 512(7514):276-81. doi: 10.1038/nature13552.

Hausser, M. and Clark, B.A. (1997) Tonic synaptic inhibition modulates neuronal output pattern and spatiotemporal synaptic integration Neuron 19 (3) 665-78.

Hodge, C.W., Mehmert, K.K., Kelley, S.P., McMahon, T., Haywood, A., Olive, M.F., Wang, D., Sanchez-Perez, A.M., Messing, R.O. (1999) Supersensitivity to allosteric GABAA receptor modulators and alcohol in mice lacking PKC epsilon. Nat Neurosci., 2:997-1002.

Homanics GE, Ferguson C, Quinlan JJ, Daggett J, Snyder K, Lagenaur C, Mi ZP, Wang XH, Grayson DR, Firestone LL. Gene knockout of the alpha6 subunit of the gamma-aminobutyric acid type A receptor: lack of effect on responses to ethanol, pentobarbital, and general anesthetics. Mol Pharmacol. 1997 Apr; 51(4):588-96.

Homanics GE, Le NQ, Kist F, Mihalek R, Hart AR, Quinlan JJ. (1998) Ethanol tolerance and withdrawal responses in GABA(A) receptor alpha 6 subunit null allele mice and in inbred C57BL/6J and strain 129/SvJ mice. Alcohol Clin Exp Res. Feb; 22(1):259-65.

Izumi Y, Murayama K, Tokuda K, Krishnan K, Covey DF, Zorumski CF. (2007) GABAergic neurosteroids mediate the effects of ethanol on long-term potentiation in rat hippocampal slices. Eur J Neurosci. Oct; 26(7):1881-8.

Jones, A., Korpi, E.R., McKernan, R.M., Pelz, R., Nusser, Z., Makela, R., Mellor, J.R., Pollard, S., Bahn, S., Stephenson, F.A., Randall, A.D., Sieghart, W., Somogyi, P., Smith, A.J., Wisden, W. (1997) Ligand-gated ion channel subunit partnerships: GABAA receptor 6 subunit gene inactivation inhibits delta subunit expression. J Neurosci., 17:1350-1362

Korpi ER, Lüddens H. (1993) Regional gamma-aminobutyric acid sensitivity of t-butylbicyclophosphoro[35S]thionate binding depends on gamma-aminobutyric acid A receptor alpha subunit. Mol Pharmacol. Jul; 44(1):87-92.

Korpi ER, Debus F, Linden AM, Malécot C, Leppä E, Vekovischeva O, Rabe H, Böhme I, Aller MI, Wisden W, Lüddens H. (2007) Does ethanol act preferentially via selected brain GABAA receptor subtypes? the current evidence is ambiguous. Alcohol. 2007 May;41(3):163-76.

Kumar S, Porcu P, Werner DF, Matthews DB, Diaz-Granados JL, Helfand RS, Morrow AL. (2009)The role of GABA(A) receptors in the acute and chronic effects of ethanol: a decade of progress. Psychopharmacology (Berl). Sep; 205(4):529-64.

Laurie, D.J., Seeburg, P.H., Wisden, W. (1992a) The distribution of 13 GABAA receptor subunit mRNAs in the rat brain. II. Olfactory bulb and cerebellum. J Neurosci., 12:1063-1076.

Laurie DJ, Wisden W, Seeburg PH. (1992b) The distribution of thirteen GABAA receptor subunit mRNAs in the rat brain. III. Embryonic and postnatal development. J Neurosci., 12:4151-4172.

Lavoie AM, Tingey JJ, Harrison NL, Pritchett DB, Twyman RE (1997) Activation and deactivation rates of recombinant GABA(A) receptor channels are dependent on alpha-subunit isoform. Biophys J. 1997 Nov;73(5):2518-26.

Liang J, Suryanarayanan A, Chandra D, Homanics GE, Olsen RW, Spigelman I.(2008) Functional consequences of GABAA receptor alpha 4 subunit deletion on synaptic and extrasynaptic currents in mouse dentate granule cells. Alcohol Clin Exp Res. Jan;32(1):19-26.

Liang J, Olsen RW. (2014) Alcohol use disorders and current pharmacological therapies: the role of GABA(A) receptors. Acta Pharmacol Sin. 2014 Aug;35(8):981-93. doi: 10.1038/aps.2014.50.

Luddens, H., Pritchett, D.B., Kohler, M., Killisch, I., Keinanen, K., Monyer, H., Sprengel, R., Seeburg, P.H. (1990) Cerebellar GABAA receptor selective for a behavioural alcohol antagonist. Nature, 346:648-651.

Lynagh T, Pless, S.A., Principles of agonist recognition in Cys-loop receptors Front Physiol. 2014 Apr 24;5:160. doi: 10.3389/fphys.2014.00160. eCollection 2014.

Macdonald, R.L., Haas, K.F. (2000) Kinetic Properties of GABAA Receptor Channels. In Martin, D.L., Olsen, R.W. (Eds.), GABA in the Nervous System: The View at Fifty Years, Lippincott Williams and Wilkins, Philadelphia, pp. 141-165.

Mameli M, Valenzuela CF. (2006) Alcohol increases efficacy of immature synapses in a neurosteroid-dependent manner. Eur J Neurosci. Feb;23(3):835-9.

Mameli M, Botta P, Zamudio PA, Zucca S, Valenzuela CF. Ethanol decreases Purkinje neuron excitability by increasing GABA release in rat cerebellar slices. J Pharmacol Exp Ther. 2008 Dec; 327(3):910-7.

Meera P, Olsen RW, Otis TS, Wallner M. (2010) Alcohol- and alcohol antagonist-sensitive human GABAA receptors: tracking δ subunit incorporation into functional receptors. Mol Pharmacol. Nov; 78(5):918-24.

Mihalek RM, Bowers BJ, Wehner JM, Kralic JE, VanDoren MJ, Morrow AL, Homanics GE. (2001) GABA(A)-receptor delta subunit knockout mice have multiple defects in behavioral responses to ethanol. Alcohol Clin Exp Res. 2001 Dec; 25(12):1708-18.

Mihic SJ, Ye Q, Wick MJ, Koltchine VV, Krasowski MD, Finn SE, Mascia MP, Valenzuela CF, Hanson KK, Greenblatt EP, Harris RA,

Harrison NL. (1997) Sites of alcohol and volatile anaesthetic action on GABA(A) and glycine receptors. Nature, 389(6649):385-9.

Mihic SJ, Harris RA. (1997) GABA and the GABAA receptor. Alcohol Health Res World. 21(2):127-31.

Miller PS, Aricescu AR. (2014) Crystal structure of a human GABAA receptor. Nature. 2014 Aug 21;512(7514):270-5. doi: 10.1038/nature13293. Epub 2014 Jun 8.

Ming Z, Criswell HE, Yu G, Breese GR. (2006) Competing presynaptic and postsynaptic effects of ethanol on cerebellar purkinje neurons. Alcohol Clin Exp Res. 2006 Aug;30(8):1400-7.

Mirheydari P, Ramerstorfer J, Varagic Z, Scholze P, Wimmer L, Mihovilovic MM, Sieghart W, Ernst M. (2014) Unexpected Properties of δ-Containing GABAA Receptors in Response to Ligands Interacting with the α+ β- Site. Neurochem Res. Jun; 39(6):1057-67.

Mody, I., Pearce, R.A. (2004) Diversity of inhibitory neurotransmission through GABAA receptors. Trends Neurosci., 27:569-575.

Mody I, Glykys J, Wei W (2007) A new meaning for “Gin & Tonic”: tonic inhibition as the target for ethanol action in the brain. Alcohol (41)145-53.

Nusser, Z., Sieghart, W., Benke, D., Fritschy, J.M., Somogyi, P. (1996) Differential synaptic localization of two major g-aminobutyric acid type A receptor a subunits on hippocampal pyramidal cells. Proc Natl Acad Sci U S A. Oct 15;93(21):11939-44.

Nusser Z, Mody I. (2002) Selective modulation of tonic and phasic inhibitions in dentate gyrus granule cells. J Neurophysiol. 87(5):2624-8.

Nusser, Z., Sieghart, W., Somogyi, P. (1998) Segregation of different GABAA receptors to synaptic and extra-synaptic membranes of cerebellar granule cells. J Neurosci., 18:1693-1703.

Olsen, R.W., Chang, C.S., Li, G., Hanchar, H.J., Wallner, M. (2004) Fishing for allosteric sites on GABAA receptors. Biochem Pharmacol., 68:1675-1684.

Olsen RW, Hanchar HJ, Meera P, Wallner M. GABAA receptor subtypes: the "one glass of wine" receptors. Alcohol. 2007 May; 41(3):201-9.

Otis TS. (2008) Comments on "Ethanol sensitivity of GABAergic currents in cerebellar granule neurons is not increased by a single amino acid change (R100Q) in the alpha6 GABA(A) receptor subunit". J Pharmacol Exp Ther. 2008 Jan; 324(1): 399-400; author reply 401-3.

Patel B, Mortensen M, Smart TG. (2014) Stoichiometry of δ subunit containing GABA(A)

receptors. Br J Pharmacol. 2014 Feb;171(4):985-94.

Roberto M, Madamba SG, Moore SD, Tallent MK, Siggins GR. (2003) Ethanol increases GABAergic transmission at both pre- and postsynaptic sites in rat central amygdala neurons. Proc Natl Acad Sci U S A. 2003 Feb 18; 100(4):2053-8.

Rudolph, U., Moehler, H. (2006) GABA-based therapeutic approaches: GABAA receptor subtype functions. Current Opinion in Pharmacology, 6:18–23.

Santhakumar V, Wallner M, Otis TS. (2007) Ethanol acts directly on extra-synaptic subtypes of GABAA receptors to increase tonic inhibition. Alcohol. May;41(3):211-21.

Schwarzer, C., Berresheim, U., Pirker, S., Wieselthaler, A., Fuchs, K., Sieghart, W., Sperk, G. (2001) Distribution of the major gamma-aminobutyric acid(A) receptor subunits in the basal ganglia and associated limbic brain areas of the adult rat. J Comp Neurol., 433:526-549.

Seeburg, P.H., Wisden, W., Verdoorn, T.A., Pritchett, D.B., Werner, P., Herb, A., Luddens, H., Sprengel, R., Sakmann, B. (1990) The GABAA receptor family: molecular and functional diversity. Cold Spring Harb Symp Quant Biol., 55:29-40.

Semyanov, A., Walker, M.C., Kullmann, D.M., Silver, R.A. (2004) Tonically active GABAA receptors: modulating gain and maintaining the tone. Trends Neurosci., 27:262-269.7.

Sieghart, W., Sperk, G. (2002) Subunit composition, distribution and function of GABAA receptor subtypes. Curr Top Med Chem., 2:795-816.

Sine, S.M., Engel, A.G. (2006) Recent advances in Cys-loop receptor structure and function. Nature 440: 448-455

Sine, S.M., Engel, A.G. (2006) Recent advances in Cys-loop receptor structure and function.

Nature 440: 448-455

Sun C, Sieghart W, Kapur J. (2004) Distribution of alpha1, alpha4, gamma2, and delta subunits of GABAA receptors in hippocampal granule cells. Brain Res. 17;1029(2):207-16.

Sundstrom-Poromaa, I., Smith, D.H., Gong, Q.H., Sabado, T.N., Li, X., Light, A., Wiedmann, M., Williams, K., Smith, S.S. (2002) Hormonally regulated alpha(4)beta(2)delta GABAA receptors are a target for alcohol. Nat Neurosci., 5:721-722.

Suzdak PD, Glowa JR, Crawley JN, Schwartz RD, Skolnick P, Paul SM. (1986) A selective imidazobenzodiazepine antagonist of ethanol in the rat. Science. Dec 5;234(4781):1243-7.

Theile JW, Morikawa H, Gonzales RA, Morrisett RA. (2008) Ethanol enhances GABAergic transmission onto dopamine neurons in the ventral tegmental area of the rat. Alcohol Clin Exp Res. Jun;32(6):1040-8.

Unwin, N. (2003) Structure and action of the nicotinic acetylcholine receptor explored by electron microscopy. FEBS Lett., 555:91-95.

Unwin, N. (2005) Refined structure of the nicotinic acetylcholine receptor at 4 Å resolution. J. Mol. Biol., 346:967–989.7.

Valenzuela CF. (1997) Alcohol and neurotransmitter interactions. Alcohol Health Res World. 21(2):144-8.

Villumsen IS, Wellendorph P, Smart TG. (2015) Pharmacological characterisation of murine α4β1δ GABAA receptors expressed in Xenopus oocytes. BMC Neurosci. 2015 Mar 5;16(1):8.

Wallner, M., Hanchar, H.J., Olsen, R.W. (2003) Ethanol enhances a4 b3 d and a6 b3 d gammaaminobutyric acid type A (GABAA) receptors at low concentrations known to affect humans. Proc Natl Acad Sci U S A., 100:15218-15223.

Wallner M, Hanchar HJ, Olsen RW. (2006) Low-dose alcohol actions on alpha4beta3delta GABAA receptors are reversed by the behavioral alcohol antagonist Ro15-4513. Proc Natl Acad Sci U S A. 103(22):8540-5.

Wallner M, Hanchar HJ, Olsen RW. (2014) Alcohol selectivity of β3-containing GABAA receptors: evidence for a unique extracellular alcohol/imidazobenzodiazepine Ro15-4513 binding site at the α+β- subunit interface in αβ3δ GABAA receptors. Neurochem Res. 2014 Jun;39(6):1118-26.

Wei, W., Zhang, N., Peng, Z., Houser, C.R., Mody, I. (2003) Perisynaptic localization of delta subunit-containing GABAA receptors and their activation by GABA spillover in the mouse dentate gyrus. J Neurosci., 23: 10650-10661.

Wisden, W., Laurie, D.J., Monyer, H., Seeburg, P.H. (1992) The distribution of 13 GABAA receptor subunit mRNAs in the rat brain I: Telencephalon, diencephalon, mesencephalon. J Neurosci., 12:1040-1062.

Yang X, Criswell HE, Breese GR. Ethanol modulation of gamma-aminobutyric acid (GABA)-mediated inhibition of cerebellar Purkinje neurons: relationship to GABAb receptor input. Alcohol Clin Exp Res. 2000 May;24(5):682-90.

You H, Dunn SM. (2007) Identification of a domain in the delta subunit (S238-V264) of the alpha4beta3delta GABAA receptor that confers high agonist sensitivity. J Neurochem. Nov; 103(3):1092-101.




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