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Heterologous Regulation of GABAA Receptors: Protein Phosphorylation

  • Chapter
Pharmacology of GABA and Glycine Neurotransmission

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 150))

Abstract

Heterologous regulation of ligand-gated ion channels has the potential for acute and chronic modulation of ion channel activity. This has important consequences for the control of neuronal excitability particularly when this involves the type A γ-aminobutyric acid (GABAA) receptor. GABA, a neurotransmitter widely known to initiate the majority of inhibitory synaptic neurotransmission in the central nervous system (CNS), activates these receptors. There are numerous ways of regulating GABAA receptors and under normal physiological conditions these receptors will inevitably be subjected to a variety of inter- and intracellular homeostatic mechanisms with the purpose of regulating not just receptor function, but also assembly and cell surface number and location. One such ubiquitous and diverse mechanism for regulating GABAA receptors involves protein phosphorylation (Moss and Smart 1996; Smart 1997). This type of regulation involves the short- or long-term covalent modification of receptor/ ion channel structure by the transfer of a charged phosphate group(s) from adenosine triphosphate to specific serine, threonine or tyrosine residues. This structural modification can lead to alterations in receptor function at the level of ligand-activated ion channel gating and also regulate mechanisms affecting receptor turnover and assembly.

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References

  • Akaike N (1990) GABA-gated CI- currents and their regulation by intracellular freeCa2+. In: Chloride channels and carriers in nerve muscle and glial cells. Ed. FJAlvarez-Leefmans, JM Russell. Plenum Press, New York, pp. 261–273

    Google Scholar 

  • Angelotti TP, Uhler MD, Macdonald RL (1993) Enhancement of recombinant γ-aminobutyric acid type A receptor currents by chronic activation of cAMP-dependent protein kinase. Mol Pharmacol 44:1202–1210

    PubMed  CAS  Google Scholar 

  • Barnard EA, Darlison MG, Seeburg PH (1987) Molecular biology of the GABAAreceptor: the receptor channel superfamily. Trends in Neurosci 10:502–509

    Article  CAS  Google Scholar 

  • Bateson AN, Lasham A, Darlison MG (1991) γ-Aminobutyric acidA receptor heterogeneity is increased by alternative splicing of a novel ß subunit gene transcript. JNeurochem 56:1437–1440

    Article  CAS  Google Scholar 

  • Bormann J, Feigenspan A (1995) GABAC receptors. Trends in Neurosc. 18:515–519

    Article  CAS  Google Scholar 

  • Browning MD, Bureau M, Dudek EM, Olsen RW (1990) Protein kinase C and cAMP-dependent protein kinase phosphorylate the beta subunit of the purified γ-aminobutyric acidA receptor. Proc Natl Acad Sci USA 87:1315–1318

    Article  PubMed  CAS  Google Scholar 

  • Browning MD, Endo S, Smith GB, Dudek E.M, Olsen RW (1993) Phosphorylation ofthe GABAA receptor by cAMP-dependent protein kinase and by protein kinaseC: analysis of the substrate domain. Neurochem Res 1:95–100

    Article  Google Scholar 

  • Bureau MH, Laschet JJ (1995) Endogenous phosphorylation of distinct γ-aminobutyric acid type A receptor polypeptides by Ser/Thr and Tyr kinase activities associated with the purified receptor. J Biol Chem 270:26482–26487

    Article  PubMed  CAS  Google Scholar 

  • Chapell R, Bueno OF, Alvarez-Hernandez X, Robinson LC, Leidenheimer NJ (1998)Activation of protein kinase C induces γ-aminobutyric acid type A receptor internalisation in Xenopus oocytes. J Biol Chem 273:32595–32601

    Article  PubMed  CAS  Google Scholar 

  • Chen QX, Stelzer A, Kay AR, Wong R (1990) GABAA receptor function is regulatedby phosphorylation in acutely dissociated guinea-pig hippocampal neurones. J Physiol 420:207–221

    CAS  Google Scholar 

  • Chen QX, Wong RKS (1995) Suppression of GABAA receptor responses by NMDAapplication in hippocampal neurones acutely isolated from the adult guinea pig. JPhysiol 482.2:353–362

    PubMed  CAS  Google Scholar 

  • Cheun JE, Yeh HH (1992) Modulation of GABAA receptor-activated current by norepinephrine in cerebellar Purkinje cells. Neurosci 51:951–960

    Article  CAS  Google Scholar 

  • Connolly CN, Krishek BJ, McDonald BJ, Smart TG, Moss SJ (1996a) Assembly and cellsurface expression of heteromeric and homomeric γ-aminobutyric acid type Areceptors. J Biol Chem 271:89–96

    Article  PubMed  CAS  Google Scholar 

  • Connolly CN, Wooltorton JR, Smart TG, Moss SJ (1996b) Subcellular localization ofγ-aminobutyric acid type A receptors is determined by receptor ß subunits. ProcNatl Acad Sci USA 93:9899–9904

    Article  CAS  Google Scholar 

  • Connolly CN Kittler JT, Thomas P, Uren JM, Brandon NJ, Smart TG, Moss SJ (1999)Cell surface stability of γ-aminobutyric acid type A receptors. Dependence onprotein kinase C activity and subunit composition. J Biol Chem 274:36565–36572

    Article  PubMed  CAS  Google Scholar 

  • Cutting GR, Luo L, O’Hara BF, Kasch LM, Montrose-Rafizadeh C, Donovan DM,Shimada S, Antonarakis SE, Guggino WB, Uhl GR, Kazazian HH (1991) Cloningof the γ-aminobutyric acid (GABA) ρ1 cDNA: a GABA receptor subunit highlyexpressed in the retina. Proc Natl Acad Sci USA 88:2673–2677

    Article  PubMed  CAS  Google Scholar 

  • Davies PA, Hanna MC, Hales TG, Kirkness EF (1997) Insensitivity to anaestheticagents conferred by a class of GABAA receptor subunit. Nature 385:820–823

    Article  PubMed  CAS  Google Scholar 

  • DelPAcqua ML, Scott JD (1997) Protein kinase A anchoring. J Biol Chem272:12881–12884

    Article  Google Scholar 

  • Draguhn A, Verdorn TA, Ewert M, Seeburg PH, Sakmann B (1990) Functional andmolecular distinction between recombinant rat GABAA receptor subtypes byZn2+. Neuron 5:781–788

    Article  PubMed  CAS  Google Scholar 

  • Dunne EL, Moss SJ, Smart TG (1998) Inhibition of GABAA receptor function by tyrosine kinase inhibitors and their inactive analogues. Mol Cell Neurosci 12:300–310

    Article  PubMed  CAS  Google Scholar 

  • Essrich C, Lorez M, Benson JA, Fritschy J-M, Luscher B (1998) Postsynaptic clustering of major GABAA receptor subtypes requires the γ2 subunit and gephyrin.Nature Neurosci. 1:563–571

    Article  PubMed  CAS  Google Scholar 

  • Feigenspan A, Bormann J (1994a) Facilitation of GABAergic signaling in the retina byreceptors stimulating adenylate cyclase. Proc Natl Acad Sci USA 91:10893–10897

    Article  PubMed  CAS  Google Scholar 

  • Feigenspan A, Bormann J (1994b) Modulation of GABAC receptors in rat retinalbipolar cells by protein kinase C. J Physiol 481:325–330

    PubMed  CAS  Google Scholar 

  • Filippova N, Dudley R Weiss DS (1999) Evidence for phosphorylation-dependentinternalization of recombinant human ρ1 GABAC receptors. J Physiol 518:385–399

    Article  PubMed  CAS  Google Scholar 

  • Francis SH, Corbin JD (1994) Structure and function of cyclic nucleotide-dependentprotein kinases. Ann Rev Physiol 56:237–272

    Article  CAS  Google Scholar 

  • Fritschy JM, Benke D, Mertens S, Oertel WH, Bachi T, Mohler H (1992) Five subtypesof type A γ-aminobutyric acid receptors identified in neurons by double and tripleimmunofluorescence staining with subunit-specific antibodies. Proc Natl Acad SciUSA 89:6726–6730

    Article  PubMed  CAS  Google Scholar 

  • Fukami S, Uchida I, Mashimo T, Takenoshita M, Yoshiya I (1998) Gamma subunitdependent modulation by nitric oxide (NO) in recombinant GABAA receptor.Neuroreport 9:1089–1093

    Article  PubMed  CAS  Google Scholar 

  • Gillette MA, Dacheux R (1995) GABA- and glycine-activated currents in the rodbipolar cell of the rabbit retina. J Neurophysiol 74:856–875

    PubMed  CAS  Google Scholar 

  • Gillette MA, Dacheux RF (1996) Protein kinase modulation of GABAA currents inrabbit retinal rod bipolar cells. J Neurophysiol 76:3070–3086

    PubMed  CAS  Google Scholar 

  • Gyenes M, Farrant M, Farb DH (1988) „Run-down“ of γ-aminobutyric acidA receptorfunction during whole-cell recording: a possible role for phosphorylation. Mol Pharmacol 34:719–723

    PubMed  CAS  Google Scholar 

  • Gyenes M, Wang Q, Gibbs TT, Farb DH (1994) Phosphorylation factors control neurotransmitter and neuromodulator actions at the γ-aminobutyric acid type Areceptor. Mol Pharmacol 46:542–549

    PubMed  CAS  Google Scholar 

  • Harrison NL, Lambert NA (1989) Modification of GABAA receptor function by ananalog of cyclic AMP. Neurosci Lett 105:137–142

    Article  PubMed  CAS  Google Scholar 

  • Hashimoto T, Ishii T, Ohmori H (1996) Release of Ca2+ is the crucial step for the potentiation of IPSCs in the cultured cerebellar Purkinje cells of the rat. J Physiol497.3:611–627

    PubMed  CAS  Google Scholar 

  • Hanley JG, Koulen P, Bedford F, Gordon-Weeks PR, Moss SJ (1999) The protein MAPIB links GABAC receptors to the cytoskeleton at retinal synapses. Nature 397:66–69

    Article  PubMed  CAS  Google Scholar 

  • Harvey RJ, Chinchetru MA, Darlison MG (1994) Alternative splicing of a 51-nucleotide exon that encodes a putative protein kinase C phosphorylation sitegenerates two forms of the chicken γ-aminobutyric acidA receptor ß2 subunit. JNeurochem 62:10–16

    Article  PubMed  CAS  Google Scholar 

  • Hedblom E, Kirkness EF (1997) A novel class of GABAA receptor subunit in tissuesof the reproductive system. J Biol Chem 272:15346–15350

    Article  PubMed  CAS  Google Scholar 

  • Heuschneider G, Schwartz RD (1989) cAMP and forskolin decrease γ-aminobutyricacid-gated chloride flux in rat brain synaptoneurosomes. Proc Natl Acad Sci USA86:2938–2942

    Article  PubMed  CAS  Google Scholar 

  • Homanics GE, Harrison NL, Quinlan JJ, Krasowski MD, Rick CEM, de Blas AL, Mehta AK, Kist F, Mihalek RM, Aul JJ, Firestone LL (1999) Normal electrophysiological and behavioural responses to ethanol in mice lacking the long splice variantof the γ2 subunit of the γ-aminobutyrate type A receptor. Neuropharmacol38:253–265

    Article  CAS  Google Scholar 

  • Huang R-Q, Dillon GH (1998) Maintenance of recombinant type A γ-aminobutyricacid receptor function: Role of protein tyrosine phosphorylation and calcineurin.J Pharm Exp Ther 286:243–255

    CAS  Google Scholar 

  • Jassar BS, Ostashewski PM, Jhamandas JH (1997) GABAA receptor modulation byprotein tyrosine kinase in the rat diagonal band of Broca. Brain Res 775:127–133

    Article  PubMed  CAS  Google Scholar 

  • Kaila K (1994) Ionic basis of GABAA receptor channel function in the nervous system.Prog Neurobiol 42:489–537

    Article  PubMed  CAS  Google Scholar 

  • Kano M, Konnerth A (1992) Potentiation of GABA-mediated currents by cAMP-dependent protein kinase. Neuroreport, 3:563–566

    Article  PubMed  CAS  Google Scholar 

  • Kano M, Rexhausen U, Dreessen J, Konnerth A (1992) Synaptic excitation produces along-lasting rebound potentiation of inhibitory synaptic signals in cerebellar Purkinje cells. Nature, 356:601–604

    Article  PubMed  CAS  Google Scholar 

  • Kano M, Kano M, Fukunaga K, Konnerth A (1996) Ca2+-induced rebound potentiation of γ-aminobutyric acid-mediated currents requires activation of Ca2+/calmodulin-dependent kinase II. Proc Natl Acad Sci USA 93:13351–13356

    Article  PubMed  CAS  Google Scholar 

  • Kapur J, Macdonald RL (1996) Cyclic-AMP-dependent protein kinase enhances hippocampal dentate granule cell GABAA receptor currents. J Neurophysiol 76:2626–2634

    PubMed  CAS  Google Scholar 

  • Kellenberger S, Malherbe P, Sigel E (1992) Function of the α1ß2γ2S γ-aminobutyricacid type A receptor is modulated by protein kinase C via multiple phosphorylation sites. J Biol Chem 267:25660–25663

    PubMed  CAS  Google Scholar 

  • Kennelly PJ, Krebs EG (1991) Consensus sequences as substrate specificity determinants for protein kinases and protein phosphatases. J Biol Chem 266:15555–15558

    PubMed  CAS  Google Scholar 

  • Kirkness EF, Bovenkerk CF, Ueda T, Turner AJ (1989) Phosphorylation of γ-aminobutyrate (GABA)/benzodiazepine receptors by cyclic AMP-dependentprotein kinase. Biochem J 259:613–616

    PubMed  CAS  Google Scholar 

  • Kofuji P, Wang JB, Moss SJ, Huganir RL, Burt DR (1991) Generation of two formsof the γ-aminobutyric acidA receptor γ2-subunit in mice by alternative splicing. JNeurochem 56:713–715

    Article  CAS  Google Scholar 

  • Korpi ER, Kuner T, Kristo P, Kohler M, Herb A, Luddens H, Seeburg PH (1994) SmallN-terminal deletion by splicing in cerebellar α6 subunit abolishes GABAA receptor function. J Neurochem 63:1167–1170

    Article  PubMed  CAS  Google Scholar 

  • Krishek BJ, Xie X, Blackstone C, Huganir RL, Moss SJ, Smart TG (1994) Regulationof GABAA receptor function by protein kinase C phosphorylation. Neuron5:1081–1095

    Article  Google Scholar 

  • Kusama T, Sakurai M, Kizawa Y, Uhl GR, Murakami H (1995) GABA ρ1 receptor:inhibition by protein kinase C activators. Eur J Pharmacol 291:431–434

    Article  PubMed  CAS  Google Scholar 

  • Kusama T, Hatama K, Sakurai M, Kizawa Y, Uhl GR, Murakami H (1998) Consensusphosphorylation sites of human GABAC/GABA ρ receptors are not critical forinhibition by protein kinase C activation. Neurosci Lett 255:17–20

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Lambert NA, Harrison NL (1990) Analogs of cyclic AMP decrease γ-aminobutyricacidA receptor-mediated chloride current in cultured rat hippocampal neurons viaan extracellular site. J Pharm Exp Ther 255:90–94

    CAS  Google Scholar 

  • Leidenheimer NJ, Browning MD, Dunwiddie TV, Hahner LDx Harris RA (1990) Phosphorylation-independent effects of second messenger system modulators on γ-aminobutyric acidA receptor complex function. Mol Pharmacol 38:823–828

    PubMed  CAS  Google Scholar 

  • Leidenheimer NJ, Machu TK, Endo S, Olsen RW, Harris RA, Browning MD (1991)Cyclic AMP-dependent protein kinase decreases γ-aminobutyric acidA receptor mediated 36C1- uptake by brain microsacs. J Neurochem, 57:722–725

    Article  PubMed  CAS  Google Scholar 

  • Leidenheimer NJ, McQuilkin SJ, Hahner LD, Whiting P, Harris RA (1992) Activationof protein kinase C selectively inhibits the γ-aminobutyric acidA receptor: role ofdesensitization. Mol Pharmacol, 41:1116–1123

    PubMed  CAS  Google Scholar 

  • Leidenheimer NJ, Whiting P, Harris RA (1993) Activation of calcium-phospholipid-dependent protein kinase enhances benzodiazepine and barbiturate potentiationof the GABAA receptor. J Neurochem, 60:1972–1975

    Article  PubMed  CAS  Google Scholar 

  • Leidenheimer NJ (1996) Effect of PKG activation on recombinant GABAA receptors.Mol Brain Res 42:131–134

    Article  PubMed  CAS  Google Scholar 

  • Leidenheimer NJ, Chapell R (1997) Effects of PKC activation and receptor desensitisation on neurosteroid modulation of GABAA receptors. Mol Brain Res52:173–181

    Article  PubMed  CAS  Google Scholar 

  • Levitan IB (1994) Modulation of ion channels by protein phosphorylation and dephosphorylation. Ann Rev Physiol 56:193–212

    Article  CAS  Google Scholar 

  • Levitan ES, Schofield PR, Burt DR, Rhee LM, Wisden W, Kohler M, Fujita N, RodriguezHF, Stephenson A, Darlison MG, Barnard EA, Seeburg PH (1988) Structural andfunctional basis for GABAA receptor heterogeneity. Nature, 335:76–79

    Article  PubMed  CAS  Google Scholar 

  • Lin Y-F, Browning MD, Dudek EM, Macdonald RL (1994) Protein kinase C enhancesrecombinant bovine αl/ß1γ2L GABAA receptor whole-cell currents expressed inL929 fibroblasts. Neuron 3:1421–1431

    Article  Google Scholar 

  • Lin Y-F, Angelotti TP, Dudek EM, Browning MD, Macdonald RL (1996) Enhancementof recombinant αl/ß1γ2L γ-aminobutyric acidA receptor whole-cell currents byprotein kinase C is mediated through phosphorylation of both ß1 and γ2L subunits. Mol Pharmacol 50:185–195

    PubMed  CAS  Google Scholar 

  • Llano I, Gerschenfeld HM (1993) ß-adrenergic enhancement of inhibitory synapticactivity in rat cerebellar stellate and Purkinje cells. J Physiol 468:210–224

    Google Scholar 

  • Macdonald RL, Olsen RW (1994) GABAA receptor channels. Ann Rev Neurosci17:569–602

    Article  PubMed  CAS  Google Scholar 

  • Machu TK, Firestone JA, Browning MD (1993) Ca2+/calmodulin-dependent proteinkinase II and protein kinase C phosphorylate a synthetic peptide correspondingto a sequence that is specific for the γ2L subunit of the GABAA receptor. J Neurochem, 61:375–377

    Article  PubMed  CAS  Google Scholar 

  • Marszalec W, Kurata Y, Hamilton BJ, Carter DB, Narahashi T (1994) Selective effectsof alcohols on γ-aminobutyric acid A receptor subunits expressed in humanembryonic kidney cells. J Pharm Exp Ther 269:157–163

    CAS  Google Scholar 

  • Martina M, Mozrzymas JW, Boddeke HWGM, Cherubini E (1996) The calcineurininhibitor cyclosporin A-cyclophilin A complex reduces desensitisation of GABAA-mediated responses in acutely dissociated rat hippocampal neurons. Neurosci Lett215:95–98

    PubMed  CAS  Google Scholar 

  • McDonald BJ, Moss SJ (1994) Differential phosphorylation of intracellular domains ofγ-aminobutyric acid type A receptor subunits by calcium/calmodulin type 2-dependent protein kinase and cGMP-dependent protein kinase. J Biol Chem269:18111–18117

    PubMed  CAS  Google Scholar 

  • McDonald BJ, Moss SJ (1997) Conserved phosphorylation of the intracellular domainsof GABAA receptor ß2 and ß3 subunits by cAMP-dependent protein kinase,cGMP-dependent protein kinase, protein kinase C and Ca2+/calmodulin type II-dependent protein kinase. Neuropharmacology 36:1377–1385

    Article  PubMed  CAS  Google Scholar 

  • McDonald BJ, Amato A, Moss SJ, Smart TG (1998) Adjacent phosphorylation sites onGABAA receptor ß subunits determine regulation by cAMP-dependent proteinkinase. Nature Neurosci 1:23–28

    Article  PubMed  CAS  Google Scholar 

  • McKinley DD, Lennon DJ, Carter DB (1995) Cloning, sequence analysis and expression of two forms of mRNA coding for the human ß2 subunit of the GABAA receptor. Mol Brain Res 28:175–179

    Article  PubMed  CAS  Google Scholar 

  • Mochly-Rosen D, Smith BL, Chen CH, Disatnik MH, Ron D (1995) Interaction ofprotein kinase C with RACK1, a receptor for activated C-kinase: a role in betaprotein kinase C mediated signal transduction. Biochem Soc Trans 23:596–600

    PubMed  CAS  Google Scholar 

  • Mochly-Rosen D, Gordon AS (1998) Anchoring proteins for protein kinase C: a meansfor isozyme selectivity. FASEB J 12:35–42

    PubMed  CAS  Google Scholar 

  • Moran O, Dascal N (1989) Protein kinase C modulates neurotransmitter responses inXenopus oocytes injected with rat brain mRNA. Mol Brain Res 5:193–202

    Article  PubMed  CAS  Google Scholar 

  • Moss SJ, Doherty CA, Huganir RL (1992a) Identification of the cAMP-dependentprotein kinase and protein kinase C phosphorylation sites within the major intracellular domains of the ß1, γ2S and γ2L subunits of the γ-aminobutyric acid typeA receptor. J Biol Chem 267:14470–14476

    PubMed  CAS  Google Scholar 

  • Moss SJ, Smart TG, Blackstone CD, Huganir RL (1992b) Functional modulation ofGABAA receptors by cAMP-dependent protein phosphorylation. Science257:661–665

    Article  PubMed  CAS  Google Scholar 

  • Moss SJ, Gorrie GH, Amato A, Smart TG (1995) Modulation of GABAA receptors bytyrosine phosphorylation. Nature 377:344–348

    Article  PubMed  CAS  Google Scholar 

  • Moss SJ, Smart TG (1996) Modulation of amino acid-gated ion channels by proteinphosphorylation. Int J Neurobiol 39:1–52

    Article  CAS  Google Scholar 

  • Mumby MC, Walter G (1993) Protein serine/threonine phosphatases: Structure, regulation, and functions in cell growth. Physiol Rev 73:673–699

    PubMed  CAS  Google Scholar 

  • Nairn AC, Shenolikar S (1992) The role of protein phosphatases in synaptic transmission, plasticity and neuronal development. Curr Opin in Neurobiol 2:296–301

    Article  CAS  Google Scholar 

  • Parfitt KD, Hoffer BJ, Bickford-Wimer PC (1990) Potentiation of gamma-aminobutyricacid-mediated inhibition by isoproterenol in the cerebellar cortex: receptor specificity. Neuropharmacol 29:909–916

    Article  CAS  Google Scholar 

  • Pearson RC, Kemp BE (1991) Protein kinase phosphorylation site sequences and consensus specificity motifs: tabulations. Meth Enzymol 200:62–81

    Article  PubMed  CAS  Google Scholar 

  • Poisbeau P, Cheney MC, Browning MD, Mody I (1999) Modulation of synaptic GABAA receptor function by PKA and PKC in adult hippocampal neurons. J Neurosci19:674–683

    PubMed  CAS  Google Scholar 

  • Porter NM, Twyman RE, Uhler MD, Macdonald RL (1990) Cyclic AMP-dependentprotein kinase decreases GABAA receptor current in mouse spinal neurons.Neuron 5:789–796

    Article  PubMed  CAS  Google Scholar 

  • Poulter MO, Barker JL, O’Carroll AM, Lolait SJ, Mahan LC (1992) Differential andtransient expression of GABAA receptor alpha-subunit mRNAs in the develop-ing rat CNS. J Neurosci 12:2888–2900

    PubMed  CAS  Google Scholar 

  • Pritchett DB, Sontheimer H, Shivers BD, Ymer S, Kettenmann H, Schofield PR,Seeburg PH (1989) Importance of a novel GABAA receptor subunit for benzodi-azepine pharmacology. Nature, 338:582–585

    Article  PubMed  CAS  Google Scholar 

  • Rabow LE, Russek SJ, Farb DH (1995) From ion currents to genomic analysis: Recentadvances in GABAA receptor research. Synapse 21:189–274

    Article  PubMed  CAS  Google Scholar 

  • Robello M, Amico C, Cupello A (1993) Regulation of GABAA receptor in cerebellargranule cells in culture: differential involvement of kinase activities. Neuroscience53:131–138

    Article  PubMed  CAS  Google Scholar 

  • Robello M, Amico C, Bucossi G, Cupello A, Rapallino MV, Thellung S (1996) Nitricoxide and GABAA receptor function in the rat cerebral cortex and cerebellargranule cells. Neurosci 74:99–105

    Article  CAS  Google Scholar 

  • Robello M, Amico C, Cupello A (1997) A dual mechanism for impairment of GABAA receptor activity by NMD A receptor activation in rat cerebellum granule cells. EurJ Biophys 25:181–187

    Article  CAS  Google Scholar 

  • Robello M, Amico C, Cupello A (1998) Cerebellar granule cell GABAA receptorsstudied at the single channel level: Modulation by protein kinase G. Biochem Biophys Res Commun 253:768–773

    Article  CAS  Google Scholar 

  • Schwartz RD, Heuschneider G, Edgar PP, Cohn JA (1991) cAMP analogs inhibit γ-aminobutyric acid-gated chloride flux and activate protein kinase A in brain synaptoneurosomes. Mol Pharmacol, 39:370–375

    PubMed  CAS  Google Scholar 

  • Scott JD, Soderling TR (1992) Serine/threonine protein kinases. Curr Opin in Neurobiol 22:289–295

    Article  Google Scholar 

  • Shingai R, Yanagi K, Fukushima T, Sakata K, Ogurusu T (1996) Functional expressionof GABA ρ3 receptors in Xenopus oocytes. Neurosci Res 26:387–390

    Article  PubMed  CAS  Google Scholar 

  • Shirasaki T, Aibara K, Akaike N (1992) Direct modulation of GABAA receptor byintracellular ATP in dissociated nucleus tractus solitarii neurones of rat. J Physiol449:551–572

    PubMed  CAS  Google Scholar 

  • Sieghart W (1995) Structure and pharmacology of γ-aminobutyric acidA receptor subtypes. Pharmacol Rev 47:182–224

    Google Scholar 

  • Sigel E, Baur R (1988) Activation of protein kinase C differentially modulates neuronal Na+, Ca2+,and γ-aminobutyrate type A channels. Proc Natl Acad Sci USA85:6192–6196

    Article  PubMed  CAS  Google Scholar 

  • Sigel E, Baur R,Trube G, Mohler H, Malherbe P (1990) The effect of subunit composition of rat brain GABAA receptors on channel function. Neuron 5(5):703–711

    Article  PubMed  CAS  Google Scholar 

  • Sigel E, Baur R, Malherbe P (1991) Activation of protein kinase C results in down-modulation of different recombinant GABAA-channels. FEBS Lett 291:150–152

    Article  PubMed  CAS  Google Scholar 

  • Sigel E, Baur R, Malherbe P (1993) Recombinant GABAA receptor function andethanol. FEBS Lett 324:140–142

    Article  PubMed  CAS  Google Scholar 

  • Smart TG (1997) Regulation of excitatory and inhibitory neurotransmitter-gated ionchannels by protein phosphorylation. Curr Opin in Neurosci 7:358–367

    Article  CAS  Google Scholar 

  • Smart TG (1998) Electrophysiology of GABAA receptors. In Amino Acid neurotransmission, Ed. FA Stephenson, AJ Turner, Portland Press, London, pp: 37–63

    Google Scholar 

  • Smart TG, Moss SJ, Xie X, Huganir RL (1991) GABAA receptors are differentially sensitive to zinc: dependence on subunit composition. Br J Pharmacol, 103:1837–1839

    Article  PubMed  CAS  Google Scholar 

  • Smith DB, Johnson KS (1988) Single-step purification of polypeptides expressed in Escherichia coli as fusions with glutathione S-transferase. Gene 67:31–40

    Article  PubMed  CAS  Google Scholar 

  • Songyang Z, Carraway KL, Eck MJ, Harrison SC, Feldman RA, Mohammadi M,Schlessinger J, Hubbard SR, Smith DP, Eng C, Lorenzo MJ, Ponder BAJ, MayerBJ, Cantley LC (1995) Catalytic specificity of protein-tyrosine kinases is criticalfor selective signalling. Nature 373:536–539

    Article  PubMed  CAS  Google Scholar 

  • Stelzer A, Kay AR, Wong RKS (1988) GABAA-receptor function in hippocampal cellsis maintained by phosphorylation factors. Science 241:339–341

    Article  PubMed  CAS  Google Scholar 

  • Stelzer A, Shi H (1995) Impairment of GABAA receptor function by N-methyl-D-aspartate-mediated calcium influx in isolated CA1 pyramidal cells. Neurosci62:813–828

    Article  Google Scholar 

  • Sweetnam PM, Lloyd J, Gallombardo P, Malison RT, Gallager DW,Tallman JF, NestlerEJ (1988) Phosphorylation of the GABAA/benzodiazepine receptor-subunit by areceptor-associated protein kinase. J Neurochem 51:1274–1284

    Article  PubMed  CAS  Google Scholar 

  • Tanaka C, Nishizuka Y (1994) The protein kinase C family for neuronal signaling. AnnRev Neurosci 17:551–567

    Article  CAS  Google Scholar 

  • Tehrani MH, Hablitz JJ, Barnes EM Jr (1989) cAMP increases the rate of GABAAreceptor desensitization in chick cortical neurons. Synapse 4:126–131

    Article  PubMed  CAS  Google Scholar 

  • Tehrani MH, Barnes EM Jr (1994) GABAA receptors in mouse cortical homogenatesare phosphorylated by endogenous protein kinase A. Mol Brain Res 24:55–64

    Article  PubMed  CAS  Google Scholar 

  • Thompson CL, Pollard S, Stephenson FA (1996) Bidirectional regulation of GABAAreceptor α1 and α6 subunit expression by a cyclic AMP-mediated signalling mechanism in cerebellar granule cells in primary culture. J Neurochem 67:434–437

    Article  PubMed  CAS  Google Scholar 

  • Ticku MK, Mehta AK (1990) γ-Aminobutyric acidA receptor desensitization in micespinal cord cultured neurons: lack of involvement of protein kinases A and C. Mol Pharmacol, 38:719–724

    PubMed  CAS  Google Scholar 

  • Unwin N (1993) Neurotransmitter action: opening of ligand gated ion channels. Cell,Suppl 72:31–41

    Article  Google Scholar 

  • Van der Geer P, Hunter T, Lindberg RA (1994) Receptor protein-tyrosine kinases andtheir signal transduction pathways. Ann Rev Cell Biol 10:251–337

    Article  PubMed  Google Scholar 

  • Valenzuela CF, Machu TK, McKernan RM, Whiting P, Van Renterghem BB, McManaman JL, Brozowski SJ, Smith GB, Olsen RW, Harris RA (1995) Tyrosine phosphorylation of GABAA receptors. Mol Brain Res 31:165–172

    Article  PubMed  CAS  Google Scholar 

  • Veruki ML, Yeh HH (1992) Vasoactive intestinal polypeptide modulates GABAAreceptor function in bipolar cells and ganglion cells of the rat retina. J Neurophysiol 67:791–797

    PubMed  CAS  Google Scholar 

  • Veruki ML, Yeh HH (1994) Vasoactive intestinal polypeptide modulates GABAA receptor function through activation of cyclic AMP. Vis Neurosci 11:899–908

    Article  PubMed  CAS  Google Scholar 

  • Wafford KA, Burnett DM, Leidenheimer NJ, Burt DR, Wang JB, Kofuji P, DunwiddieTV, Harris RA, Sikela JM (1991) Ethanol sensitivity of the GABAA receptorexpressed in Xenopus oocytes requires 8 amino acids contained in the γ2L subunit.Neuron 7:27–33

    Article  PubMed  CAS  Google Scholar 

  • Wafford KA, Whiting PJ (1992) Ethanol potentiation of GABAA receptors requiresphosphorylation of the alternatively spliced variant of the γ2 subunit. FEBS Lett313:113–117

    Article  PubMed  CAS  Google Scholar 

  • Walaas SI, Greengard P (1991) Protein phosphorylation and neuronal function. Pharmacol Rev 43:300–334

    Google Scholar 

  • Wan Q, Man HY, Braunton J, Wang W, Salter MW, Becker L, Wang YT (1997a) Modulation of GABAA receptor function by tyrosine phosphorylation of ß subunits. JNeurosci 17:5062–5069

    PubMed  CAS  Google Scholar 

  • Wan Q, Xiong ZG, Man HY, Ackerley CA, Braunton J, Lu WY, Becker LE, MacDonald JF, Wang YT (1997b) Recruitment of functional GABAA receptors to postsynaptic domains by insulin. Nature 388:686–690

    Article  PubMed  CAS  Google Scholar 

  • Wang H-L, Li A, Wu T (1997) Vasoactive intestinal polypeptide enhances the GABAergic synaptic transmission in cultured hippocampal neurons. Brain Res 746:294–300

    Article  PubMed  CAS  Google Scholar 

  • Wang RA, Cheng G, Kolaj M, Randic M (1995) α-subunit of calcium/calmodulin-dependent protein kinase II enhances γ-aminobutyric acid and inhibitory synaptic responses of rat neurons in vitro. J Neurophysiol 73:2099–2106

    PubMed  CAS  Google Scholar 

  • Wang H, Bedford FK, Brandon NJ, Moss SJ, Olsen RW (1999) GABAA-receptor-associated protein links GABAA receptors and the cytoskeleton. Nature 397:69–72

    Article  PubMed  CAS  Google Scholar 

  • Waterhouse BD, Moises HC, Yeh HH, Woodward DJ (1982) Norepinephrine enhancement of inhibitory synaptic mechanisms in cerebellum and cerebral cortex: mediation by beta adrenergic receptors. J Pharm Exp Ther 221:495–506

    CAS  Google Scholar 

  • Weiner JL, Zhang L, Carlen PL (1994) Potentiation of GABAA-mediated synapticcurrent by ethanol in hippocampal CA1 neurons: possible role of protein kinaseC. J Pharm Exp Ther 268:1388–1395

    CAS  Google Scholar 

  • Wexler EM, Stanton PK, Nawy S (1998) Nitric oxide depresses GABAA receptorfunction via coactivation of cGMP-dependent kinase and phosphodiesterase. JNeurosci 18:2342–2349

    CAS  Google Scholar 

  • White G, Li C, Ishac E (1992) 19-Dideoxyforskolin does not mimic all cAMP andprotein kinase A independent effects of forskolin on GABA activated ion currents in adult rat sensory neurons. Brain Res 586:157–161

    Article  PubMed  CAS  Google Scholar 

  • Whiting P, McKernan RM, Iversen LL (1990) Another mechanism for creating diversity in γ-aminobutyrate type A receptors: RNA splicing directs expression of twoforms of γ2 subunit, one of which contains a protein kinase C phosphorylationsite. Proc Natl Acad Sci USA 87:9966–9970

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Xu W, Harrison SC, Eck MJ (1997) Three-dimensional structure of the tyrosine kinasec-Src. Nature 385:595–602

    Article  PubMed  CAS  Google Scholar 

  • Yamada K, Akasu T (1996) Substance P suppresses GABAA receptor function viaprotein kinase C in primary sensory neurones of bullfrogs. J Physiol 496.2:439–449

    PubMed  CAS  Google Scholar 

  • Zarri I, Bucossi G, Cupello A, Rapallino MV, Robello M (1994) Modulation by nitricoxide of rat brain GABAA receptors. Neurosci Lett 180:239–242

    Article  PubMed  CAS  Google Scholar 

  • Zhai J, Stewart RR, Friedberg MW, Li C (1998) Phosphorylation of the GABAA receptor γ2L subunit in rat sensory neurons may not be necessary for ethanolsensitivity. Brain Res 805:116–122

    Article  PubMed  CAS  Google Scholar 

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Authors
  1. T. G. Smart
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  2. P. Thomas
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  3. N. J. Brandon
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  4. S. J. Moss
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Editors and Affiliations

  1. Institute of Pharmacology and Toxicology, ETH and University of Zürich, Winterthurerstr. 190, CH-8057, Zürich, Switzerland

    Hanns Möhler

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Smart, T.G., Thomas, P., Brandon, N.J., Moss, S.J. (2001). Heterologous Regulation of GABAA Receptors: Protein Phosphorylation. In: Möhler, H. (eds) Pharmacology of GABA and Glycine Neurotransmission. Handbook of Experimental Pharmacology, vol 150. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-56833-6_7

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  • DOI: https://doi.org/10.1007/978-3-642-56833-6_7

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