Skip to main content
SpringerLink
Log in

GABAB Receptor Signaling Pathways

  • Chapter
Pharmacology of GABA and Glycine Neurotransmission

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

Abstract

The GABAB receptor was first identified and characterized on the basis of its sensitivity to baclofen and insensitivity to bicuculline, benzodiazepines, and other agents known to interact with the GABAA site (Bowery et al. 1980). Earlier and subsequent electrophysiological studies with baclofen revealed that it causes a neuronal hyperpolarization and an increase in membrane conductance (Curtis et al. 1974; Newberry and Nicoll 1985). Unlike the GABAA receptor, which is a C1− ionophore, the electrophysiological responses to baclofen are due to changes in K+ and Ca++ conductances (Newberry and Nicoll 1985). Moreover, GABAB receptor activation inhibits the evoked release of a number of transmitters from brain tissue, including glutamate, serotonin, dopamine and GABA itself (Bowery et al. 1980; Gray and Green 1987; Huston et al. 1990; Pende et al. 1993). Taken together, these data provided compelling evidence that the GABAA and GABAB receptors represent pharmacologically, physiologically and molecularly distinct entities. The subsequent cloning of these sites provided unequivocal confirmation of this hypothesis (Barnard 1995; Mohler 1995; Kaupmann et al. 1997).

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 39.99
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 54.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  • Alger BE, Nicoll R (1982) Pharmacological evidence for two kinds of GABA receptor on rat hippocampal pyramidal cells studied in vitro. J Physiol (Lond) 328: 125–141

    CAS  Google Scholar 

  • Andrade R, Malenka RC, Nicoll RR (1986) A G protein couples serotonin and GABAB receptors to the same channels in hippocampus. Science 234:1261–1265

    Article  PubMed  CAS  Google Scholar 

  • Barnard EA (1995) The molecular biology of GABAA receptors and their structural determinants. In: Biggio G, Sanna E, Serra M, Costa E (eds) GABAA receptors and anxiety. From neurobiology to treatment advances in biochemical psychopharmacology, Raven Press, New York, ppl–16

    Google Scholar 

  • Barthel F, Campard PK, Demeneix BA, Feltz P, Loeffler J (1995) GABAB receptors negatively regulate transcription in cerebellar granular neurons through cyclic AMP responsive element binding protein dependent mechanisms. Neuroscience 70:417–427

    Article  Google Scholar 

  • Bettler B, Kaupman K, Bowery N (1998) GABAB receptors: drugs meet clones. Curr Opin Neurobiol 8:345–350

    Article  PubMed  CAS  Google Scholar 

  • Bowery NG, Hill DR, Hudson AL, Doble A, Middlemiss DN, Shaw J,Turnbull M (1980) (-)Baclofen decreases neurotransmitter release in mammalian CNS by an action at a novel GABA receptor. Nature 283:92–94

    Article  PubMed  CAS  Google Scholar 

  • Campbell V, Berrow N, Dolphin AC (1993) GABAB receptor modulation of Ca2+ currents in rat sensory neurones by the G protein G(o): antisense oligonucleotide studies. J Physiol 470:1–11

    PubMed  CAS  Google Scholar 

  • Chen G, van den Pol AN (1998) Presynaptic GABAB autoreceptor modulation of P/Qtype calcium channels and GABA release in rat suprachiasmatic nucleus neurons. J Neurosci 18:1913–1922

    PubMed  CAS  Google Scholar 

  • Corradotti R, Ruggiero M, Chiarugi VP, Pepeu G (1987) GABA-receptor stimulation enhances norepinephrine-induced polyphosphoinositide metabolism in rat hippocampal slices. Brain Res 411:196–199

    Article  Google Scholar 

  • Crawford ML, Young JM (1988) GABAB receptor-mediated inhibition of histamine HI-receptor-induced inositol phosphate formation in slices of rat cerebral cortex. J Neurochem 51:1441–1447

    Article  PubMed  CAS  Google Scholar 

  • Crunelli V, Leresche N (1991) A role for GABAB receptors in excitation and inhibition of thalamocortical cells. Trends Neursci 14:16–21

    Article  CAS  Google Scholar 

  • Cunningham MD, Enna SJ (1996) Evidence for pharmacologically distinct GABAB receptors associated with cAMP production in rat brain. Brain Res 720:220–224

    Article  PubMed  CAS  Google Scholar 

  • Cunningham M, Enna SJ (1997) Cellular and biochemical responses to GABAB receptor activation. In: Enna SJ, Bowery NG (eds) The GABA receptors (2nd edn), Humana Press, Totowa, New Jersey, pp 237–258

    Chapter  Google Scholar 

  • Curtis DR, Game CJA, Johnston GAR, McCulloch RM (1974) Central effects of ß(pchlorophenyl)-γ-Aaminobutyric acid. Brain Res 70:493–499

    Article  PubMed  CAS  Google Scholar 

  • Deisz DA, Lux HD (1985) γ-Aminobutyric acid induced depression of Ca2+ currents of chick sensory neurons. Neurosci Lett 56:205–210

    Article  PubMed  CAS  Google Scholar 

  • Desarmenien M, Feltz P, Occhipinti G, Santangelo F, Schlichter R (1984) Coexistence of GABAA and GABAB receptors on Aδ and C primary afferents. Br J Pharmacol 81:327–333

    Article  PubMed  CAS  Google Scholar 

  • Dittman JS, Regehr WG (1996) Contributions of calcium-dependent and calcium-independent mechanisms to presynaptic inhibition at a cerebellar synapse. J Neurosci 16:1623–1633

    PubMed  CAS  Google Scholar 

  • Dolphin AC, McGuirk SM, Scott RH (1989) An investigation into the mechanisms of inhibition of calcium channel currents in cultured sensory neurones of the rat by guanine nucleotide analogues and (-)-baclofen. Br J Pharmacol 97:263–273

    Article  PubMed  CAS  Google Scholar 

  • Duman RS, Karbon EW, Harrington C, Enna SJ (1986) An examination of the involvement of phospholipases A2 and C in the alpha-adrenergic and gammaaminobutyric acid receptor modulation of cyclic AMP accumulation in rat brain slices. J Neurochem 47:800–810

    Article  PubMed  CAS  Google Scholar 

  • Dunlap K (1981) Two types of γ-aminobutyric acid receptor on embryonic sensory neurones. Br J Pharmacol 74:579–585

    Article  PubMed  CAS  Google Scholar 

  • Enna SJ, Bowery NG (eds) (1997) The GABA receptors (2nd edn), Humana Press, Totowa, New Jersey

    Google Scholar 

  • Enna SJ, Harstad EB, McCarson KE (1998) Regulation of neurokinin-1 receptor expression by GABAB receptor agonists. Life Sci 62:1525–1530

    Article  PubMed  CAS  Google Scholar 

  • Galoetti N, Ghelardini C, Papucci L, Capaccioli S, Quattrone A, Bartolini A (1997) An antisense oligonucleotide on the mouse Shaker-like potassium channel Kv 1.1 gene prevents antinociception induced by morphine and baclofen. J Pharmacol Exp Ther 281:941–949

    Google Scholar 

  • Godfrey PP, Grahame-Smith DG, Gray JA (1988) GABAB receptor activation inhibits 5-hydroxytryptamine-stimulated inositol phospholipid turnover in mouse cerebral cortex. Eur J Pharmacol 152:185–188

    Article  PubMed  CAS  Google Scholar 

  • Gray, JA, Green AR (1987) GABAB-receptor mediated inhibition of potassiumevoked release of endogenous 5-hydroxytryptamine from mouse frontal cortex. Br J Pharmacol 91:517–522

    Article  PubMed  CAS  Google Scholar 

  • Harayama N, Shibuya I, Tanaka K, Kabashima N, Ueta Y, Yamashita H (1998) Inhibition of N- and P/Q-type calcium channels by postsynaptic GABAB receptor activation in rat supraoptic neurones. J Physiol 509:371–383

    Article  PubMed  CAS  Google Scholar 

  • Hashimoto T, Kuriyama K (1997) In vivo evidence that GABAB receptors are negatively coupled to adenylate cyclase in rat striatum. J Neurochem 69:365–370

    Article  PubMed  CAS  Google Scholar 

  • Heidelberger R, Matthews G (1991) Inhibition of calcium influx and calcium current by γ-aminobutyric acid in single synaptic terminals. Proc Natl Acad Sci USA 88:7135–7139

    Article  PubMed  CAS  Google Scholar 

  • Hescheler J, Rosenthal W, Trautwein W, Schultz G (1987) The GTP-binding protein, G0, regulates neuronal calcium channels. Nature 325:445–447

    Article  PubMed  CAS  Google Scholar 

  • Hill DR (1985) GABAB receptor modulation of adenylate cyclase activity in rat brain slices. Br J Pharmacol 84:249–257

    PubMed  CAS  Google Scholar 

  • Hill DR, Bowery NG, Hudson AL (1984) Inhibition of GABAB receptor binding by guanyl nucleotides. J Neurochem 42:652–657

    Article  PubMed  CAS  Google Scholar 

  • Howe JR, Sutor B, Zieglgansberger W (1987) Characteristics of long-duration inhibitory postsynaptic potentials in rat neocortical neurons in vitro. Cell Mol Neurobiol 7:1–18

    Article  PubMed  CAS  Google Scholar 

  • Huston E, Cullen GP, Burley JR, Dolphin AC (1995) The involvement of multiple calcium channel sub-types in glutamate release from cerebellar granule cells and its modulation by GABAB receptor activation. Neuroscience 68:465–478

    Article  PubMed  CAS  Google Scholar 

  • Huston E, Scott RH, Dolphin AC (1990) A comparison of the effect of calcium channel ligands and GABAB agonists and antagonists on transmitter release and somatic calcium currents in cultured neurons. Neuroscience 38:721–729

    Article  PubMed  CAS  Google Scholar 

  • Jarolimek W, Baurle J, Misgeld U (1998) Pore mutation in a G-protein-gated inwardly rectifying K+-dependent inhibition in Weaver hippocampus. J Neurosci 18: 4001–4007

    PubMed  CAS  Google Scholar 

  • Jones KA, Borowsky B, Tamm JA, Craig DA, Durkin MM, Dai M, Yao WJ, Johnson M, Gunwaldsen C, Huang LY, Tang C, Shen Q, Salon JA, Morse K, Laz T, Smith KE, Nagaraathnam DD, Noble TA, Branchek TA, Gerald C (1998) Functional GABAB receptors require co-expression of GABABR1 and GABABR2. Nature 396:674–678

    Article  PubMed  CAS  Google Scholar 

  • Karbon EW, Duman RS, Enna SJ (1984) GABAB receptors and norepinephrine-stimulated cAMP production in rat brain cortex. Brain Res 306:327–332

    Article  PubMed  CAS  Google Scholar 

  • Karbon EW, Enna SJ (1985) Characterization of the relationship between γ-aminobutyric acid B agonists and transmitter-coupled cyclic nucleotide-generating systems in rat brain. Mol Pharm 27:53–59

    CAS  Google Scholar 

  • Kaupmann K, Bettler B (1998) Heteromerization of GABAB receptors: a new principle for G protein-coupled receptors. CNS Drug Rev 4:376–379

    Article  Google Scholar 

  • Kaupmann K, Huggel K, Heid J, Flor PJ, Bischoff S, Mickel SJ, McMaster G, Angst C, Bittiger H, Froestl W, Bettler B (1997) Expression cloning of GABAB receptors uncovers similarity to metabotrophic glutamate receptors. Nature 386:239–246

    Article  PubMed  CAS  Google Scholar 

  • Kaupmann K, Malitschek B, Schuler V, Heid J, Froestl W, Beck P, Mosbacher J, Bischoff S, Kulik A, Shigemoto R, Kaischin A, Bettler B (1998) GABAB receptor subtypes assemble into functional heteromeric complexes. Nature 396:683–687

    Article  PubMed  CAS  Google Scholar 

  • Knight AR, Bowery NG (1996) The pharmacology of adenylyl cyclase modulation by GABAB receptors in rat brain slices. Neuropharmacology 35:703–712

    Article  PubMed  CAS  Google Scholar 

  • Komastsu Y (1996) GABAB receptors, monoamine receptors, and postsynaptic inositol triphosphate-induced Ca2+ release are involved in the induction of long-term potentiation and visual cortical inhibitory synapses. J Neurosci 16:6342–6352

    Google Scholar 

  • Kuner R, Kohr G, Grunewald S, Eisenhardt G, Bach A, Kornau HC (1999) Role of heteromer formation in GABAB receptor function. Science 283:74–77

    Article  PubMed  CAS  Google Scholar 

  • Luscher C, Jan LY, Stoffel M, Malenka R, Nicoll R (1997) G protein-coupled inwardly rectifying K+ channels (GIRKs) mediate postsynaptic but not presynaptic transmitter actions in hippocampal neurons. Neuron 19:687–695

    Article  PubMed  CAS  Google Scholar 

  • Mailman RB, Mueller RA, Breese GR (1978) The effects of drugs which alter GABAergic function on cerebellar guanosine-3’,5’-monophosphate content. Life Sci 623–627

    Google Scholar 

  • Malcangio M, Bowery NG (1995) Possible therapeutic application of GABAB receptor agonists and antagonists. Clin Neuropharmacol 18:285–305

    Article  PubMed  CAS  Google Scholar 

  • Marescaux C, Vergenes M, Bernasconi R (1992) GABAB receptor antagonists: potential new anti-absence drugs. J Neural Transm Suppl 35:179–188

    CAS  Google Scholar 

  • McCarson KE, Enna SJ (1996) Relationship between GABAB receptor activation and neurokinin receptor expression in spinal cord. Pharmacol Rev Comm 8:191–194

    CAS  Google Scholar 

  • McCarson KE, Enna SJ (1999) Nociceptive regulation of GABAB receptor gene expression in rat spinal cord. Neuropharmacology 38:1767–1773

    Article  PubMed  CAS  Google Scholar 

  • Menon-Johansson AS, Berrow N, Dolphin AC (1993) Go transduces GABAB-receptor modulation of N-type calcium channels in cultured dorsal root ganglion neurons. Pflugers Arch 425:335–343

    Article  PubMed  CAS  Google Scholar 

  • Mintz IM, Bean BP (1993) GABAB receptor inhibition of P-type Ca2+ channels in central neurons. Neuron 10:889–898.

    Article  PubMed  CAS  Google Scholar 

  • Mohler H, Knoflach F, Payson J, Motejlek K, Benke D, Lurscher B, Fritschy JM (1995) Heterogeneity of GABAA-receptors: cell-specific expression, pharmacology, and regulation. Neurochem Res 20:631–636

    Article  PubMed  CAS  Google Scholar 

  • Morishita R, Kato K, Asano T (1990) GABAB receptors couple to G proteins Go, Go * and Gil, but not Gi2. FEBS Lett 271:231–235

    Article  PubMed  CAS  Google Scholar 

  • Newberry NR, Nicoll RA (1985) Comparison of the actions of baclofen with gammaaminobutyric acid on rat hippocampal pyramidal cells in vitro. J Physiol 360:161–185

    PubMed  CAS  Google Scholar 

  • O’Callaghan JFX, Jarolimek W, Lewen A, Misgeld U (1996) (-)-Baclofen-induced and constitutively active inward rectifying potassium conductances in cultured rat midbrain neurons. Pflugers Arch-Eur J Physiol 433:49–57

    Article  Google Scholar 

  • Pende M, Lanza M, Bonnano G, Raiteri M (1993) Release of endogenous glutamic and aspartic acids from cerebrocortex synaptosomes and its modulation through activation of gamma-aminobutyric acid B (GABAB) receptor subtype. Brain Res 604:325–330.

    Article  PubMed  CAS  Google Scholar 

  • Reuveny E, Slesinger PA, Inglese J, Morales JM, Iniguez-Lluhi JA, Lefkowitz RJ, Bourne HR (1994) Activation of cloned muscarinic potassium channel by G protein beta gamma subunits. Nature 370:143–146

    Article  PubMed  CAS  Google Scholar 

  • Scanziani M, Capogna M, Gahwiler BH, Thompson SM (1992) Presynaptic inhibition of miniature excitatory synaptic currents by baclofen and adenosine in the hippocampus. Neuron 9:919–927

    Article  PubMed  CAS  Google Scholar 

  • Scherer RW, Ferkany JW, Enna SJ (1988) Evidence for pharmacologically distinct subsets of GABAB receptors. Brain Res Bull 21:439–443

    Article  PubMed  CAS  Google Scholar 

  • Schoepp DD, Johnson BG, Wright RA, Salhoff CR, Mann JA (1998) Potent, stereoselective, and brain region selective modulation of second messengers in rat brain by (+)LY354740, a novel group II metabotropic glutamate receptor agonist. Naunyn Schmiedebergs Arch Pharmacol 358:175–180

    Article  PubMed  CAS  Google Scholar 

  • Surprenant A, Shen K-Z, North RA, Tatsumi H (1990) Inhibition of calcium currents by noradrenaline, somatostatin and opioids in guinea pig submucosal neurones. J Physiol 431:585–608

    PubMed  CAS  Google Scholar 

  • Takao K, Yoshi M, Kanda A, Kokubun S, Nukada T (1994) A region of the muscarinic-gated atrial K+ channel critical for activation by G protein beta gamma subunits. Neuron 13:747–755

    Article  PubMed  CAS  Google Scholar 

  • Takahashi T, Kajikawa Y, Tsujimoto T (1998) G-protein-coupled modulation of presynaptic calcium currents and transmitter release by a GABAB receptor. J Neurosci 18:3138–3146

    PubMed  CAS  Google Scholar 

  • Tang W, Gilman AG (1991) Type-specific regulation of adenylyl cyclase by G protein beta-gamma subunits. Science 254:102–108

    Article  Google Scholar 

  • Tang WJ, Gilman AG (1992) Adenylyl cyclases. Cell 70:869–872

    Article  PubMed  CAS  Google Scholar 

  • Tang WJ, Iniguez-Lluhi JA, Mumby S, Gilman AG (1992) Regulation of mammalian adenylyl cylase by G-protein alpha and beta gamma subunits. Cold Spring Harb Symp Quant Biol 57:135–144

    Article  PubMed  CAS  Google Scholar 

  • Taussig R, Quarmby LM, Gilman AG (1993) Regulation of purified type I and type II adenylyl cyclases by G protein beta gamma subunits. J Biol Chem 268:9–12

    PubMed  CAS  Google Scholar 

  • Thompson SM, Gahwiler BH (1992) Comparison of the actions of baclofen at pre- and postsynaptic receptors in rat hippocampus in vitro. J Physiol 451:329–345

    PubMed  CAS  Google Scholar 

  • Uezono Y, Akihara M, Kaibara M, Kawano C, Shibuya I, Ueda Y, Yanagihara N, Toyohira Y, Yamashita H, Taniyama K, Izumi F (1998) Activation of inwardly rectifying K+ channels by GABA-B receptors expressed in Xenopus oocytes. Neuro Report 9:583–587

    CAS  Google Scholar 

  • Uezono Y, Ueda Y, Ueno S, Shibuya I, Yanagihara N, Toyohira Y, Yamashita H, Izumi F (1997) Enhancement by baclofen of the Gs-coupled receptor-mediated cAMP production in Xenopus oocytes expressing rat brain cortex poly (A)+ RNA: a role of G-protein ßγ subunits. Biochem Biophys Res Comm 241:476–480

    Article  PubMed  CAS  Google Scholar 

  • White JH, Wise A, Main MJ, Green A, Fraser NJ, Disney GH, Barnes AA, Emson P, Foord SM, Marshall FH (1998) Heterodimerization is required for the formation of a functional GABAB receptor. Nature 396:679–682

    Article  PubMed  CAS  Google Scholar 

  • Wojcik WJ, Neff NH (1984) Gamma-aminobutyric acid B receptors are negatively coupled to adenylate cyclase in brain, and in cerebellum these receptors may be associated with granule cells. Mol Pharmacol 25:24–28

    PubMed  CAS  Google Scholar 

  • Wojcik WJ, Ulivi M, Paez X, Costar E (1989) Islet-activating protein inhibits the beta-adrenergic receptor facilitation elicited by gamma-aminobutyric acid B receptors. J Neurochem 53:753–758

    Article  PubMed  CAS  Google Scholar 

  • Xu J, Wojcik WJ (1986) Gamma-aminobutyric acid B receptor mediated inhibition of adenylate cyclase in cultured cerebellar granule cells: blockade by islet-activating protein. J Pharmacol Exp Ther 239:568–573

    PubMed  CAS  Google Scholar 

  • Yoshimura M, Cooper DM (1993) Type-specific stimulation of adenyl cyclase by protein kinase C. J Biol Chem 268:4604–4607

    PubMed  CAS  Google Scholar 

Download references

Authors
  1. S. J. Enna
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

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

    Hanns Möhler

Rights and permissions

Reprints and permissions

Copyright information

© 2001 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Enna, S.J. (2001). GABAB Receptor Signaling Pathways. 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_13

Download citation

  • DOI: https://doi.org/10.1007/978-3-642-56833-6_13

  • Publisher Name: Springer, Berlin, Heidelberg

  • Print ISBN: 978-3-642-63191-7

  • Online ISBN: 978-3-642-56833-6

  • eBook Packages: Springer Book Archive

Publish with us

Policies and ethics

Search

Navigation