Skip to main content
SpringerLink
Log in
Book cover

Inhibitory Regulation of Excitatory Neurotransmission pp 87–98Cite as

The Role of GABAB Receptors in the Regulation of Excitatory Neurotransmission

  • Chapter
  • First Online:

Part of the book series: Results and Problems in Cell Differentiation ((RESULTS,volume 44))

Abstract

GABAB receptors are the metabotrophic receptors for GABA. They are members of the G-protein coupled superfamily of receptors but are highly unusual as they are made up of a dimer of 7-transmembrane spanning subunits. The receptors are widely distributed throughout the central nervous system where they act post-synaptically to cause a long-lasting hyperpolarisation through the activation of a potassium conductance. They are also present pre-synaptically where they act as auto and heteroreceptors to inhibit neurotransmitter release. GABAB receptors play a complex role in the regulation of excitatory transmission and their activation can have both inhibitory and dis-inhibitory effects. This has profound physiological and behavioural consequences including modification of LTP and memory, regulation of seizure activity and nociception.

This is a preview of subscription content, 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   169.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   219.99
Price excludes VAT (USA)
  • Durable hardcover 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

Learn about institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Addolorato G, Caputo F, Capristo E, Colombo G, Gessa GL, Gasbarrini G (2000) Ability of baclofen in reducing alcohol craving and intake: II preliminary clinical evidence. Alcohol Clin Exp Res 24:67–71

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  3. Ataka T, Kumamoto E, Shimoji K, Yoshimura M (2000) Baclofen inhibits more effectively C-afferent than A delta-afferent glutamatergic transmission in substantia gelatinosa neurons of adult rat spinal cord slices. Pain 86:273

    Article  PubMed  CAS  Google Scholar 

  4. Badran S, Schmutz M, Olpe HR (1997) Comparative in vivo and in vitro studies with the potent GABAB receptor antagonist, CGP 56999A. Eur J Pharmacol 333(2–3):135–142

    Article  PubMed  CAS  Google Scholar 

  5. Barral J, Toro S, Galarraga E, Bargas J (2000) GABAergic presynaptic inhibition of rat neostriatal afferents is mediated by Q-type Ca(2+) channels. Neurosci Lett 283(1):33–36

    Article  PubMed  CAS  Google Scholar 

  6. Benke D, Honer M, Michel C, Bettler B, Mohler HJ (1999) Biol Chem 274(38):27323–27330

    Article  CAS  Google Scholar 

  7. Billinton A, Upton N, Bowery NG (1999) GABAB receptor isoforms GBR1a and GBR1b, appear to be associated with pre- and post-synaptic elements respectively in rat and human cerebellum. Br J Pharmacol 126:1387–1392

    Article  PubMed  CAS  Google Scholar 

  8. Bittiger H, Froestl W, Mickel S, Olpe HR (1993) GABAB receptor antagonists: from synthesis to therapeutic applications. Trends Pharmacol Sci 14(11):391–394

    Article  PubMed  CAS  Google Scholar 

  9. Bonanno G, Raiteri M (1993) Multiple GABAB receptors. Trends Pharmacol Sci 14:259–261

    Article  PubMed  CAS  Google Scholar 

  10. Bowery NG, Hudson AL, Price GW (1987) GABAA and GABAB receptor site distribution in the rat central nervous system. Neuroscience 20:365–383

    Article  PubMed  CAS  Google Scholar 

  11. Bowery NG, Bettler B, Froestl W, Gallagher JP, Marshall F, Raiteri M, Bonner TI, Enna SJ (2002) International Union of Pharmacology. XXXIII. Mammalian gamma-aminobutyric acid(B) receptors: structure and function. Pharmacol Rev 54(2):247–264

    Article  PubMed  CAS  Google Scholar 

  12. Bowery NG, Hill DR, Hudson AL, Doble A, Middlemiss DN, Shaw J, Turnbull M (1980) (-)Baclofen decreases neurotransmitter release in the mammalian CNS by an action at a novel GABA receptor. Nature 283(5742):92–94

    Article  PubMed  CAS  Google Scholar 

  13. Brown JT, Gill CH, Farmer CE, Lanneau C, Randall AD, Pangalos MN, Collingridge GL, Davies CH (2003) Mechanisms contributing to the exacerbated epileptiform activity in hippocampal slices of GABAB1 receptor subunit knockout mice. Epilepsy Res 57(2–3):121–136

    Article  PubMed  CAS  Google Scholar 

  14. Calver AR, Robbins MJ, Cosio C, Rice SQJ, Babbs AJ, Hirst WD, Boyfield I, Wood MD, Russell RB, Price GW, et al. (2001) The C-terminal domains of the GABAB receptor subunits mediate intracellular trafficking but are not required for receptor signaling. Neuroscience 21:1203–1210

    PubMed  CAS  Google Scholar 

  15. Charpier S, Leresche N, Deniau JM, Mahon S, Hughes SW, Crunelli V (1999) On the putative contribution of GABAB receptors to the electrical events occurring during spontaneous spike and wave discharges. Neuropharmacology 38:1699–1706

    Article  PubMed  CAS  Google Scholar 

  16. Chen G, van den Pol AN (1998) Presynaptic GABAB autoreceptor modulation of P/Q-type calcium channels and GABA release in rat suprachiasmatic nucleus neurons. J Neurosci 18(5):1913–1922

    PubMed  CAS  Google Scholar 

  17. Clark JA, Mezey E, Lam AS, Bonner TI (2000) Distribution of the GABA(B) receptor subunit gb2 in rat CNS. Brain Res 860(1–2):41–52

    Article  PubMed  CAS  Google Scholar 

  18. Corrigall WA, Coen KM, Adamson KL, Chow BLC, Zhang J (2000) Response of nicotine self-administration in the rat to manipulations of mu-opioid and gamma-aminobutyric acid receptors in the ventral tegmental area. Psychopharmacology 149:107–114

    Article  PubMed  CAS  Google Scholar 

  19. Cortez MA, Wu Y, Gibson KM, Snead OC 3rd (2004) Absence seizures in succinic semialdehyde dehydrogenase deficient mice: a model of juvenile absence epilepsy. Pharmacol Biochem Behav 79(3):547–553

    Article  PubMed  CAS  Google Scholar 

  20. Cryan JF, Kelly PH, Chaperon F, Gentsch C, Mombereau C, Lingenhoehl K, Froestl W, Bettler B, Kaupmann K, Spooren WP (2004) Behavioural characterization of the novel gamma-aminobuytric acid (B) (GABAB) receptor positive modulator GS39783 (n, n′-dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine): anxiolytic-like activity without side-effects associated with baclofen or benzodiazepines. J Pharmacol Exp Ther 310(3):952–963

    Article  PubMed  CAS  Google Scholar 

  21. 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 

  22. Davies CH, Starkey SJ, Pozza MF, Collingridge GL (1991) GABA autoreceptors regulate the induction of LTP. Nature 349(6310):609–611

    Article  PubMed  CAS  Google Scholar 

  23. Dirig DM, Yaksh TL (1995) Intrathecal baclofen and muscimol, but not midazolam, are antinociceptive using the rat-formalin model. J Pharmacol Exp Ther 275(1):219–227

    PubMed  CAS  Google Scholar 

  24. Doze VA, Cohen GA, Madison DV (1995) Calcium channel involvement in GABAB receptor-mediated inhibition of GABA release in area CA1 of the rat hippocampus. J Neurophysiol 74:43–53

    PubMed  CAS  Google Scholar 

  25. Enna SJ (2000) GABAB receptor signaling pathways. In: Möhler H (ed) Pharmacology of GABA and Glycine Neurotransmission. Springer, Berlin Heidelberg New York, pp 329–342

    Google Scholar 

  26. Fearon IM, Zhang M, Vollmer C, Nurse CA (2003) GABA mediates autoreceptor feedback inhibition in the rat carotid body via presynaptic GABAB receptors and TASK-1. J Physiol 553(Pt 1):83–94

    Article  PubMed  CAS  Google Scholar 

  27. Fritschy JM, Meskenaite V, Weinmann O, Honer M, Benke D, Mohler H (1999) GABAB-receptor splice variants GB1a and GB1b in rat brain: developmental regulation, cellular distribution and extrasynaptic localization. Eur J Neurosci 11(3):761–768

    Article  PubMed  CAS  Google Scholar 

  28. Fritschy JM, Sidler C, Parpan F, Gassmann M, Kaupmann K, Bettler B, Benke D (2004) Independent maturation of the GABA(B) receptor subunits GABA(B1) and GABA(B2) during postnatal development in rodent brain. J Comp Neurol 477(3):235–252

    Article  PubMed  CAS  Google Scholar 

  29. Froestl W, Mickel SJ (1997) Chemistry of GABAB modulators. In: Enna SJ, Bowery NG (eds) The GABA Receptors. Humana Press, Totowa, NJ, pp 271–296

    Google Scholar 

  30. Fromm GH, Terrence CF, Chattha AS (1984) Baclofen in the treatment of trigeminal neuralgia: double-blind study and long-term follow-up. Ann Neurol 15(3):240–244

    Article  PubMed  CAS  Google Scholar 

  31. Galvez T, Duthey B, Kniazeff J, Blahos J, Rovelli G, Bettler B, Prezeau L, Pin JP (2001) Allosteric interactions between GB1 and GB2 subunits are required for optimal GABA(B) receptor function. EMBO J 20:2152–2159

    Article  PubMed  CAS  Google Scholar 

  32. Gassmann M, Shaban H, Vigot R, Sansig G, Haller C, Barbieri S, Humeau Y, Schuler V, Muller M, Kinzel B, Klebs K, Schmutz M, Froestl W, Heid J, Kelly PH, Gentry C, Jaton AL, Van der Putten H, Mombereau C, Lecourtier L, Mosbacher J, Cryan JF, Fritschy JM, Luthi A, Kaupmann K, Bettler B (2004) Redistribution of GABAB(1) protein and atypical GABAB responses in GABAB(2)-deficient mice. J Neurosci 24(27):6086–6097

    Article  PubMed  CAS  Google Scholar 

  33. Hammond DL, Washington JD (1993) Antagonism of L-baclofen-induced antinociception by CGP 35348 in the spinal cord of the rat. Eur J Pharmacol 234(2–3):255–262B(2)

    Google Scholar 

  34. Hosford DA, Clark S, Cao Z, Wilson WA, Lin F, Morrisett RA, Huin A (1992) The role of GABAB receptor activation in absence seizures of lethargic (lh/lh) mice. Science 257:398–401 (Washington, DC)

    Article  PubMed  CAS  Google Scholar 

  35. Hosford DA, Lin FH, Wang Y, Caddick SJ, Rees M, Parkinson NJ, Barclay J, Cox RD, Gardiner RM, Hosford DA, Denton P, Wang Y, Seldin MF, Chen B (1999) Studies of the lethargic (lh/lh) mouse model of absence seizures: regulatory mechanisms and identification of the lh gene. Adv Neurol 79:239–252

    PubMed  CAS  Google Scholar 

  36. 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(2):465–478

    Article  PubMed  CAS  Google Scholar 

  37. Ikeda SR, Dunlap K (1999) Voltage-dependent modulation of N-type calcium channels: role of G protein subunits. Adv Second Messenger Phosphoprotein Res 33:131–151

    PubMed  CAS  Google Scholar 

  38. Ipponi A, Lamberti C, Medica A, Bartolini A, Malmberg-Aiello P (1999) Tiagabine antinociception in rodents depends on GABA(B) receptor activation: parallel antinociception testing and medial thalamus GABA microdialysis. Eur J Pharmacol 368(2–3):205–211

    Article  PubMed  CAS  Google Scholar 

  39. Isaacson JS (1998) GABAB receptor-mediated modulation of presynaptic currents and excitatory transmission at a fast central synapse. J Neurophysiol 80:1571–1576

    PubMed  CAS  Google Scholar 

  40. Kabashima N, Shibuya I, Ibrahim N, Ueta Y, Yamashita H (1997) Inhibition of spontaneous EPSCs and IPSCs by presynaptic GABAB receptors on rat supraoptic magnocellular neurons. J Physiol 504(Pt1):113–126

    Article  PubMed  CAS  Google Scholar 

  41. 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 metabotropic glutamate receptors. Nature 386:239–246

    Article  PubMed  CAS  Google Scholar 

  42. Kaupmann K, Schuler V, Mosbacher J, Bischoff S, Bittiger H, Heid J, Froestl W, Leonhard S, Pfaff T, Karschin A, Bettler B (1998) Human gamma-aminobutyric acid type B receptors are differentially expressed and regulate inwardly rectifying K+ channels. Proc Natl Acad Sci USA 95(25):14991–14996

    Article  PubMed  CAS  Google Scholar 

  43. Kim U, Sanchez-Vives MV, McCormick DA (1997) Science 278(5335):130–134

    Article  PubMed  CAS  Google Scholar 

  44. 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 

  45. Lambert NA, Wilson WA (1996) High-threshold Ca2+ currents in rat hippocampal interneurones and their selective inhibition by activation of GABA(B) receptors. J Physiol 492(Pt1):115–127

    PubMed  CAS  Google Scholar 

  46. Ling W, Shoptaw S, Majewska D (1998) Baclofen as a cocaine anti-craving medication: a preliminary clinical study. Neuropsychopharmacology 18:403–404

    Article  PubMed  CAS  Google Scholar 

  47. Liu J, Maurel D, Etzol S, Brabet I, Ansanay H, Pin JP, Rondard P (2004) Molecular determinants involved in the allosteric control of agonist affinity in the GABAB receptor by the GABAB2 subunit. J Biol Chem 279:15824–15830

    Article  PubMed  CAS  Google Scholar 

  48. Malcangio M, Bowery NG (1996) GABA and its receptors in the spinal cord. Trends Pharmacol Sci 17(12):457–462

    Article  PubMed  CAS  Google Scholar 

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

    CAS  Google Scholar 

  50. Margeta-Mitrovic M, Jan YN, Jan LY (2000) A trafficking checkpoint controls GABAB receptor heterodimerization. Neuron 27:97–106

    Article  PubMed  CAS  Google Scholar 

  51. Marshall FH, Jones KA, Kaupmann K, Bettler B (1999a) GABAB receptors- the first 7TM heterodimers. Trends Pharmacol Sci 20:396–399

    Article  PubMed  CAS  Google Scholar 

  52. Mondadori C, Jaekel J, Preiswerk G (1993) CGP 36742: the first orally active GABAB blocker improves the cognitive performance of mice, rats and rhesus monkeys. Behav Neural Biol 60:62–68

    Article  PubMed  CAS  Google Scholar 

  53. Mott DD, Lewis DV (1991) Facilitation of the induction of long-term potentiation by GABAB receptors. Science 252(5013):1718–1720

    Article  PubMed  CAS  Google Scholar 

  54. Mouginot D, Gahwiler BH (1996) Presynaptic GABAB receptors modulate IPSPs evoked in neurons of deep cerebellar nuclei in vitro. J Neurophysiol 75(2):894–901

    PubMed  CAS  Google Scholar 

  55. Nakagawa Y, Sasaki A, Takashima T (1999) The GABAB receptor antagonist CGP36742 improves learned helplessness in rats. Eur J Pharmacol 381:1–7

    Article  PubMed  CAS  Google Scholar 

  56. Obrietan K, van den Pol ANJ (1999) Neurophysiology 82(1):94–102

    PubMed  CAS  Google Scholar 

  57. Olpe HR, Karlsson G (1990) The effects of baclofen and two GABAB-receptor antagonists on long-term potentiation. Naunyn Schmiedebergs Arch Pharmacol 342(2):194–197

    Article  PubMed  CAS  Google Scholar 

  58. Olpe HR, Worner W, Ferrat T (1993) Stimulation parameters determine role of GABAB receptors in long-term potentiation. Experientia 49(6–7):542–546

    Article  PubMed  CAS  Google Scholar 

  59. Pagano A, Rovelli G, Mosbacher J, Lohmann T, Duthey B, Stauffer D, Ristig D, Schuler V, Meigel I, Lampert C, et al. (2001) C-terminal interaction is essential for surface trafficking but not for heteromeric assembly of GABAB receptors. J Neurosci 21:1189–1202

    PubMed  CAS  Google Scholar 

  60. Patel S, Naeem S, Kesingland A, Froestl W, Capogna M, Urban L, Fox A (2001) The effects of GABA(B) agonists and gabapentin on mechanical hyperalgesia in models of neuropathic and inflammatory pain in the rat. Pain 90(3):217–226

    Article  PubMed  CAS  Google Scholar 

  61. Penn RD, Savoy SM, Corcos D, Latash M, Gottlieb G, Parke B, Kroin JS (1989) Intrathecal baclofen for severe spinal spasticity. N Engl J Med 320:1517–1521

    Article  PubMed  CAS  Google Scholar 

  62. Pin JP, Acher F (2002) The metabotropic glutamate receptors: structure, activation mechanism and pharmacology. Curr Drug Targets CNS Neurol Disord 1:297–317

    Article  PubMed  CAS  Google Scholar 

  63. Pin JP, Galvez T, Prezeau L (2003) Evolution, structure, and activation mechanism of family 3/C G-protein-coupled receptors. Pharmacol Ther 98(3):325–354

    Article  PubMed  CAS  Google Scholar 

  64. Plassat R, Perrouin Verbe B, Menei P, Menegalli D, Mathe JF, Richard I (2004) Treatment of spasticity with intrathecal Baclofen administration: long-term follow-up, review of 40 patients. Spinal Cord 42(12):686–693

    Article  PubMed  CAS  Google Scholar 

  65. Poorkhalkali N, Juneblad K, Jonsson AC, Lindberg M, Karlsson O, Wallbrandt P, Ekstrand J, Lehmann A (2000) Immunocytochemical distribution of the GABA(B) receptor splice variants GABA(B) R1a and R1b in the rat CNS and dorsal root ganglia. Anat Embryol (Berl) 201(1):1–13

    Article  CAS  Google Scholar 

  66. Princivalle AP, Pangalos MN, Bowery NG, Spreafico R (2001) Distribution of GABA(B(1a)), GABA(B(1b)) and GABA(B2) receptor protein in cerebral cortex and thalamus of adult rats. Neuroreport 12(3):591–595

    Article  PubMed  CAS  Google Scholar 

  67. Richman RW, Tombler E, Lau KK, Anantharam A, Rodriguez J, O'Bryan JP, Diverse-Pierluissi MA (2004) N-type Ca2+ channels as scaffold proteins in the assembly of signaling molecules for GABAB receptor effects. J Biol Chem 279(23):24649–24658

    Article  PubMed  CAS  Google Scholar 

  68. Scanziani M (2000) GABA spillover activates postsynaptic GABA(B) receptors to control rhythmic hippocampal activity. Neuron 25(3):673–681

    Article  PubMed  CAS  Google Scholar 

  69. Schuler V, Lüscher C, Blanchet C, Klix N, Sansig G, Klebs K, Schmutz M, Heid J, Gentry C, Urban L, Fox A, Spooren W, Jaton AL, Vigouret JM, Pozza M, Kelly PH, Mosbacher J, Froestl W, Käslin E, Korn R, Bischoff S, Kaupmann K, van der Putten H, Bettler B (2001) Epilepsy, hyperalgesia, impaired memory, and loss of pre- and postsynaptic GABAB responses in mice lacking GABAB(1). Neuron 31:47–58

    Article  PubMed  CAS  Google Scholar 

  70. Slesinger PA, Stoffel M, Jan YN, Jan LY (1997) Defective γ-aminobutyric acid type B receptor-activated inwardly rectifying K+ currents in cerebellar granule cells isolated from weaver and Girk2 null mutant mice. Proc Natl Acad Sci USA 94(22):12210–12217

    Article  PubMed  CAS  Google Scholar 

  71. Snead OC (1992) Evidence for GABAB-mediated mechanisms in experimental generalized absence seizures. Eur J Pharmacol 213:343–349

    Article  PubMed  CAS  Google Scholar 

  72. Staubli U, Scafidi J, Chun D (1999) GABAB receptor antagonism: facilitatory effects on memory parallel those on LTP induced by TBS but not HFS. Neurosci 19(11):4609–4615

    CAS  Google Scholar 

  73. Tabata T, Araishi K, Hashimoto K, Hashimotodani Y, van der Putten H, Bettler B, Kano M (2004) Ca2+ activity at GABAB receptors constitutively promotes metabotropic glutamate signaling in the absence of GABA. Proc Natl Acad Sci USA 101(48):16952–16957

    Article  PubMed  CAS  Google Scholar 

  74. Vacher CM, Bettler B (2003) GABA(B) receptors as potential therapeutic targets. Curr Drug Targets CNS Neurol Disord 2:248–259

    Article  PubMed  CAS  Google Scholar 

  75. Yamada K, Yu B, Gallagher JP (1999) Different subtypes of GABAB receptors are present at pre- and postsynaptic sites within the rat dorsolateral septal nucleus. J Neurophysiol 81:2875–2883

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmacology, University of Cambridge, Tennis Court Road, CB2 1QJ, Cambridge, UK

    Fiona H. Marshall

Authors
  1. Fiona H. Marshall
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Fiona H. Marshall .

Editor information

Mark G. Darlison

Rights and permissions

Reprints and permissions

Copyright information

© 2007 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Marshall, F.H. (2007). The Role of GABAB Receptors in the Regulation of Excitatory Neurotransmission. In: Darlison, M.G. (eds) Inhibitory Regulation of Excitatory Neurotransmission. Results and Problems in Cell Differentiation, vol 44. Springer, Berlin, Heidelberg. https://doi.org/10.1007/400_2007_038

Download citation

Publish with us

Policies and ethics

Search

Navigation