Skip to main content
SpringerLink
Log in

Co-application of the GABAB receptor agonist, baclofen, and the mGlu receptor agonist, L-CCG-I, facilitates [3H]GABA release from rat cortical nerve endings

  • Translational Neurosciences - Original Article
  • Published:
Journal of Neural Transmission Aims and scope Submit manuscript

Abstract

Interaction between different transmitter receptor systems is an emerging feature of neurotransmission at central synapses. G protein-coupled receptors’ ability to form dimers or larger hetero-oligomers probably serves to facilitate the integration of diverse signals within the cell. We found that, in nerve terminals isolated from the cerebral cortices of rats, co-application of the GABAB agonist, baclofen, and of the non-selective mGlu agonist, L-CCG-I, potentiates the basal and depolarization-evoked release of [3H]GABA via a mechanism that involves mobilization of intracellular Ca2+ ions. The effect of L-CCG-I + baclofen was abolished by the phospholipase C inhibitor U73122, reduced by Xestospongin C (an IP3 receptor blocker), and blocked by 2-APB, an IP3 receptor antagonist. Pretreatment of the synaptosomes with the lipid-soluble Ca2+ chelator BAPTA-AM also inhibited the effects of L-CCG-I + baclofen. Subtype-selective non-competitive group I mGlu receptor antagonists, MPEP and CPCCOEt, had no effect on the release enhancement produced by baclofen + L-CCG-I. The enhancement was reversed by the GABAB receptor antagonist, CGP54626, and by the group I/group II mGlu receptor antagonist (R,S)-MCPG. The GABA release-enhancing effects of L-CCG-I + baclofen in our model might reflect the presence on cortical nerve endings of GABAB/group I mGlu receptor heteromers with pharmacological properties distinct from those of the component receptors. Activation of these heteromeric receptors might modify the function of the GABAB receptor in such a way that it facilitates GABAergic transmission, an effect that might be useful under conditions of excessive glutamatergic activity.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  • Bettler B, Tiao JY (2006) Molecular diversity, trafficking and subcellular localization of GABAB receptors. Pharmacol Ther 110:533–543

    Article  PubMed  CAS  Google Scholar 

  • Bonanno G, Raiteri M (1993) Gamma-Aminobutyric acid (GABA) autoreceptors in rat cerebral cortex and spinal cord represent pharmacologically distinct subtypes of the GABAB receptor. J Pharmacol Exp Ther 265:765–770

    PubMed  CAS  Google Scholar 

  • 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 

  • Brabet I, Parmentier ML, De Colle C, Bockaert J, Acher F, Pin JP (1998) Comparative effect of L-CCG-I, DCG-IV and gamma-carboxy-L-glutamate on all cloned metabotropic glutamate receptor subtypes. Neuropharmacology 37:1043–1051

    Article  PubMed  CAS  Google Scholar 

  • Conn PJ, Pin JP (1997) Pharmacology and functions of metabotropic glutamate receptors. Annu Rev Pharmacol Toxicol 37:205–237

    Article  PubMed  CAS  Google Scholar 

  • Dittman JS, Regehr WG (1997) Mechanism and kinetics of heterosynaptic depression at a cerebellar synapse. J Neurosci 17:9048–9059

    PubMed  CAS  Google Scholar 

  • Duthey B, Caudron S, Perroy J, Bettler B, Fagni L, Pin JP, Prézeau L (2002) A single subunit (GB2) is required for G-protein activation by the heterodimeric GABA(B) receptor. J Biol Chem 277:3236–3241

    Article  PubMed  CAS  Google Scholar 

  • Ferré S, Baler R, Bouvier M, Caron MG, Devi LA, Durroux T, Fuxe K, George SR, Javitch JA, Lohse MJ, Mackie K, Milligan G, Pfleger KD, Pin JP, Volkow ND, Waldhoer M, Woods AS, Franco R (2009) Building a new conceptual framework for receptor heteromers. Nat Chem Biol 5:131–134

    Article  PubMed  Google Scholar 

  • Franco R, Casadó V, Cortés A, Mallol J, Ciruela F, Ferré S, Lluis C, Canela EI (2008) G-protein-coupled receptor heteromers: function and ligand pharmacology. Br J Pharmacol 153:S90–S98

    Article  PubMed  CAS  Google Scholar 

  • Fredholm BB, Hökfelt T, Milligan G (2007) G-protein-coupled receptors: an update. Acta Physiol 190:3–7

    Article  CAS  Google Scholar 

  • Gafni J, Munsch JA, Lam TH, Catlin MC, Costa LG, Molinski TF, Pessah LN (1997) Xestospongins: potent membrane permeable blockers of the inositol 1,4,5-triphosphate receptor. Neuron 19:723–733

    Article  PubMed  CAS  Google Scholar 

  • Gaiarsa JL, Kuczewski N, Porcher C (2011) Contribution of metabotropic GABA(B) receptors to neuronal network construction. Pharmacol Ther 132(2):170–179

    Article  PubMed  CAS  Google Scholar 

  • Galvez T, Parmentier ML, Joly C, Malitschek B, Kaupmann K, Kuhn R, Bittiger H, Froestl W, Bettler B, Pin JP (1999) Mutagenesis and modeling of the GABAB receptor extracellular domain support a venus flytrap mechanism for ligand binding. J Biol Chem 274:13362–13369

    Article  PubMed  CAS  Google Scholar 

  • Gasparini F, Lingenhöhl K, Stoehr N, Flor PJ, Heinrich M, Vranesic I, Biollaz M, Allgeier H, Heckendorn R, Urwyler S, Varney MA, Johnson EC, Hess SD, Rao SP, Sacaan AI, Santori EM, Veliçelebi G, Kuhn R (1999) 2-Methyl-6-(phenylethynyl)-pyridine (MPEP), a potent, selective and systemically active mGlu5 receptor antagonist. Neuropharmacology 38:1493–1503

    Article  PubMed  CAS  Google Scholar 

  • Gurevich VV, Gurevich EV (2008) How and why do GPCRs dimerize? Trends in Pharmacol Sci 29:234–240

    Article  CAS  Google Scholar 

  • Hermans E, Nahorski SR, Challiss RA (1998) Reversible and non-competitive antagonist profile of CPCCOEt at the human type 1α metabotropic glutamate receptor. Neuropharmacology 37:1645–1647

    Article  PubMed  CAS  Google Scholar 

  • Hirono M, Yoshioka T, Konishi S (2001) GABA(B) receptor activation enhances mGluR-mediated responses at cerebellar excitatory synapses. Nat Neurosci 4:1207–1216

    Article  PubMed  CAS  Google Scholar 

  • Ichise T, Kano M, Hashimoto K, Yanagihara D, Nakao K, Shigemoto R, Katsuki M, Aiba A (2000) mGluR1 in cerebellar Purkinje cells essential for long-term depression, synapse elimination, and motor coordination. Science 288:1832–1835

    Article  PubMed  CAS  Google Scholar 

  • Ito M (1989) Long-term depression. Ann Rev Neurosci 12:85–102

    Article  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, Nagarathnam D, Noble SA, Branchek TA, Gerald C (1998) GABA(B) receptors function as a heteromeric assembly of the subunits GABA(B)R1 and GABA(B)R2. Nature 396:674–679

    Article  PubMed  CAS  Google Scholar 

  • Kamikubo Y, Tabata T, Kakizawa S, Kawakami D, Watanabe M, Ogura A, Iino M, Kano M (2007) Postsynaptic GABAB receptor signalling enhances LTD in mouse cerebellar Purkinje cells. J Physiol 585:549–563

    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, Karschin A, Bettler B (1998) GABAB-receptor subtypes assemble into functional heteromeric complexes. Nature 396:683–687

    Article  PubMed  CAS  Google Scholar 

  • Kingston AE, Ornstein PL, Wright RA, Johnson BG, Mayne NG, Burnett JP, Belagaje R, Wu S, Schoepp DD (1998) LY341495 is a nanomolar potent and selective antagonist of group II metabotropic glutamate receptors. Neuropharmacology 37:1–12

    Article  PubMed  CAS  Google Scholar 

  • Kniazeff J, Prézeau L, Rondard P, Pin JP, Goudet C (2011) Dimers and beyond: the functional puzzles of class C GPCRs. Pharmacol Ther 130:9–25

    Article  PubMed  CAS  Google Scholar 

  • Kornau HC (2006) GABA(B) receptors and synaptic modulation. Cell Tissue Res 326(2):517–533

    Article  PubMed  CAS  Google Scholar 

  • Linden DJ, Connor JA (1995) Long-term synaptic depression. Annu Rev Neurosci 18:319–357

    Article  PubMed  CAS  Google Scholar 

  • Margeta-Mitrovic M, Jan YN, Jan LY (2001) Function of GB1 and GB2 subunits in G protein coupling of GABA(B) receptors. Proc Natl Acad Sci USA 98:14649–14654

    Article  PubMed  CAS  Google Scholar 

  • Marino MJ, Conn PJ (2006) Glutamate-based therapeutic approaches: allosteric modulators of metabotropic glutamate receptors. Curr Opin Pharmacol 6:98–102

    Article  PubMed  CAS  Google Scholar 

  • Martire M, Castaldo P, D’Amico M, Preziosi P, Annunziato L, Tagliatatela M (2004) M Channels containing KCNQ2 subunits modulate norepinephrine, asparatate, and GABA release from hippocampal nerve terminals. J Neurosci 24:592–597

    Article  PubMed  CAS  Google Scholar 

  • Maruyama T, Kanaji T, Nakade S, Kanno T, Mikoshiba K (1997) 2APB, 2-aminoethoxydiphenyl borate, a membrane-penetrable modulator of Ins(1,4,5)P3-induced Ca2+ release. J Biochem 122:498–505

    Article  PubMed  CAS  Google Scholar 

  • Maurel D, Comps-Agrar L, Brock C, Rives ML, Bourrier E, Ayoub MA, Bazin H, Tinel N, Durroux T, Prézeau L, Trinquet E, Pin JP (2008) Cell-surface protein–protein interaction analysis with time-resolved FRET and snap-tag technologies: application to GPCR oligomerization. Nat Methods 5:561–567

    Article  PubMed  CAS  Google Scholar 

  • Milligan G (2006) G-protein-coupled receptor heterodimers: pharmacology, function and relevance to drug discovery. Drug DiscovToday 11:541–549

    CAS  Google Scholar 

  • Milligan G (2009) G protein-coupled receptor hetero-dimerization: contribution to pharmacology and function. Br J Pharmacol 158:5–14

    Article  PubMed  CAS  Google Scholar 

  • Nakanishi S (1992) Molecular diversity of glutamate receptors and implications for brain function. Science 258:597–603

    Article  PubMed  CAS  Google Scholar 

  • Pierce KL, Premont RT, Lefkowitz RJ (2002) Seven-transmembrane receptors. Nat Rev Mol Cell Biol 3(9):639–650

    Article  PubMed  CAS  Google Scholar 

  • 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 

  • Pin JP, Duvoisin R (1995) The metabotropic glutamate receptors: structure and functions. Neuropharmacology 34:1–26

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Prezeau L, Rives ML, Comps-Agrar L, Maurel D, Kniazeff J, Pin JP (2010) Functional crosstalk between GPCRs: with or without oligomerization. Curr Opin Pharmacol 10:6–13

    Article  PubMed  CAS  Google Scholar 

  • Raiteri M (2008) Presynaptic metabotropic glutamate and GABAB receptors. Handb Exp Pharmacol 184:373–407

    Article  PubMed  CAS  Google Scholar 

  • Rives ML, Vol C, Fukazawa Y, Tinel N, Trinquet E, Ayoub MA, Shigemoto R, Pin JP, Prézeau L (2009) Crosstalk between GABAB and mGlu1a receptors reveals new insight into GPCR signal integration. EMBO J 28:2195–2208

    Article  PubMed  CAS  Google Scholar 

  • Roenker NL, Gudelsky GA, Ahlbrand R, Horn PS, Richtand NM (2012) Evidence for involvement of nitric oxide and GABA(B) receptors in MK-801- stimulated release of glutamate in rat prefrontal cortex. Neuropharmacology 63(4):575–581

    Article  PubMed  CAS  Google Scholar 

  • Rozenfeld R, Devi LA (2010) Receptor heteromerization and drug discovery. Trends Pharmacol Sci 31:124–130

    Article  PubMed  CAS  Google Scholar 

  • Schoepp DD, Goldsworthy J, Johnson BG, Salhoff CR, Baker SR (1994) 3,5-Dihydroxyphenylglycine is a highly selective agonist for phosphoinositide-linked metabotropic glutamate receptors in the rat hippocampus. J Neurochem 63:769–772

    Article  PubMed  CAS  Google Scholar 

  • Swanson CJ, Bures M, Johnson MP, Linden AM, Monn JA, Schoepp DD (2005) Metabotropic glutamate receptors as novel targets for anxiety and stress disorders. Nat Rev Drug Discov 4:131–144

    Article  PubMed  CAS  Google Scholar 

  • 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 101:16952–16957

    Article  PubMed  CAS  Google Scholar 

  • Toms NJ, Jane DE, Kemp MC, Bedingfield JS, Roberts PJ (1996) The effects of (RS)-alpha-cyclopropyl-4-phosphonophenylglycine ((RS)-CPPG), a potent and selective metabotropic glutamate receptor antagonist. Br J Pharmacol 119:851–854

    Article  PubMed  CAS  Google Scholar 

  • Watkins J, Collingridge G (1994) Phenylglycine derivatives as antagonists of metabotropic glutamate receptors. Trends Pharmacol Sci 15(9):333–342

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

Supported by Fondi Ateneo 2011 of the Catholic University of the Sacred Heart, Rome.

Author information

Authors and Affiliations

  1. Institute of Pharmacology, Faculty of Medicine, Catholic University of Sacred Heart, Largo F. Vito 1, 00168, Rome, Italy

    Irene A. Samengo, Valerio Scotti & Maria Martire

Authors
  1. Irene A. Samengo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Valerio Scotti
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Maria Martire
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Maria Martire.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Samengo, I.A., Scotti, V. & Martire, M. Co-application of the GABAB receptor agonist, baclofen, and the mGlu receptor agonist, L-CCG-I, facilitates [3H]GABA release from rat cortical nerve endings. J Neural Transm 120, 1641–1649 (2013). https://doi.org/10.1007/s00702-013-1057-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00702-013-1057-2

Keywords

Search

Navigation