Metabotropic Actions of Kainate Receptors in the Control of GABA Release

  • Talvinder S. SihraEmail author
  • Antonio Rodríguez-MorenoEmail author
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 717)


Kainate receptors (KARs) are members of the family of ionotropic glutamate receptors (iGluRs) which also include NMDA and AMPA receptors. As ionotropic receptors, KARs have been characterized, pre and postsynaptically, in several brain regions. In this chapter we review evidence that suggests that KARs mediate some of their effects without invoking ion-fluxes. Beginning with seminal experiments described some ten years ago, when the notion of a metabotropic action of KAR was first posited in the modulation of GABA release from hippocampal interneurons, increasingly, there have been reports indicating that some KAR functions overtly depend on G-protein activation and involve the participation of intracellular signalling cascades. Thus, KAR activation instigates a cascade involving Gi/o, phospholipase C and protein kinase C to suppress the release of GABA and therefore underpins disinhibition of pyramidal cells in the CA1 region of the hippocampus. This type of metabotropic function of KARs in controlling GABA release represents an additional level of activity-dependent control of synaptic inhibition which is independent of any ionotropic activity of KARs.


AMPA Receptor Pertussis Toxin Kainate Receptor Hippocampal Interneuron IPSC Amplitude 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    Hollmann M, Heinemann S. Cloned glutamate receptors. Annu Rev Neurosci 1994; 17:81–108.CrossRefGoogle Scholar
  2. 2.
    Jonas P, Monyer H. Ionotropic glutamate reeptors in the CNS. Berlin: Springer, 1999.Google Scholar
  3. 3.
    Lerma J, Paternain AV, Rodríguez-Moreno A. López-García JC. Physiol Rev 2001; 81:971–998.PubMedGoogle Scholar
  4. 4.
    Lerma J. Role and rules of kainate receptors in synaptic transmission. Nat Rev Neurosci 2003; 4:481–495.PubMedCrossRefGoogle Scholar
  5. 5.
    Huettner JE. Kainate receptors and synaptic transmission. Prog Neurobiol 2003; 70:387–407.PubMedCrossRefGoogle Scholar
  6. 6.
    Wang Y, Durkin JP. a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, but not N-mathyl-D-aspartate, activates mitogen-activated protein kinase through G-protein βγ subunits in rat cortical neurons. J Biol Chem 1995; 270:22783–22787.PubMedCrossRefGoogle Scholar
  7. 7.
    Wang Y, Small, DL, Stanimirovic DB et al (1997) AMPA receptor-mediated regulation of a Giprotein in cortical neurons. Nature 1997; 389:502–504.PubMedCrossRefGoogle Scholar
  8. 8.
    Hayashi T, Umemori H, Mishina M et al. The AMPA receptor interacts with and signals through the protein tyrosine kinase Lyn. Nature 1999; 397:72–76.PubMedCrossRefGoogle Scholar
  9. 9.
    Kawai F, Sterling P. AMPA receptor activates a G-protein that suppresses a cGMP-gated current. J Neurosci 1999; 19:2954–2959.PubMedGoogle Scholar
  10. 10.
    Perkinton MS, Sihra TS, Willians RJ. Ca2+-permeable AMPA receptors induce phosphorilation of cAMP response element-binding protein through a phosphatidylinositol 3-kinase-dependent stimulation of the mitogen-activated protein kinase signalling cascade in neurons. J Neurosci 1999; 19:5861–5874.PubMedGoogle Scholar
  11. 11.
    Marin P, Fagni L, Torrens Y et al. AMPA receptor activation induces association of G-beta protein with the alpha subunit of the sodium channel in neurons. Eur J Neurosci 2001; 14:1953–1960.PubMedCrossRefGoogle Scholar
  12. 12.
    Satake S, Saitow F, Rusakov D et al. AMPA receptor-mediated presynaptic inhibition at cerebellar GABA-ergic synapses: a characterization of molecular mechanisms. Eur J Neurosci 2004; 19:2464–2474.PubMedCrossRefGoogle Scholar
  13. 13.
    Takago H, Nakamura Y, Takahashi T. G protein-dependent presynaptic inhibition mediated by AMPA receptors at the calyx of Held. Proc Natl Acad Sci USA 2005; 102:7368–7373.PubMedCrossRefGoogle Scholar
  14. 14.
    Rodríguez-Moreno A, Herreras O, Lerma J. Kainate receptors presynaptic ally downregulate GAB Aergic inhibition in the rat hippocampus. Neuron 1997; 19:893–901.PubMedCrossRefGoogle Scholar
  15. 15.
    Clarke VRJ, Ballyk BA, Hoo KH et al. A hippocampal GluR5 kainate receptor regulating inhibitory synaptic transmission. Nature 1997; 389:599–603.PubMedCrossRefGoogle Scholar
  16. 16.
    Rodríguez-Moreno A, Lerma J. Kainate receptor modulation of GABA release involves a metabotropic function. Neuron 1998; 20:1211–1218.PubMedCrossRefGoogle Scholar
  17. 17.
    Min MY, Melyan Z, Kullmann D. Synaptically released glutamate reduces γ-amonobutiric acid (GABA)ergic inhibition in the hippocampus via kainate receptors. Proc Natl Acad Sci USA 1999; 96:9932–9937.PubMedCrossRefGoogle Scholar
  18. 18.
    Semyanov A, Kullmann DM. Kainate receptor-dependent axonal depolarization and action potential initiation in interneurons. Nat Neurosci 2001; 4:718–723.PubMedCrossRefGoogle Scholar
  19. 19.
    Frerking M, Petersen CC, Nicoll RA. Mechanisms underlying kainate receptor-mediated disinhibition in the hippocampus. Proc Natl Acad Sci USA 1999; 96:12917–12922.PubMedCrossRefGoogle Scholar
  20. 20.
    Bureau I, Bischoff S, Heinemann SF et al. Kainate receptor-mediated responses in the CA1 field of wild-type and GluR6-deficient mice. J Neurosci 1999; 9:653–663.Google Scholar
  21. 21.
    Rodríguez-Moreno A, López-García JC, Lerma J. Two populations of kainate receptors with separate signalling mechanisms in hippocampal interneurons. Proc Natl Acad Sci USA 2000; 97:1293–1298.PubMedCrossRefGoogle Scholar
  22. 22.
    Frerking M, Malenka RC, Nicoll RA. Synaptic activation of kainate receptors on hippocampal interneurons. Nat Neurosci 1998; 1:479–486.PubMedCrossRefGoogle Scholar
  23. 23.
    Kerchner GA, Wang GD, Qiu CS et al. Direct presynaptic regulation of GABA/glycine release by kainate receptors in the dorsal horn: an ionotropic mechanism. Neuron 2001; 32:477–488.PubMedCrossRefGoogle Scholar
  24. 24.
    Cunha RA, Constantino MD, Ribeiro JA. Inhibition of (3H)gamma-aminobutiric acid release by kainate receptor activation in rat synaptosomes. Eur J Pharmacol 1997; 323:167–172.PubMedCrossRefGoogle Scholar
  25. 25.
    Perkinton MS, Sihra TS. A high-affinity presynaptic kainate-type glutamate receptor facilitates glutamate exocytosis from cerebral cortex nerve terminals (synaptosomes). Neuroscience 1999; 90:1281–1292.PubMedCrossRefGoogle Scholar
  26. 26.
    Cunha RA, Malva JO, Ribeiro JA. Kainate receptors coupled to G(i)/G(o) proteins in the rat hippocampus. Mol Pharmacol 1999; 56:429–433.PubMedGoogle Scholar
  27. 27.
    Cunha RA, Malva JO, Ribeiro JA. Pertussis toxin prevents inhibition by kainate receptors of rat hippocampal (3H) GABA release. FEBS Letters 2000; 469:159–162.PubMedCrossRefGoogle Scholar
  28. 28.
    Maingret F, Lauri SE, Taira T et al. Profound regulation of neonatal CA1 rat hippocampal GABAergic transmission by functionally distinct kainate receptor populations. J Physiol 2005; 567:131–142.PubMedCrossRefGoogle Scholar
  29. 29.
    Christensen JK, Paternain AV, Selak S et al. A mosaic of functional kainate receptors at hippocampal interneurons. J Neurosci 2004; 24:8986–8993.PubMedCrossRefGoogle Scholar
  30. 30.
    Jaskolski F, Coussen F, Nagarajam N et al. Subcellular localization and trafficking of kainate receptors. Trends Pharmacol Sci 2005; 26:20–26.PubMedCrossRefGoogle Scholar
  31. 31.
    Cossart R, Tyzio R, Dinocourt C et al. Presynaptic kainate receptors that enhance the release of GABA on CA1 hippocampal interneurons. Neuron 2001; 29:497–508.PubMedCrossRefGoogle Scholar
  32. 32.
    Jiang L, Xu J, Nedergaard M et al. A kainate receptor increases the efficacy of GABergic synapses. Neuron 2001; 30:503–513.PubMedCrossRefGoogle Scholar
  33. 33.
    Liu QS, Patrylo PR, Gao XB et al. Kainate acts at presynaptic receptors to increase GABA release from hypothalamic neurons. J Neurophysiol 1999; 82:1059–1062.PubMedGoogle Scholar
  34. 34.
    Ali AB, Rossier J, Staiger JF et al. Kainate receptors regulate unitary IPSCs elicited in pyramidal cells by fast-spiking interneurons in the neocortex. J Neurosci 2001; 21:2992–2999.PubMedGoogle Scholar
  35. 35.
    Braga MF, Aroniadou-Anderjaska V, Xie J et al. Bidirectional modulation of GABA release by presynaptic glutamate receptor 5 kainate receptors in the basolateral amygdala. J Neurosci 2003; 23:442–452.PubMedGoogle Scholar
  36. 36.
    Chergui K, Bouron A, Normand E et al. Functional GluR6 kainate receptors in the striatum: indirect downregulation of synaptic transmission. J Neurosci 2000; 20:2175–2182.PubMedGoogle Scholar
  37. 37.
    Rodríguez-Moreno, Sihra TS. Kainate receptors with a metabotropic modus operandi. Trends Neurosci 2007; 30(12):630–637.PubMedCrossRefGoogle Scholar
  38. 38.
    Rodríguez-Moreno A, Sihra TS. Metabotropic actions of kainate receptors in the CNS. J Neurochem 2007; 103:2121–2135.PubMedCrossRefGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Department of Neuroscience, Physiology and PharmacologyUniversity College LondonLondonUK
  2. 2.Departamento de Fisiologfía, Anatomfía y Biología CelularUniversidad Pablo de OlavideSevillaSpain

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