Kainate receptor modulation of GABA release involves a metabotropic function.
The mechanism through which kainate receptors downregulate the release of GABA in the hippocampus is not known. We have found that the action of kainate on the hippocampal inhibitory postsynaptic current (IPSC) is mediated by a metabotropic process that is sensitive to Pertussis toxin (PTx) and independent of ion channel current. The downregulation of GABA IPSCs by kainate was also prevented in a dose-dependent manner by calphostin C, a specific inhibitor of PKC, and the inhibition of phospholipase C (PLC) drastically reduced the action of kainate. The effect of kainate was completely occluded by phorbol esters and by increasing extracellular Ca2+ but remained unaltered after inhibition or activation of protein kinase A (PKA). These results demonstrate that the activation of kainate receptors triggers a second messenger cascade, which results in the stimulation of PKC, and therefore document a metabotropic action of kainate receptors, which results in the inhibition of GABA release.
Rodríguez-Moreno
A
A
Instituto Cajal, Consejo Superior de Investigaciones Cientificas, Madrid, Spain.
Lerma
J
J
D000818:Animals; D002118:Calcium / Q000494:pharmacology / Q000502:physiology; D002273:Carcinogens / Q000494:pharmacology; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004963:Estrenes / Q000494:pharmacology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism; D006624:Hippocampus / Q000737:chemistry* / Q000201:enzymology*; D007546:Isoquinolines / Q000494:pharmacology; D007608:Kainic Acid / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects; D037342:Pertussis Toxin; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism; D011760:Pyrrolidinones / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018092:Kainic Acid Receptors / Q000378:metabolism*; D018094:Receptors, Metabotropic Glutamate / Q000502:physiology*; D015290:Second Messenger Systems / Q000502:physiology; D012964:Sodium / Q000494:pharmacology; D019311:Staurosporine / Q000494:pharmacology; D013449:Sulfonamides; D019789:Tetraethylammonium / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology; D013873:Thionucleotides / Q000494:pharmacology; D010738:Type C Phospholipases / Q000378:metabolism; D010566:Virulence Factors, Bordetella; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D002118:Calcium; D002273:Carcinogens; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D004791:Enzyme Inhibitors; D004963:Estrenes; D018690:Excitatory Amino Acid Agonists; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D007546:Isoquinolines; D007608:Kainic Acid; D037342:Pertussis Toxin; D015240:Phorbol 12,13-Dibutyrate; D010726:Phosphodiesterase Inhibitors; D011493:Protein Kinase C; D011760:Pyrrolidinones; D018092:Kainic Acid Receptors; D018094:Receptors, Metabotropic Glutamate; D012964:Sodium; D019311:Staurosporine; D013449:Sulfonamides; D019789:Tetraethylammonium; D013779:Tetrodotoxin; D013873:Thionucleotides; D010738:Type C Phospholipases; D010566:Virulence Factors, Bordetella; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D005680:gamma-Aminobutyric Acid; C060229:1-(6-((3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione; C016957:adenosine-3',5'-cyclic phosphorothioate; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide