Evidence that phospholipase D activation prevents group I mGluR-induced persistent prolongation of epileptiform bursts.
Selective activation of group I metabotropic glutamate receptors (mGluRs) with (S)-3,5-dihydroxyphenylglycine (DHPG) in guinea pig hippocampal slices converts 275- to 475-ms picrotoxin-induced interictal bursts into persistent seizure-length discharges typically over 1 s in duration. Here we report that l-cysteine sulfinic acid (CSA), a sulfur-containing amino acid, prevented the induction of this persistent group I mGluR-mediated epileptiform burst prolongation. However, CSA had no effect on baseline interictal bursting activity and failed to suppress the expression of the group I mGluR-induced persistent prolonged bursts once they were fully induced. (2R,1'S,2'R,3'S)-2-(2'-carboxy-3'-phenylcyclopropyl)glycine (PCCG-13), a selective antagonist at the phospholipase D (PLD)-coupled mGluR, had no effect of its own on DHPG-induced burst prolongation; however, CSA applied in the presence of PCCG-13 could no longer fully block the burst prolongation induced by DHPG, suggesting that CSA's antiepileptogenic effect is mediated by agonist action at this PLD-coupled receptor. These data parallel our previous data revealing that protein synthesis inhibitors prevent induction but not expression of group I mGluR-mediated persistent seizure-length discharges. Hence, PLD activation with CSA may prevent the synthesis of a protein critical for the induction of group I mGluR-mediated epileptogenesis.
Rico
Marjorie J
MJ
Neural and Behavioral Science Program, School of Graduate Studies, State University of New York Downstate Medical Center, Brooklyn, New York 11203, USA.
Merlin
Lisa R
LR
D000818:Animals; D003521:Cyclopropanes / Q000494:pharmacology; D003545:Cysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004827:Epilepsy / Q000503:physiopathology*; D018756:GABA Antagonists / Q000494:pharmacology; D058787:GABA-A Receptor Antagonists; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D006168:Guinea Pigs; D008734:Methoxyhydroxyphenylglycol / Q000031:analogs & derivatives* / Q000494:pharmacology; D018377:Neurotransmitter Agents / Q000494:pharmacology; D010739:Phospholipase D / Q000378:metabolism*; D010852:Picrotoxin / Q000494:pharmacology; D018094:Receptors, Metabotropic Glutamate / Q000502:physiology*
D003521:Cyclopropanes; D003545:Cysteine; D018756:GABA Antagonists; D058787:GABA-A Receptor Antagonists; D005998:Glycine; D008734:Methoxyhydroxyphenylglycol; D018377:Neurotransmitter Agents; D010739:Phospholipase D; D010852:Picrotoxin; D018094:Receptors, Metabotropic Glutamate; C099854:2-(2'-carboxy-3'-phenylcyclopropyl)glycine; C104077:metabotropic glutamate receptor type 1; C010117:3,4-dihydroxyphenylglycol; C013461:cysteine sulfinic acid