Excitatory amino acids modulate phosphoinositide signal transduction in human epileptic neocortex.
Stimulation of phosphoinositide (PI) hydrolysis by norepinephrine (NE), carbachol (Carb), and excitatory amino acids (EAAs) was measured in slices prepared from neocortex excised during epilepsy surgery. NE and Carb markedly enhanced PI turnover (EC50: NE, 12 microM; Carb, 661 microM) as reflected by [3H]inositol monophosphate (IP1) accumulation in tissue slices prelabeled with [3H]myoinositol. These effects were dose-dependent, saturable, and five to six times higher than basal IP1 accumulation. A weaker stimulation (twofold) was observed with quisqualate (QUIS; EC50, 1.1 microM) and glutamate (GLU; EC50, greater than 1 mM), while minimal or no stimulation was seen with kainate (KA) and N-methyl-D-aspartate (NMDA). Agonist-stimulated PI turnover was significantly reduced in samples from actively spiking epileptic neocortex versus nonspiking areas as defined by electrocorticography (NE, -23%, p less than 0.05; Carb, -44%, p less than 0.01). Preincubation of slices with various EEAs inhibited Carb-induced IP1 formation. The maximal extent of inhibition (1 mM) was both amino acid-dependent (IC50: NMDA, 5 microM; KA, 3.3 microM; QUIS, 47 microM; GLU, greater than 1 mM). These data suggest that epileptic activity modulates PI metabolism and alters receptor-effector coupling. As important mediators of epileptogenesis, EAAs may interfere++ with the efficiency of this second messenger system.
Dubeau
F
F
Montreal Neurological Institute, Quebec, Canada.
Sherwin
A
A
Olivier
A
A
Villemure
J
J
Leblanc
R
R
Quesney
L F
LF
Andermann
E
E
Andermann
F
F
D002217:Carbachol / Q000494:pharmacology; D002540:Cerebral Cortex / Q000378:metabolism* / Q000503:physiopathology; D004305:Dose-Response Relationship, Drug; D004569:Electroencephalography / Q000379:methods; D004827:Epilepsy / Q000378:metabolism* / Q000503:physiopathology; D005971:Glutamates / Q000494:pharmacology; D006801:Humans; D006868:Hydrolysis; D066298:In Vitro Techniques; D007608:Kainic Acid / Q000494:pharmacology; D016202:N-Methylaspartate / Q000494:pharmacology; D009638:Norepinephrine / Q000494:pharmacology; D010716:Phosphatidylinositols / Q000378:metabolism*; D016318:Quisqualic Acid / Q000494:pharmacology; D017981:Receptors, Neurotransmitter / Q000187:drug effects / Q000378:metabolism; D015290:Second Messenger Systems / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology
D005971:Glutamates; D010716:Phosphatidylinositols; D017981:Receptors, Neurotransmitter; D016202:N-Methylaspartate; D016318:Quisqualic Acid; D002217:Carbachol; D007608:Kainic Acid; D009638:Norepinephrine