Phorbol esters attenuate glutamate-stimulated inositol phospholipid hydrolysis in neuronal cultures.
The phorbol diesters 12-O-tetradecanoyl-phorbol-13-acetate (TPA) and phorbol-12,13-dibutyrate, but not 4-alpha-phorbol-didecanoate, inhibited the stimulation of inositol phospholipid hydrolysis by excitatory amino acids and carbamylcholine in primary cultures of cerebellar neurons. This inhibition was mimicked by the synthetic diacylglycerol 1,2-dioleoyl-rac-glycerol (DOG) and was selective for a specific glutamate-phosphoinositide receptor subtype (GP2 receptor) activated by glutamate and quisqualate. TPA was nearly inactive in inhibiting the stimulation of inositol phospholipid hydrolysis by N-methyl-D-aspartate, a selective agonist of the GP1 receptor. Phorbol diesters and DOG attenuated the stimulation of inositol phospholipid hydrolysis by glutamate and quisqualate also in cerebellar slices from 9-15-day-old rats; however, using this preparation, their action was weak and required high concentrations (greater than 1 microM). The inhibition of signal transduction by phorbol diesters was not consequent to a reduced binding of glutamate to its membrane recognition sites. In fact, TPA induced only a small increase in the KD but no change in the Bmax of [3H]glutamate binding in cerebellar membranes. Phorbol diesters may act to inhibit specific GTP-binding proteins or particular molecular forms of phosphoinositidase C associated with GP2 or muscarinic cholinergic receptors.
D000818:Animals; D001224:Aspartic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D002217:Carbachol / Q000494:pharmacology; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism*; D004075:Diglycerides / Q000494:pharmacology; D005971:Glutamates / Q000494:pharmacology*; D018698:Glutamic Acid; D006868:Hydrolysis; D007295:Inositol Phosphates / Q000378:metabolism; D016202:N-Methylaspartate; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D010069:Oxadiazoles / Q000494:pharmacology; D015240:Phorbol 12,13-Dibutyrate; D010703:Phorbol Esters / Q000494:pharmacology*; D010716:Phosphatidylinositols / Q000378:metabolism*; D016318:Quisqualic Acid; D051381:Rats; D011919:Rats, Inbred Strains; D017470:Receptors, Glutamate; D017981:Receptors, Neurotransmitter / Q000187:drug effects / Q000378:metabolism; D013110:Sphingosine / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D004075:Diglycerides; D005971:Glutamates; D007295:Inositol Phosphates; D010069:Oxadiazoles; D010703:Phorbol Esters; D010716:Phosphatidylinositols; D017470:Receptors, Glutamate; D017981:Receptors, Neurotransmitter; D001224:Aspartic Acid; D015240:Phorbol 12,13-Dibutyrate; D018698:Glutamic Acid; D016202:N-Methylaspartate; D016318:Quisqualic Acid; D002217:Carbachol; D013110:Sphingosine; D013755:Tetradecanoylphorbol Acetate; C013965:diolein