NEUROTRANSMITTER-SPECIFIC PROFILES OF INOSITOL PHOSPHATES IN RAT-BRAIN CORTEX - RELATION TO THE MODE OF RECEPTOR ACTIVATION OF PHOSPHOINOSITIDE PHOSPHOLIPASE-C

Phosphoinositide breakdown, as stimulated by six different neurotransm itter receptor agonists (carbachol, serotonin, norepinephrine, trans-( +/-)-aminocyclopentyl-1,3-dicarboxylic acid, endothelin-1 and histamin e), has been studied in rat brain cortical slices. The accumulation wa s monitored of total H-3-inositol phosphates (InsPs) and [H-3]CDP-diac ylglycerol (CDP-DAG) in [H-3]inositol or [H-3]cytidine-prelabeled tiss ue, respectively, and the profile of the major InsPs was quantified as the index log [(inositol 4-monophosphate + inositol 1,4-bisphosphate) /inositol 1-monophosphate]. The efficacy of the six agonists to stimul ate the accumulation of CDP-DAG, relative to that of InsPs, was not co nstant, which revealed varying degrees of defective recycling of DAG t o CDP-DAG. The value of the index for the profile of InsPs was not con stant either but was characteristic of each agonist. Both parameters ( ratio of efficacies CDP-DAG/InsPs and InsPs profile) were not independ ent and defined two groups of agonists as follows: group a, carbachol and serotonin, with balanced CDP-DAG and InsPs responses, and Ins1P pr evailing against inositol 4-monophosphate + inositol 1,4-bisphosphate and group b, norepinephrine, trans-(+/-)-aminocyclopentyl-1,3-dicarbox ylic acid, endothelin-1 and histamine, with weak CDP-DAG responses and high accumulation of inositol 4-monophosphate + inositol 1,4-bisphosp hate compared with that of inositol l-monophosphate, In a membrane pre paration from brain cortex, only agonists in group a stimulated phosph olipase C in the presence of guanosine 5'-O-(3-thiotriphosphate) and i n a receptor antagonist-sensitive fashion, which indicated that brain cortical alpha-1, H-1, endothelin and glutamate metabotropic receptors stimulate phospholipase C indirectly. These results show that both th e efficacy of the CDP-DAG response and the profile of InsPs are charac teristics inherent to the proper mode of receptor activation of phosph olipase C, either direct (via receptor-G protein-phospholipase C inter action) or indirect, probably secondary to calcium entry.