Transmembrane signaling through phospholipase C in human cortical membranes

Stimulation of phosphoinositide-specific phospholipase C (PLC) by carbachol, dopamine and serotonin was measured by supplying exogenous ³H]phosphatidylinositol 4,5-bisphosphate to membranes prepared from human cortex dissected and frozen at autopsy. Subjects with Alzheimer's disease, Parkinson's disease or schizophrenia were compared to age-matched controls with no known neurological disorders. Stimulation of PLC by the neurotransmitters was dependent on the presence of GTPS. Carbachol elicited the greatest stimulations of PLC followed by serotonin and then dopamine. The maximal stimulations of PLC evoked by a neurotransmitter were similar for the various categories of subjects except in Parkinson's patients, where dopamine failed to stimulate PLC beyond the activity attained with carbachol. In the presence of carbachol, the sensitivity of PLC to GTPS was significantly increased in Alzheimer's membranes, but not in age-matched controls or Parkinson's. Overall, the experiments demonstrate the feasibility for using the exogenous substrate assay to study the functionality of the phosphoinositide transmembrane signaling system in human brain.Abbreviations PLC phospholipase C - GTPS guanosine 3-O-thiotriphosphate - Gpp(NH)p 5-guanylyl-imidodiphosphate - DA dopamine - CCh earbachol - 5-HT serotonin - PIP₂ phosphatidylinositol 4,5-bisphosphate - PIP phosphatidylinositol 4-bisphosphate