Diminished muscarinic receptor-stimulated [3H]-PIP2 hydrolysis in Alzheimer's disease.
The functional integrity of the cortical muscarinic receptor (MR)-mediated phosphatidylinositol 4,5-bisphosphate (PIP2)-specific phospholipase C signalling pathway was assessed in Alzheimer disease (AD) and age-matched control subjects. There was no difference in the basal hydrolysis of [3H]-PIP2 to [3H]-inositol phosphates between control and AD membrane preparations. However, muscarinic agonist-stimulated PIP2 hydrolysis was significantly diminished in the AD cases. Diminished agonist-stimulated PIP2 hydrolysis correlated with the loss in high affinity agonist binding (KL/KH ratio) to the M1 muscarinic receptor subtype in the disease. These data further support the hypothesis that muscarinic receptor-mediated signal transduction is altered in AD, and that the defect lies at the level of muscarinic receptor-G protein/effector coupling.
Ferrari-DiLeo
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G
Department of Molecular & Cellular Pharmacology, University of Miami School of Medicine, Florida 33101.
Flynn
D D
DD
D000368:Aged; D000544:Alzheimer Disease / Q000378:metabolism*; D001667:Binding, Competitive; D002217:Carbachol / Q000494:pharmacology; D002462:Cell Membrane / Q000378:metabolism; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D005625:Frontal Lobe / Q000201:enzymology / Q000378:metabolism*; D006801:Humans; D006868:Hydrolysis; D007295:Inositol Phosphates / Q000378:metabolism; D007700:Kinetics; D019269:Phosphatidylinositol 4,5-Diphosphate; D043265:Phosphatidylinositol Diacylglycerol-Lyase; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D010890:Pirenzepine / Q000378:metabolism; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D012016:Reference Values; D013570:Synaptic Membranes / Q000201:enzymology*; D010738:Type C Phospholipases / Q000378:metabolism*
D007295:Inositol Phosphates; D019269:Phosphatidylinositol 4,5-Diphosphate; D018129:Phosphatidylinositol Phosphates; D011976:Receptors, Muscarinic; D010890:Pirenzepine; D002217:Carbachol; D002795:Choline O-Acetyltransferase; D010727:Phosphoric Diester Hydrolases; D010738:Type C Phospholipases; D043265:Phosphatidylinositol Diacylglycerol-Lyase