Regional alterations in M1 muscarinic receptor-G protein coupling in Alzheimer's disease.
Previous studies examining the functional status of cortical muscarinic cholinergic M1 receptors have demonstrated an impairment in receptor-G protein coupling in Alzheimer's disease (AD) as measured by the inability of the receptor to form a high affinity agonist binding site. In order to investigate whether this alteration was a global phenomenon or a regional specific defect in signal transduction, we examined agonist binding at M1 receptors in three brain areas (superior frontal cortex, Brodmann areas 8 and 9; primary visual cortex, Brodmann area 17; and the dorsal striatum) within the same brain in controls and moderate to severe AD cases. Competition binding studies using the M1 antagonist 3H-pirenzepine (4 nM) in the presence of varying concentrations of the cholinergic agonist carbachol (50 nM to 1 mM) were performed in the presence and absence of GppNHp (100 microM), a non-hydrolyzable analog of GTP. In control membrane preparations, computer-assisted analysis of antagonist-agonist competition curves revealed that M1 receptor agonist binding fit a two site model with high and low affinity states in all three brain areas in the absence of GppNHp but only a single site in the presence of GppNHp. This is consistent with the ternary complex model of G protein-linked receptors. In contrast, curves obtained from both cortical regions from AD brains fit a single site model with low affinity in the presence or absence of GppNHp. On the other hand, agonist binding data obtained from the dorsal striatum of AD cases exhibited a two site fit, similar to that seen in controls.(ABSTRACT TRUNCATED AT 250 WORDS)
Ladner
C J
CJ
Neuroscience Program, Stritch School of Medicine, Loyola University-Chicago, Maywood, IL 60153, USA.
Celesia
G G
GG
Magnuson
D J
DJ
Lee
J M
JM
D000368:Aged; D000544:Alzheimer Disease / Q000378:metabolism*; D001665:Binding Sites; D001921:Brain / Q000378:metabolism*; D002217:Carbachol / Q000494:pharmacology; D005625:Frontal Lobe / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006801:Humans; D010890:Pirenzepine / Q000494:pharmacology; D011976:Receptors, Muscarinic / Q000378:metabolism*; D014793:Visual Cortex / Q000378:metabolism
D011976:Receptors, Muscarinic; D010890:Pirenzepine; D002217:Carbachol; D019204:GTP-Binding Proteins