Regional alterations in M1 muscarinic receptor-G protein coupling in Alzheimer's disease.

Abstract

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)

• Authors: C J Ladner, G G Celesia, D J Magnuson, J M Lee
• Journal: Journal of neuropathology and experimental neurology (J Neuropathol Exp Neurol) Vol. 54 Issue 6 Pg. 783-9 (Nov 1995) ISSN: 0022-3069 [Print] England
• PMID: 7595651 (Publication Type: Journal Article)

Chemical References

• Receptors, Muscarinic
• Pirenzepine
• Carbachol
• GTP-Binding Proteins

Topics

• Aged
• Alzheimer Disease (metabolism)
• Binding Sites
• Brain (metabolism)
• Carbachol (pharmacology)
• Frontal Lobe (metabolism)
• GTP-Binding Proteins (metabolism)
• Humans
• Pirenzepine (pharmacology)
• Receptors, Muscarinic (metabolism)
• Visual Cortex (metabolism)