Acetylcholine Muscarinic M2 Receptor Stimulated [35S]GTPγS Binding Shows Regional Selective Changes in Alzheimer's Disease Postmortem Brain (original) (raw)

THE ACETYLCHOLINE MUSCARINIC receptor family consists of five different gene products that activate different signal transduction pathways via intermediate GTP binding 'G'-proteins. The m2 and m4 receptors are coupled via pertussis toxin-sensitive G-proteins to the inhibition of adenylyl cyclase activity (Peralta et al., 1988), whereas the m1, m3 and m5 receptors act via pertussis toxin-insensitive G-proteins to stimulate phospholipases C, D and A2 (Conklin et al., 1988; Peralta et al., 1988; Sandman et al., 1991). The m1, m2 and m3 gene products correspond, respectively, to the pharmacologically defined M1, M2 and M3 receptor types. The idea that disrupted acetylcholine muscarinic receptor-mediated signal transduction could limit the success of cholinergic replacement therapies for Alzheimer's disease dementia (Fowler et al., 1990; Flynn et al., 1991) has provided the impetus for a number of studies to determine the functional integrity of muscarinic receptors in this disorder. When investigating the effects of guanylylimidodiphosphate (Gpp[NH]p) on carbachol agonist displacement of [ 3 H]pirenzepine antagonist binding, Smith et al. and Flynn and colleagues found that the ability of putative muscarinic M1 receptors to form high affinity agonistreceptor complexes with G-proteins was impaired in Alzheimer's disease parietal (Smith et al., 1987) and pre-frontal (Flynn et al., 1991) cortices. Muscarinic receptor-G-protein interactions have also been suggested to be disrupted in Alzheimer's disease thalamus (Warpman et al., 1993), whereas others have