Attenuation of muscarinic receptor-G-protein interaction in Alzheimer disease

Abstract

Cortical M1 muscarinic receptor-G-protein coupling, high-affinity, guanine nucleotide-sensitive agonist binding (Flynn et al., 1991; Warpman et al., 1993) and muscarinic receptor-stimulated [3H]PIP2 hydrolysis (Ferrari-DiLeo and Flynn, 1993) are known to be defective in Alzheimer disease. Whether this defect reflects an alteration in the M1 muscarinic receptor, its respective guanine nucleotide binding (G) protein or both is not known. This study compares the number and both basal and muscarinic receptor-mediated function of G-proteins in synaptosomal membranes from cerebral cortical samples of age-matched control subjects and Alzheimer disease patients. Immunoblotting with anti-G alpha q/11 and anti-G beta antibodies demonstrated no alteration in the number of these G-protein subunits in Alzheimer disease. Basal [35S]GTP gamma S binding and hydrolysis of [gamma-32P]GTP by high-affinity GTPase also were not significantly altered in Alzheimer disease compared to control membrane samples. However, muscarinic agonist-stimulated GTP gamma S binding and GTP hydrolysis were significantly reduced (80-100%) in Alzheimer disease cortical samples. Diminished agonist-stimulated GTP gamma S binding and GTP hydrolysis correlated with the loss of guanine nucleotide-sensitive, high-affinity agonist binding (KL/KH) ratio) to the M1 receptor subtype. These data provide further evidence for the loss of muscarinic receptor-G protein coupling in Alzheimer disease and support the hypothesis that muscarinic receptor-mediated cortical activation may be compromised in Alzheimer disease.

Sympathetic Sprouting Drives Hippocampal Cholinergic Reinnervation That Prevents Loss of a Muscarinic Receptor-Dependent Long-Term Depression at CA3–CA1 Synapses

“…In hippocampus, several studies show that M 1 receptor-Gq coupling and subsequent PI turnover is compromised in humans with AD and in animal models after loss of cholinergic innervation (Pearce and Potter, 1991;Ferrari-DiLeo and Flynn, 1993;Ferrari-DiLeo et al, 1995;Ladner et al, 1995;Ladner and Lee, 1998;Potter et al, 1999Potter et al, , 2002Muma et al, 2003;Kelly et al, 2005). However, in cortex, muscarinic stimulation of PI turnover after lesion of the cholinergic basal forebrain is much less affected (Rossner et al, 1995), which could result from activity of cholinergic interneurons in cortex that maintains receptor coupling.…”

Functional Activation of G-Proteins Coupled With Muscarinic Acetylcholine Receptors in Rat Brain Membranes

“…of the indicated number of separate experiments, each performed in duplicate. The concentration-dependent increases in specific [ 35 S]GTPgS binding by CCh and ACh were expressed as the percentage increase over the basal unstimulated value and analyzed using a nonlinear regression method with GraphPad Prism (GraphPad Software; La Jolla, CA, USA), to produce the concentration eliciting the half-maximal effect (EC 50 ) and the maximal percentage increase (%E max ). In the case of other mAChR agonists, the increases in specific […”

“…The inhibition curve for mAChR antagonists against 100 mM CCh was also analyzed by a nonlinear regression method, with the basal and the CCh-stimulated binding regarded as 0% and 100%, respectively, to generate the concentration that inhibited the binding to 50% (IC 50 ).…”

Heterotrimeric G Proteins: Insights into the Neurobiology of Mood Disorders

“…This possibility was first raised in a study where GTP binding to brain membranes was performed in rat chronically treated with lithium [7]. Several works have been published showing alterations in heterotrimeric G proteins in both psychiatric [10,51,83,115], and neurodegenerative [22,[36][37][38]55,70,108,180] disorders. In this regard, the possible role of heterotrimeric G proteins in the pathophysiology of mood disorders, as well as the G protein signaling cascade as a molecular target for antidepressant therapy, has been mainly studied in three research lines: effects of antidepressant treatments in animal models, studies in peripheral tissue of depressive patients, and studies in postmortem human brain of suicide victims with mood disorders.…”