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

G Protein-Coupled Receptors (GPCRs) in Alzheimer’s Disease: A Focus on BACE1 Related GPCRs

“…M 1 , M 3 and M 5 mAChRs can activate phospholipase C (PLC) and mobilize intracellular calcium through G q/11 , which is critical in neuronal communication and synaptic plasticity. While M 2 and M 4 mAChRs are coupled to G i and then inhibit adenylate cyclase activity (Langmead et al, 2008 ) as well as several ion channels such as N-methyl-D-aspartate receptor (NMDAR; Salter and Kalia, 2004 ) and calcium channels (Zhou et al, 2008 ), leading to the reduction of cyclic adenosine monophosphate (cAMP), the inhibition of voltage-gated Ca 2+ channels, and the increasing efflux of K + , in general, leading to inhibitory effects (Odagaki et al, 2014 ). mAChRs and ligand-gated ion channel nicotinic (nAChR) together can mediate the actions of acetylcholine (ACh).…”

Comparative analysis of pharmacological properties of xanomeline and N-desmethylclozapine in rat brain membranes

“…In our previous report, it has been clarified that mAChR-stimulated [ 35 S]GTPγS binding determined by the conventional filtration assay is mediated by M 2 /M 4 mAChRs. Detailed pharmacological investigations using a series of mAChR agonists and antagonists, muscarinic toxins, and allosteric modulators, have indicated that M 4 mAChR subtype is most likely involved in the stimulatory effects of carbachol on [ 35 S]GTPγS binding to Gα i/o (Odagaki et al, 2014a). Furthermore, the response induced by acetylcholine or carbachol was highest in striatum as compared with the other two brain regions (Odagaki et al, 2014a).…”

“…Detailed pharmacological investigations using a series of mAChR agonists and antagonists, muscarinic toxins, and allosteric modulators, have indicated that M 4 mAChR subtype is most likely involved in the stimulatory effects of carbachol on [ 35 S]GTPγS binding to Gα i/o (Odagaki et al, 2014a). Furthermore, the response induced by acetylcholine or carbachol was highest in striatum as compared with the other two brain regions (Odagaki et al, 2014a). Therefore, the data in the present study are likely interpreted to indicate that N -desmethylclozapine exhibits agonistic effects at native M 4 mAChR in rat brain membranes, at least in striatum.…”

“…In our recent studies on mAChR-mediated guanosine-5′- O -(3-[ 35 S]thio)triphosphate ([ 35 S]GTPγS) binding to rat brain membranes (Odagaki et al, 2013a, 2014a), we included both xanomeline and N -desmethylclozapine as a stimulant. In the study using [ 35 S]GTPγS binding assay with conventional filtration technique (Odagaki et al, 2014a), we reported that both compounds stimulated specific [ 35 S]GTPγS binding to G i/o proteins in a concentration-dependent manner in all three brain regions investigated—that is, cerebral cortex, hippocampus, and striatum. However, the pharmacological properties of the stimulatory effects of these compounds have not been investigated.…”

Structure–activity relationship of pyrazol-4-yl-pyridine derivatives and identification of a radiofluorinated probe for imaging the muscarinic acetylcholine receptor M4

“…Previous studies revealed that muscarinic M 4 receptors are markedly expressed in the mammalian brain, with high abundancies in the striatum, thalamus and cortex 15 , 16 , 17 , 18 . Notably, considerable species differences have been described for the localization and structure of M 4 7 , 19 , 20 , 21 , explaining the variability of binding affinities for some synthetic M 4 ligands across different species 22 , 24 . Strenuous drug development efforts prompted the discovery of several M 4 agonists, however, due to the high degree of structural homology among the orthosteric site of the different mAChR subtypes, the identification of an orthosteric M 4 -selective ligand has proven challenging 23 , 24 , 25 , 26 .…”