Muscarinic M4 receptor

Zeng XP, Le F, Richelson E. 1997. Muscarinic m4 receptor activation by some atypical antipsychotic drugs. Eur J Pharmacol 321 349-354. 

Zorn SH, Jones SB, Ward KM, Liston DR. 1994. Clozapine is a potent and selective muscarinic M4 receptor agonist. Eur J Pharmacol 269 R1-R2. 

EEG slow waves. The differential EEG and ACh responses to dialysis delivery of AF-DX 116 (M2/M4) versus pirenzepine (M1/M4) supports the conclusion that, in B6 mouse, postsynaptic muscarinic receptors of the Ml subtype form one receptor mechanism by which ACh activates the EEG (Douglas et al, 2002a). The data summarized in Fig. 5.11 provide direct measures of G protein activation in basal forebrain and prefrontal cortex by muscarinic cholinergic receptors (DeMarco et al, 2004). The in vitro data of Fig. 5.11A indicate the presence of functional muscarinic receptors in regions of B6 mouse prefrontal cortex where in vivo microdialysis studies (Douglas et al, 2002a, b) revealed modulation of ACh release and EEG by pre- and postsynaptic muscarinic receptors (Figs. 5.9 and 5.10). 

Both nicotinic and muscarinic receptors are widespread in the CNS. Muscarinic receptors with a high affinity for pirenzepine (PZ), M, receptors, predominate in the hippocampus and cerebral cortex, whereas M2 receptors predominate in the cerebellum and brainstem, and M4 receptors are most abundant in the striatum. Central muscarinic and nicotinic receptors are targets of intense pharmacological interest for their potential roles in regulating abnormal neurological signaling in Alzheimer s disease, Parkinson s disease and certain seizure disorders. Nicotinic receptors are largely localized at prejunctional sites and control the release of neurotransmitters [10,11],... 

Both the M2 and M4 receptors are, as indicated above, coupled to Gj pathways and appear to mediate similar responses. The M2 receptor is widely expressed in the CNS but also present in heart and smooth muscle, while M4 is preferentially expressed in the CNS, especially in forebrain. Ablation of the M2 receptor leads to complete loss of muscarinic-agonist-stimulated bradycardia [55]. In the CNS, deletion of the M2 receptor abolishes oxotremorine induced akinesia and tremors [56]. Memory and learning tasks including passive avoidance and working memory are impaired in M2-receptor knockout mice, and there is decreased LTP in hippocampal slices [12],... 

Muscarinic and dopaminergic pathways in the CNS interact in control of numerous pathways implicated in diseases, especially those controlling involuntary motor systems. Muscarinic effects on dopamine release are mediated in several ways via different mAChR subtypes. Thus mAChR facilitation of DA release appears to involve M4 receptors on GABA projection neurons to the striatum, while M3 receptors on striatal DA neurons are predicted to inhibit striatal DA release [12],... 

Stengel, R W., Gomeza, J., Wess, J. and Cohen, M. L. M2 and M4 receptor knockout mice muscarinic receptor function in cardiac and smooth muscle in vitro. /. Pharmacol. Exp. Ther. 292 877-85, 2000. 

To date, five subtypes of these receptors have been cloned. However, initial studies relied on the pharmacological effects of the muscarinic antagonist pirenzepine which was shown to block the effect of several muscarinic agonists. These receptors were termed Mi receptors to distinguish them from those receptors for which pirenzepine had only a low affinity and therefore failed to block the pharmacological response. These were termed M2 receptors. More recently, M3, M4 and M5 receptors have been identified which, like the Mi and M2 receptors occur in the brain. Recent studies have shown that Mi and M3 are located posts)maptically in the brain whereas the M2 and M4 receptors occur pres)maptically where they act as inhibitory autoreceptors that inhibit the release of acetylcholine. The M2 and M4 receptors are coupled to the inhibitory Gi protein which reduces the formation of cyclic adenosine monophosphate (cyclic AMP) within the neuron. By contrast, the Mi, M3 and M5 receptors are coupled to the stimulatory Gs protein which stimulates the intracellular hydrolysis of the phosphoinositide messenger within the neuron (see Figure 2.8). 

The muscarinic ACh receptors influence the cAMP level in the postsynaptic cells (Mi, M3 and Ms increase it, while subtypes M2 and M4 reduce it). 

E.M. Jagoda, D.O. Kiesewetter, K. Shimoji, L. Ravasi, M. Yamada, J. Gomeza, J. Wess, W.C. Eckelman, Regional brain uptake of the muscarinic ligand, [ F]FP-TZTP, is greatly decreased in M2 receptor knockout mice but not in Ml, M3 and M4 receptor knockout mice. Neuropharmacology 44 (2003) 653-661. 

Shannon, H.E., Rasmussen, K., Bymaster, F.P., Hart, J.C., Peters, S.C., Swedberg, M.D.B., Jeppesen, L., Sheardown, M.J., Sauer-berg, P., and Fink-Jensen, A. (2000) Xanomeline, an M1/M4 preferring muscarinic cholinergic receptor agonist, produces antipsychotic-like activity in rats and mice. Schizophr Res 42 249-259. 

Muscarinic M4 CNS neurons possibly vagal nerve endings Like M2 receptor-ligand binding... 

Yamakawa, T., Ando, M. Koito, S., Ohwaki, K., Kimura, T., Saeki, T., Miyaji, M., Iwahori, Y., Fujikawa, T., Otake, N., Noguchi, K. (Banyu Pharmaceutical Co.) Preparation of substituted imidazolidinone derivatives as agonists of muscarinic acetylcholine receptor M4, W00127104 (2001). 

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