Phosphoinositides muscarinic receptors

The selectivity in muscarinic receptor coupling is not, however, absolute. Overexpression of receptors or of particular G proteins supports interactions that may differ from those described above. For example, M2 receptors expressed in Chinese hamster ovary cells not only inhibit adenylyl cyclase but also can stimulate phosphoinositide hydrolysis through a pertussis-toxin-sensitive G protein [52] this is not seen, however, when M2 receptors are expressed in Y1 cells. These findings indicate that caution must be exercised in interpreting data obtained when receptors are expressed, often at high levels, in cells in which they normally do not function. 

Ashkenazi, A., Winslow, J. W., Peralta, E. G. etal. An M2 muscarinic receptor subtype coupled to both adenylyl cyclase and phosphoinositide turnover. Science 238 672-675,1987. 

Balduini W, Cimino M, Reno F, Marini P, Princivalle A, Cattabeni F. Effects of postnatal or adult chronic acetylcholinesterase inhibition on muscarinic receptors, phosphoinositide turnover and ml mRNA expression. Eur J Pharm 1993 248 281-288. 

Bymaster FP, Carter PA, Yamada M, Gomeza J, Wess J, Hamilton SE, Nathanson NM, McKinzie DL, Felder CC (2003a) Role of specific muscarinic receptor subtypes in cholinergic parasympathomimetic responses, in vivo phosphoinositide hydrolysis, and pilocarpine-induced seizure activity. The Eur J Neurosci 17 1403-10... 

Each of the test compounds (168a-h) bound with high affinity to muscarinic receptors from rat brain. The 3-methyl homolog (168a) displayed high efficacy at muscarinic receptors coupled to phosphoinositide metab-... 

Only the 5-carbomethoxy isomer (169c) displayed high affinity and activity at muscarinic receptors coupled to phosphoinositide metabolism in rat cortex. Evaluation of other alkyl esters (170a-c) of the 5-carboxylic acid revealed that only the propargyl derivative (170c) retained substantial agonist activity. 

Tan, X.X., and Costa, L.G. Inhibition of muscarinic receptor-stimulated phosphoinositide metabolism by cocaine, norcocaine and eoeaethylene in rat brain. Develop Brain Res 79 132-135, 1994. 

Katz, L.S. and Marquis, J.K., Organophosphate-induced alterations in muscarinic receptor binding and phosphoinositide hydrolysis in the human SK-N-SH cell line. Neurotoxicology, 13, 365, 1992. 

Moscona-Amir, E., Henis, Y. I., and Sokolovsky, M., Aging of rat heat myocytes disrupts muscarinic receptor coupling that leads to inhibition of cAMP accumulation and alters the pathway of muscarinic-stimulated phosphoinositide hydolysis. Biochemistry 28, 7130 (1989). 

The muscarinic cholinergic system has quite a different mode of operation in that the receptor is connected to the final action by a chain of events. Thus its response is slower than the nicotinic, where the receptor and ion channel are closely connected. Five distinct muscarinic receptors have been identified in mammals, based on anatomical location, genetic analysis, function, and amino acid sequence. All of them have seven transmembrane domains [166, 167, 168, 169]. The N- terminal domain outside the cell binds acetylcholine or other ligands at a site that includes an aspartate residue, while the C-terminal domain inside the cell is coupled to a so-called G-protein , which is initially bound to guanosine diphosphate (GDP), but exchanges it for guanosine triphosphate (GTP) when activated by its transmitter. The activated G-protein then activates phospholipase C, which hydrolyzes phosphoinositides to release 1,4,5-inositol triphosphate [170]. The final action depends on which type of cell is involved so that in some types ion channels are opened just as with the nicotinic receptor, but in other cases other processes are affected, for example the release of dopamine [171]. Since there are these differences... 

Brown, J.H. and Goldstein, D. (1986) Differences in muscarinic receptor reserve for inhibition of adenylate cyslcase and stimulation of phosphoinositide hydrolysis in heart cells. Mol. Pharmacol. 30 566-570. 

B. Mechanism of Action The mechanism of action of lithium is not well defined. The drug inhibits the recycling of neuronal membrane phosphoinositides involved in the generation of inositol trisphosphate (IP3) and diacylglycerol (DAG). These second messengers are important in amine neurotransmission, including that mediated by central adrenoceptors and muscarinic receptors (Figure 29-2). 

Nicotinic and muscarinic effects are mediated by nicotinic and muscarinic receptors, respectively. These receptors are the products of two distinct gene super-families, and their only common prc eity is that bey are activated by A. The slower muscarinic receptor response operates via G-protein-coupled receptors (see G-proteins). Depending on the receptor subtype, the suteequent effector mechanism involves inhibition of adenylate cyclase, formation of inositol 1,4,5-(ruphosphate from phosphoinositides by a specific phospholipase C, or modulation (opening) of certain K channels [D. Brown Nature 319 (1986) 358-359]. 

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). 

Phosphoinositides were shown to turn over rapidly in brain and participate in many processes of neurotransmission. The phosphoinositide signaling system is involved in the activation of muscarinic acetylcholine receptors. Early... 

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