Receptor activity muscarinic

Anatoxin-a is the most potent and most stereospecific nicotinic acetylcholine receptor agonist thus far identified. It is also highly selective for nicotinic receptors over muscarinic receptors. The molecular parameters which influence the binding affinity, channel activation, channel blockade, and receptor desensitization are being studied. Modifications of the carbonyl and amine moieties can reduce or nearly eliminate the receptor agonist potency of the compounds and also determine the channel blocking characteristics. 

Many measurements in pharmacology rely on a chain of events following receptor activation to produce a measurable response — for example, contraction of the smooth muscle of a piece of guinea-pig ileum in response to muscarinic receptor activation by acetylcholine. This means that the relationship between receptor occupancy and response is likely to be complex, and mechanisms of drug action in such systems are often difficult to define. 

Douglas, C. L., Baghdoyan, H. A. Lydic, R. (2002a). Postsynaptic muscarinic Ml receptors activate prefrontal cortical EEG of C57BL/6J mouse. J. Neurophysiol. 88, 3003-9. 

The answer is d. (Hardman, pp 142—M3.) ACh will stimulate both muscarinic and nicotinic receptors. Skeletal muscle contraction is mediated through NM receptors, and ganglionic stimulation is an effect of NN receptors All of the other effects listed in the question occur following muscarinic receptor activation and will be blocked by atropine and scopolamine, both of which are muscarinic receptor antagonists. Skeletal muscle contraction will not be affected by these drugs rather, a neuromuscular blocker (e.g., tubocurarine) is required to antagonize this effect of ACh. 

Muscarinic receptor activation causes inhibition of adenylyl cyclase, stimulation of phospholipase C and regulation of ion channels 203... 

Muscarinic receptor activation causes inhibition of adenylyl cyclase, stimulation of phospholipase C and regulation of ion channels. Many types of neuron and effector cell respond to muscarinic receptor stimulation. Despite the diversity of responses that ensue, the initial event that follows ligand binding to the muscarinic receptor is, in all cases, the interaction of the receptor with a G protein. Depending on the nature of the G protein and the available effectors, the receptor-G-protein interaction can initiate any of several early biochemical events. Common responses elicited by muscarinic receptor occupation are inhibition of adenylyl cyclase, stimulation of phos-phoinositide hydrolysis and regulation of potassium or other ion channels [47] (Fig. 11-10). The particular receptor subtypes eliciting those responses are discussed below. (See also Chs 20 and 21.)... 

Fanelli, F., Menziani, M.C. and De Benedetti, P.G. (1995) Molecular dynamics simulations of m3-muscarinic receptor activation and QSAR analysis. Bioorganic el Medicinal Chemistry, 3, 1465-1477. 

Muscarinic Agonists. Another approach is to use a medication that directly activates subtypes of the acetylcholine receptors, namely, muscarinic receptor agonists. The muscarinic agonists used in the past have not been effective. This includes bethanecol, pilocarpine, and oxotremorine. This line of treatment, however, has not been entirely abandoned, and several medications are currently in testing. 

The TCAs have affinity for both receptors and transporters of monoamine transmitters and behave as antagonists in both respects. Thus, the neuronal reuptake of norepinephrine (p. 82) and serotonin (p. 116) is inhibited, with a resultant increase in activity. Muscarinic acetylcholine receptors, a-adrenocep-tors, and certain 5-HT and hista-mine(Hi) receptors are blocked. Interference with the dopamine system is relatively minor. 

Muscarinic receptor activation of cortical pyramidal cells occurs with a latency of around 250 msec (Taylor 8c Brown, 1999). There is also an approximate 500 msec time lag between the occurrence of a stimulus and consciousness of that stimulus (Libet et ah, 1991). Hence the typical delay associated with muscarinic action (and that of other metabotropic receptors) coincides with the time lag for stimuli reaching consciousness. Thus, cholinergic affer-ents to the cerebral cortex may contribute to 40 Hz activity, as well as to larger envelopes of activity (or inactivity) lasting 250-500 msec. 

Muscarinic receptor activation of an intradendritic site mediating conscious activity... 

Many different receptor types are coupled to G proteins, including receptors for norepinephrine and epinephrine (a- and p-adrenoceptors), 5-hydroxytrypta-mine (serotonin or 5-HT receptors), and muscarinic acetylcholine receptors. Figure 2.1 presents the structure of one of these, the uz-adrenoceptor from the human kidney. All members of this family of G protein-coupled receptors are characterized by having seven membrane-enclosed domains plus extracellular and intracellular loops. The specific binding sites for agonists occur at the extracellular surface, while the interaction with G proteins occurs with the intracellular portions of the receptor. The general term for any chain of events initiated by receptor activation is signal transduction. 

Classical studies by Sir Henry Dale demonstrated that the receptors activated by muscarine, an alkaloid isolated from the mushroom Amanita muscaria, are the same receptors activated by ACh released from parasympathetic nerve endings, from which the general notion that muscarinic agonists have parasympathomimetic properties was born. This conclusion is true but incomplete, and we now know that muscarinic receptors have a broader distribution and many functional roles. To understand the actions of cholinomimetic drugs it is essential to recognize that muscarinic receptors (1) mediate the activation of effectors by ACh released from parasympathetic nerve... 

All muscarinic receptors are members of the seven transmembrane domain, G protein-coupled receptors, and they are structurally and functionally unrelated to nicotinic ACh receptors. Activation of muscarinic receptors by an agonist triggers the release of an intracellular G-protein complex that can specifically activate one or more signal transduction pathways. Fortunately, the cellular responses elicited by odd- versus even-numbered receptor subtypes can be conveniently distinguished. Activation of Ml, M3, and M5 receptors produces an inosine triphosphate (IP3) mediated release of intracellular calcium, the release of diacylglyc-erol (which can activate protein kinase C), and stimulation of adenylyl cyclase. These receptors are primarily responsible for activating calcium-dependent responses, such as secretion by glands and the contraction of smooth muscle. 

H. C. HartzeU (1982). Physiological consequences of muscarinic receptor activation. In J. W. 

Stimulation of the parasympathetic nervous system modifies the organ functions by two main pathways. Firstly, the acetylcholine released from parasympathetic nerves can activate muscarinic receptors which are present in gland cells (sweat glands), smooth muscles and heart. The... 

The EOs reduced the contraction induced by acetylcholine, histamine [226-228, 210, 225, 232, 233], carbachol (muscarinic receptor activator) [237] and 5-hydroxytryptamine [229]. The EOs were found to relax intestinal smooth muscle by reducing the influx of Ca [227, 234], K+ [210, 224-226, 229, 230] and Ba [229, 237]. However, other reports have shown that lavender and geranium EOs were unlikely to act as cationic channel blockers [232]. The activities of the EOs resembled those of dicyclomine and atropine (muscarinic receptor antagonists) and dihydropyridine (calcium antagonist) by producing smooth-muscle relaxation [225, 236]. 

Bethanechol Receptors, parasympathetic effector cells (smooth muscle, glands) Binds and activates muscarinic receptors... 

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