Muscarinic ACh receptor

The muscarinic ACh receptors (of which there are at least five subtypes) are metabotropic. Their name is derived from the alkaloid muscarine, which is found in the fly agaric mushroom (Amanita muscaria), for example. Like ACh, muscarine is bound at the receptor, but in contrast to ACh (see C), it is not broken down and therefore causes permanent stimulation of muscle. 

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). 

Muscarinic ACh receptors, which mediate their atropine-like effects... 

Succinylcholine Agonist at nicotinic acetylcholine (ACh) receptors, especially at neuromuscular junctions depolarizes may stimulate ganglionic nicotinic ACh and cardiac muscarinic ACh receptors Initial depolarization causes transient contractions, followed by prolonged flaccid paralysis depolarization is then followed by repolarization that is also accompanied by paralysis Placement of tracheal tube at start of anesthetic procedure t rarely, control of muscle contractions in status epilepticus Rapid metabolism by plasma cholinesterase normal duration, 5 min Toxicities Arrhythmias hyperkalemia transient increased intraabdominal, intraocular pressure postoperative muscle pain... 

Miyamoto, T., Nojima, H., Nakahashi, T., and Kuraishi, Y. Involvement of cutaneous ACh and M3 muscarinic ACH receptors in dry skin-associated pruritus in mice, in Proceedings of the Second International Workshop for the Study of Itch, Toyoma, Japan, (2003), p. 61. 

Earlier studies with /-tubocurarine and atropine indicated that nicotinic and muscarinic ACh receptor blockers can modulate the release of ACh induced by an inhibitor of AChE (Carlson and Dettbam, 1987, 1988). The effects of these dmgs, whether inhibiting or stimulating ACh release, are concentration dependent and determined by the frequency of nerve activity (Bowman, 1980 Wessler et al, 1987a, b). Therefore, dmgs that reduce axonal hyperexcitability by decreasing amount of ACh released from the nerve terminals without interfering with normal transmission... 

Existing treatment protocols emphasize three complementary approaches antagonize the muscarinic ACh receptor, reactivate endogenous AChE with oxime therapy, and manage the severe toxicity symptomatically (Lee, 2003). Atropine is the dmg of choice for mitigating the synaptic ACh accumulation, and is titrated until the patient... 

Of the five known classes of muscarinic ACh receptors, M-current is preferentially inhibited by m 1 or m3 subtypes (515,516). Experiments with mice lacking the m 1 receptor exhibit a loss of muscarinic regulation of M-current and are resistant to pilocarpine-induced seizures (517). Recently, specific anti-sense plasmids have been used to strongly suggest the G-protein as the primary transducer of muscarinic inhibition of /rcm) (518). 

The toxicity of nerve agents may include direct action on nicotinic as well as muscarinic ACh receptors when their concentration in circulation rises above micromolar levels. At nanomolar levels, their toxicity is the result mainly of their inhibition of AChE. However, at these low concentrations, many OP agents (e.g., soman and VX) may directly affect a small population of muscarinic ACh receptors that have a high affinity for [ H]-cis-methyldioxalane binding. Aas ° demonstrated... 

Stimulation or inhibition of autonomic effector cells by ACh results from interaction of ACh with muscarinic ACh receptors. In this case, the effector is coupled to the receptor by a G protein (see Chapter 1). In contrast to skeletal muscle and neurons, smooth muscle and the cardiac conduction system (sinoatrial [SA] node, atrium, atrioventricular [AV] node, and the His-Purkinje system) normally exhibit intrinsic activity, both electrical and mechanical, that is modulated but not initiated by nerve impulses. At some smooth muscle, ACh causes a decrease in the resting potential (i.e., the membrane potential becomes less negative) and an increase in the frequency of spike production, accompanied by a rise in tension. A primary action of ACh in initiating these effects through muscarinic receptors is probably partial depolarization of the cell membrane brought about by an increase in Na and, in some instances, Ca conductance activation of muscarinic receptors can also activate the G -PLC-IP pathway leading to the mobilization of stored Ccf. Hence, ACh stimulates ion fluxes across membranes and/or mobilizes intracellular Ca to cause contraction. 

In mammals, five distinct subtypes of muscarinic ACh receptors (mAChRs) have been identified, each produced by a different gene. Like the different forms of nicotinic receptors, these variants have distinct anatomical locations in the periphery and CNS and differing chemical specificities. 

The foregoing account is of the nicotinic variety of ACh receptor from the voluntary neuromuscular junction. This work has been extended by isolation of the muscarinic ACh receptor from ox brain by extraction with sodium cholate. Nicotinic and muscarinic are defined at the beginning of Section 12.6. The brain receptor was characterized by its intense power to bind the specific muscarinic antagonist, pHjatropine, with the high inhibitory constant of 2x10 . This label can be displaced by unlabelled atropine, and also by ACh and its agonists (Carson etal.., 1977 Carson, 1982). 

Autoradiographic studies of the cat (45) and rabbit carotid body (45-47) showed that glomus cells contain not only nAChRs, but also muscarinic ACh receptors (mAChRs). Physiological studies suggested that the Ml and M2 mAChRs ean alter... 

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