Skeletal muscles acetylcholine receptors

Red blood cell enzyme activity returns at the rate of red blood cell turnover, which is 1% per day. Tissue and plasma activities return with synthesis of new enzymes. The rates of return of these enzymes are not identical. However, the nerve agent can be removed from the enzymes. This removal is called reactivation, which can be accomplished therapeutically by the use of oximes prior to aging. Aging is the biochemical process by which the agent-enzyme complex becomes refractory to oxime reactivation. The toxicity of nerve agents may include direct action on nicotine acetylcholine receptors (skeletal muscle and ganglia) as well as on muscarinic acetylcholine receptors and the central nervous system. 

Acetylcholine receptor (skeletal muscle) CHRNAl Congenital myasthenic syndrome... 

Autoantibodies are directed against nicotinic acetylcholine receptors in myasthenia gravis, resulting in receptor loss, skeletal muscle paralysis, and dysfunction (100). In addition, antibodies directed against voltage-gated Ca " channels produce similar neuromuscular dysfunction of Lambert-Eaton... 

Nicotinic receptors (nicotinic acetylcholine receptors, nACHR) exist not only in the membrane of vertebrate skeletal muscle at the synapse between nerve and muscle (muscle-type nAChR) but also at various synapses throughout the brain, mainly at presynaptic positions (neuronal-type nAChR). Whereas the muscle-type nAChR is precisely composed of two a 1-subunits, one (3 -subunit, one y -subunit and one y -subunit (adult)... 

Another possible target for toxins are the receptors for neurotransmitters since such receptors are vital, especially for locomotion. In vertebrates the most strategic receptor is that for acetylcholine, the nicotinic receptor. In view of the breadth of action of the various conotoxins it is perhaps not surprising that alpha-conotoxin binds selectively to the nicotinic receptor. It is entirely possible that similar blockers exist for the receptors which are vital to locomotion in lower species. As mentioned previously, lophotoxin effects vertebrate neuromuscular junctions. It appears to act on the end plate region of skeletal muscle (79,59), to block the nicotinic receptor at a site different from the binding sites for other blockers (81). 

FIGURE 1.9 Records of the minute electrical currents (downward deflections) that flow through single ligandgated ion channels in the junctional region of frog skeletal muscle. The currents arise from brief transitions of individual nicotinic receptors to an active (channel open) state in response to the presence of various agonists (ACh = acetylcholine SubCh = suberyldicholine DecCh = the dicholine ester of decan-1,10-dicarboxylic acid CCh = carbamylcholine). (From Colquhoun, D. and Sakmann, B., J. Physiol., 369,501-557, 1985. With permission.)... 

Lingle, C. L., Maconochie, D., and Steinbach, J. H., Activation of skeletal muscle nicotinic acetylcholine receptors, J. Memb. Biol., 126, 195-217, 1992 (excellent review of much of the evidence concerning the mechanism of receptor activation). 

Stimulation of the motoneuron releases acetylcholine onto the muscle endplate and results in contraction of the muscle fiber. Contraction and associated electrical events can be produced by intra-arterial injection of ACh close to the muscle. Since skeletal muscle does not possess inherent myogenic tone, the tone of apparently resting muscle is maintained by spontaneous and intermittent release of ACh. The consequences of spontaneous release at the motor endplate of skeletal muscle are small depolarizations from the quantized release of ACh, termed miniature endplate potentials (MEPPs) [15] (seeCh. 10). Decay times for the MEPPs range between l and 2 ms, a duration similar to the mean channel open time seen with ACh stimulation of individual receptor molecules. Stimulation of the motoneuron results in the release of several hundred quanta of ACh. The summation of MEPPs gives rise to a postsynaptic excitatory potential (PSEP),... 

The effect of Li+ upon the synthesis and release of acetylcholine in the brain is equivocal Li+ is reported to both inhibit and stimulate the synthesis of acetylcholine (reviewed by Wood et al. [162]). Li+ appears to have no effect on acetyl cholinesterase, the enzyme which catalyzes the hydrolysis of acetylcholine [163]. It has also been observed that the number of acetylcholine receptors in skeletal muscle is decreased by Li+ [164]. In the erythrocytes of patients on Li+, the concentration of choline is at least 10-fold higher than normal and the transport of choline is reduced [165] the effect of Li+ on choline transport in other cells is not known. A Li+-induced inhibition of either choline transport and/or the synthesis of acetylcholine could be responsible for the observed accumulation of choline in erythrocytes. This choline is probably derived from membrane phosphatidylcholine which is reportedly decreased in patients on Li+ [166],... 

Fambrough DM (1979) Control of acetylcholine receptors in skeletal muscle. Physiol Rev 59 165-227... 

Carbachol is a powerful cholinic ester that stimulates both muscarinic and nicotinic receptors, as well as exhibits all of the pharmacological properties of acetylcholine while in addition resulting in vasodilation, a decrease in heart rate, an increase in tone and con-tractability of smooth muscle, stimulation of salivary, ocular, and sweat glands as well as autonomic ganglia and skeletal muscle. For this reason, use of carbachol, like acetylcholine, is limited. The exception is that it is used in ophthalmological practice and post-operational intestines and bladder atony. Upon administration in the eye, the pupil constricts and the intraocular pressure is reduced. It is used for severe chronic glaucoma. Synonyms of this drag are doryl and miostat. 

Beside this there are some major differences with the neurotransmission in the autonomous nervous system The contractile activity of the skeletal muscle is almost completely dependent on the innervation. There is no basal tone and a loss of the innervation is identical to a total loss in function of the particular skeletal muscle. In contrast to the target organs of the parasympathetic nervous system the skeletal muscle cells only have acetylcholine receptors at the site of the so-called end-plate, the connection between neuron and muscle cell with the rest of the cell surface being insensitive to the transmitter. The release of acetylcholine results in a postjunctional depolarization which is either above the threshold to induce an action potential and a contraction or below the threshold with no contractile response at all. In contrast to the graduated reactions of the parasympathetic target organs, this is an all or nothing transmission. 

The action of acetylcholine at the skeletal muscle motor end plate resembles that produced by nicotine. Thus, the choUnoreceptor on skeletal muscle is a nicotinic receptor. Based on antagonist selectivity, however, the autonomic and somatic nicotinic receptors are not pharmacologically identical (see Chapter 14). 

There is considerable diversity among nicotinic acetylcholine receptors, and at least one source of this diversity is the multiplicity of acetylcholine receptor genes. Cholinergic-nicotinic receptors in skeletal muscle are different from those in autonomic ganglia and the central nervous system. 

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