Acetylcholine receptors in skeletal muscle

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... 

Myasthenia gravis is a disease of autoimmunity caused by the production of an antibody directed against the acetylcholine receptor in skeletal muscle. In this disease, B and T lymphocytes cooperate in producing a variety of antibodies against the nicotinic acetylcholine receptor. The antibodies then bind to various locations in the receptor and cross-link the receptors, forming a multireceptor antibody complex. The complex is endocytosed and incorporated into lyso-somes, where it is degraded. Mya Sthenia, therefore, has fewer functional receptors for acetylcholine to activate. 

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. 

Acetylcholine and agents acting at the autonomic ganglia or the neuromuscular junctions interact with nicotinic cholinergic receptors to initiate the end plate potential in muscle or an excitatory postsynaptical potential in nerve. The nicotinic receptor in skeletal muscle is a pentamer composed of four distinct subunits. 

The acetylcholine receptor from skeletal muscle is a pen-tameric protein with a subunit composition of a2P78. The a, (3, y, and 8 subunits have considerable sequence homology on average, about 35-40 percent of the residues in any two subunits are similar. The complete receptor has fivefold symmetry, and the actual cation channel is a tapered central pore lined by homologous segments from each of the five subunits (Figure 7-45). 

The ensuing discussion will deal with that major category of receptors that are essentially components of cellular membranes. For example, the acetylcholine receptor involving skeletal muscles exerts its effect at the end of the motor nerve and its junction with the muscle (neuromuscular junction, see Chapter 7) by a depolarizing action. The fact that receptors are embedded in muscle cell membranes can be surmised by the fact that the contractile effect can be initiated by simply applying acetylcholine to the surface of the muscle preparation intracellular injection of the agonist produces no effect. A more interesting... 

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... 

Csillik B, Nemcsok J, Chase B, et al. Infraterminal spreading and extrajunctional expression of nicotinic acetylcholine receptors in denervated rat skeletal muscle. Exp Brain Res. 1999 125 426-434. 

The effects of curare develop rapidly after it enters the body. Victims develop rapid weakness of voluntary muscles followed by paralysis, respiratory failure, and death. The cause is a blockade of nicotinic cholinergic receptors at the neuromuscular junctions in skeletal muscle. Unlike botulinum toxin, release of acetylcholine by the cholinergic nerve terminals is not affected. When curare is present, however, the acetylcholine that is released cannot bind to the receptors because they are reversibly occupied by the curare. As a consequence, nerve-muscle communication fails and paralysis ensues. 

Nicotiana tabacum, and lobeline, present in the dried leaves and tops of the herb, Lobelia inflata (13). Both nicotine and lobeline act as agonists on a specific type of acetylcholine receptor, the nicotinic cholinergic receptor. In mammals, nicotinic cholinergic receptors mediate cholinergic neurotransmission in skeletal muscles, autonomic ganglia, and the central nervous system. At these sites nicotine s action has two phases, excitation and depression. Insect central nervous tissues are rich in nicotinic cholinergic receptors (cf. 14), but their role in behavior is not well understood. 

Brett RS, Schmidt JH, Gage JS, Schartel SA, Poppers PJ. Measurement of acetylcholine receptor concentration in skeletal muscle from a patient with multiple sclerosis and resistance to atracurium. Anesthesiology 1987 66(6) 837-9. 

Anticholinesterase insecticides phosphorylate the active site of cholinesterase in all parts of the body. Inhibition of this enzyme leads to accumulation of acetylcholine at affected receptors and results in widespread toxicity. Acetylcholine is the neurohormone responsible for physiologic transmission of nerve impulses from preganglionic and postganglionic neurons of the cholinergic (parasympathetic) nervous system, preganglionic adrenergic (sympathetic) neurons, the neuromuscular junction in skeletal muscles, and multiple nerve endings in the central nervous system (Fig. 10-5). 

Fig. 47.3. Events leading to sarcoplasmic reticulum calcium release in skeletal muscle. 1. Acetylcholine, released at the synaptic cleft, binds to acetylcholine receptors on the sar-colemma, leading to a change of conformation of the receptors such that they now act as an ion pore. This allows sodium to enter the cell and potassium to leave. 2. The membrane polarization that results from these ion movements is transmitted throughout the muscle fiber by the T-tubule system. 3. A receptor in the T-tubules (the dihydropyridine receptor, DHPR) is activated by membrane polarization (a voltage-gated activation) such that activated DHPR physically binds to and activates the ryanodine receptor in the sarcoplasmic reticulum (depolarization-induced calcium release). 4. The activation of the ryanodine receptor, which is a calcium channel, leads to calcium release from the SR into the sarcoplasm. In cardiac muscle, activation of DHPR leads to calcium release from the T-tubules, and this small calcium release is responsible for the activation of the cardiac ryanodine receptor (calcium-induced calcium release) to release large amounts of calcium into the sarcoplasm.

List the locations and types of acetylcholine receptors in the major organ systems (CNS, autonomic ganglia, eye, heart, vessels, bronchi, gut, genitourinary tract, skeletal muscle, exocrine glands). 

EXAMPLE 6.8 The nicotinic acetylcholine receptor is a ligand-gated ion channel. This receptor is located in skeletal muscle cells at the synapses between them and motor neurons. The neurotransmitter acetylcholine that is released from the motor neuron binds to the receptor, leading to opening of its ion channels. This allows an influx of Na+ ions into the muscle cell. In turn this leads to the release of Ci ions from their intracellular store, the sarcoplasmic reticulum, into the cytosol the resulting rise in cytosolic Ca + concentration induces muscle contraction. 

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)... 

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