Neuromuscular junction interactions

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. 

Xu et al. [5] described the effect of (z>)-penicillamine on the binding of several antiacetylcholine receptor monoclonal antibodies to the Torpedo acetylcholine receptor. Penicillamine is covalently incorporated into the acetylcholine receptor through SS exchange at the cysteine residues of the a-subunit, altering the antigenic structure of the receptor. This effect on the structure of the native receptor at the neuromuscular junction may be responsible for the establishment of the autoimmune response to the acetylcholine receptor in (i))-penicillamine-induced myasthenia gravis. Cysteine and penicillamine interact to form penicillamine-cysteine mixed disulfide complexes [6] ... 

Brailoiu, E., Patel, S. and Dun, N. J. Modulation of spontaneous transmitter release from the frog neuromuscular junction by interacting intracellular Ca2+ stores critical role for nicotinic acid-adenine dinucleotide phosphate (NAADP). Biochem. J. 373 313-318, 2003. 

Perhaps the most prominent and well-studied class of synthetic poisons are so-called cholinesterase inhibitors. Cholinesterases are important enzymes that act on compounds involved in nerve impulse transmission - the neurotransmitters (see the later section on neurotoxicity for more details). A compound called acetylcholine is one such neurotransmitter, and its concentration at certain junctions in the nervous system, and between the nervous system and the muscles, is controlled by the enzyme acetylcholinesterase the enzyme causes its conversion, by hydrolysis, to inactive products. Any chemical that can interact with acetylcholinesterase and inhibit its enzymatic activity can cause the level of acetylcholine at these critical junctions to increase, and lead to excessive neurological stimulation at these cholinergic junctions. Typical early symptoms of cholinergic poisoning are bradycardia (slowing of heart rate), diarrhea, excessive urination, lacrimation, and salivation (all symptoms of an effect on the parasympathetic nervous system). When overstimulation occurs at the so-called neuromuscular junctions the results are tremors and, at sufficiently high doses, paralysis and death. 

Acetylcholine release. Policosanol produced some interactions in the modulation of the acetylcholine (ACh) release at the mouse neuromuscular junction. Policosanol enhanced to a small extent either the spontaneous or the evoked ACh release. An increase in the rate of the conformational change induced at the nicotinic receptor-channel complex by ACh was also observed L... 

Inhaled (volatile) anesthetics potentiate the neuromuscular blockade produced by nondepolarizing muscle relaxants in a dose-dependent fashion. Of the general anesthetics that have been studied, inhaled anesthetics augment the effects of muscle relaxants in the following order isoflurane (most) sevoflurane, desflurane, enflurane, and halothane and nitrous oxide (least) (Figure 27-9). The most important factors involved in this interaction are the following (1) nervous system depression at sites proximal to the neuromuscular junction (ie, central nervous system) (2) increased muscle blood flow (ie, due to peripheral vasodilation produced by volatile anesthetics), which allows a larger fraction of the injected muscle relaxant to reach the neuromuscular junction and (3) decreased sensitivity of the postjunctional membrane to depolarization. 

Acetylcholine released by an excited neuron diffuses a few micrometers across the synaptic cleft or neuromuscular junction to the postsynaptic neuron or myocyte, where it interacts with the acetylcholine receptor and triggers electrical excitation (depolarization) of the receiving cell. The acetylcholine receptor is an allosteric protein with two high-affinity binding sites for acetylcholine, about 3.0 nm from the ion gate, on the two a... 

Syncoilin is highly expressed in skeletal and cardiac muscle and is localized to the neuromuscular junction, sarcolemma, and Z-lines. Likewise, desmuslin is expressed in heart and skeletal muscle and localized at Z-lines. It was shown that syncoilin and desmin interact directly, but do not coassemble into filaments in fact, evidence suggests that syncoilin does not participate in filament formation at all. It was proposed that syncoilin helps anchor the desmin IF network at the sarcolemma and the neuromuscular junction (Poon et al, 2002). More recent work has analyzed patients with a desmin-related cardiomyopathy in which patients with desmin accumulation also exhibit an upregulation of syncoilin and accumulation of other elements of the DPC. These defects were correlated with a disappearance of both o-dystrobrevin-l and neuronal nitric oxide... 

Raciborska DA, Charlton MP (1999) Retention of cleaved synaptosome-associated protein of 25 kDa (SNAP-25) in neuromuscular junctions a new hypothesis to explain persistence of botulinum A poisoning. Can J Physiol Pharmacol 77 679-88 Raciborska DA, Trimble WS, Charlton MP (1998) Presynaptic protein interactions in vivo evidence from botulinum A, C, D and E action at frog neuromuscular junction. Eur J Neurosci 10 2617-28... 

Matsuo S, Rao DB, Chaudry I, Foldes FF. Interaction of muscle relaxants and local anesthetics at the neuromuscular junction. Anesth Analg 1978 57(5) 580-7. 

Central nervous system and neuromuscular junction. A remarkable number of alkaloids interfere with the metabolism and activity of neurotransmitters in the brain and nerve cells, a fact known to man for a thousand years (Table IV). The cellular interactions have been discussed above. Disturbance of neurotransmitter metabolism impairs sensory faculties, smell, vision, or hearing, or they may produce euphoric or hallucinogenic effects. 

AH of the nerve agents under consideration are anticholinesterase compounds and induce accumulation of the neurotransmitter acetylcholine (ACh) at neural synapses and neuromuscular junctions by phosphorylating acetylcholinesterase (AChE). Depending on the route of exposure and amount absorbed, the PNS and/or CNS can be affected and muscarinic and/or nicotinic receptors may be stimulated. Interaction with other esterases may also occur, and direct effects to the nervous system have been observed. 

Marshall IG. Pharmacological effects of neuromuscular blocking agents interaction with choUnoceptors other than nicotinic receptors of the neuromuscular junction. Anest Rianim 1986 27 19. 

Marshall IG, Henderson F. Drug interactions at the neuromuscular junction. Clin Anaesthesiol 1985 3 261. 

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