Neurotransmitters cholinergic junction

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 is a neurotransmitter at the neuromuscular junction in autonomic ganglia and at postgangHonic parasympathetic nerve endings (see Neuroregulators). In the CNS, the motor-neuron collaterals to the Renshaw cells are cholinergic (43). In the rat brain, acetylcholine occurs in high concentrations in the interpeduncular and caudate nuclei (44). The LD q (subcutaneous) of the chloride in rats is 250 mg/kg. 

Acetylcholine serves as a neurotransmitter. Removal of acetylcholine within the time limits of the synaptic transmission is accomplished by acetylcholinesterase (AChE). The time required for hydrolysis of acetylcholine at the neuromuscular junction is less than a millisecond (turnover time is 150 ps) such that one molecule of AChE can hydrolyze 6 105 acetylcholine molecules per minute. The Km of AChE for acetylcholine is approximately 50-100 pM. AChE is one of the most efficient enzymes known. It works at a rate close to catalytic perfection where substrate diffusion becomes rate limiting. AChE is expressed in cholinergic neurons and muscle cells where it is found attached to the outer surface of the cell membrane. 

The primary mechanism used by cholinergic synapses is enzymatic degradation. Acetylcholinesterase hydrolyzes acetylcholine to its components choline and acetate it is one of the fastest acting enzymes in the body and acetylcholine removal occurs in less than 1 msec. The most important mechanism for removal of norepinephrine from the neuroeffector junction is the reuptake of this neurotransmitter into the sympathetic neuron that released it. Norepinephrine may then be metabolized intraneuronally by monoamine oxidase (MAO). The circulating catecholamines — epinephrine and norepinephrine — are inactivated by catechol-O-methyltransferase (COMT) in the liver. 

Botulinum exotoxin impedes release of neurotransmitter vesicles from cholinergic terminals at neuromuscular junctions. Botulinum exotoxin is ingested with food or, in infants, synthesized in situ by anaerobic bacteria that colonize the gut. A characteristic feature of botulinum paralysis is that the maximal force of muscle contraction increases when motor nerve electrical stimulation is repeated at low frequency, a phenomenon attributable to the recruitment of additional cholinergic vesicles with repetitive depolarization of neuromuscular presynaptic terminals. Local administration of Clostridium botulinum exotoxin is now in vogue for its cosmetic effects and is used for relief of spasticity in dystonia and cerebral palsy [21]. 

Acetylcholine (ACh) is an example of an endogenous neurotransmitter that binds to more than one receptor type, the nicotinic acetylcholine receptor (nAChR) which preferentially binds nicotine and the muscarinic receptor which binds muscarine, a mushroom alkaloid. The latter is a G protein-coupled receptor while the nACh receptor is an excitatory ligand-gated ion channel that transports Na-i- ions. Nicotinic cholinergic receptors are found in the CNS, autonomic ganglia, and at the neuromuscular junction of skeletal muscles. They are a possible target for anaesthetics. 

For almost one century, acetylcholine has been recognized as a neurotransmitter both in the central nervous system and the peripheral nervous system. In the peripheral nervous system, acetylcholine has been identified as the neurotransmitter of autonomic ganglia and the neuromuscular junction. Acetylcholine is involved in different peripheral functions such as heart rate, blood flow, gastrointestinal tract motility, and sweat production and smooth muscle activity. In the CNS, cholinergic neurotransmission plays a crucial role in a variety of CNS functions including sensory perception, motor function, cognitive processing, memory, arousal, attention, sleep, nociception, motivation, reward, mood, and psychosis. 

Aldridge and Reiner 1972). The A esterases have a serine catalytic site. The tertiary structure and amino acid sequences of several AChEs and BuChEs have been established (Taylor 1994). AChEs regulate excitation at cholinergic synapses, destroying the neurotransmitter ACh. AChE is one of the most active enzymes known, cycling within a few milliseconds (Taylor 1996). AChEs are found at synapses and neuromuscular junctions, and in central-nervous-system (CNS) neuron cell bodies, axons, muscles, red blood cells (RBCs), and platelets of ovine and rodent species (Silver 1974 Traina and Serpietri 1984 Hoffmann et al. 1989). 

Many of the physiological effects of anti-ChEs are attributable to excess neurotransmitter ACh (Taylor 1996). The precise symptoms and the time course depend on the chemicals and the localization of the receptors affected. Early symptoms of cholinergic poisoning represent stimulation of muscarinic neuro-effectors of the parasympathetic system. Effects include slowing of the heart (bradycardia), constriction of the pupil of the eye, diarrhea, urination, lacrimation, and salivation. Actions at nicotinic skeletal neuromuscular junctions (motor end plates) result in muscle fasciculation (disorganized twitching) and, at higher doses. 

Botulinum toxin is one of several toxins produced by the bacterium Clostridium botulinum. The toxin binds with high affinity to peripheral cholinergic nerve endings, such as those at the neuromuscular junction and in the autonomic nervous system, preventing the release of the neurotransmitter acetylcholine (1). This action at the neuromuscular junction can cause weakness and even paralysis of the muscles supplied by the affected nerves. Sprouting of the terminal nerves eventually results in re-innervation of the muscles and return of function. Doses are measured in mouse units (MU), IMU being the LD50 in Swiss-Webster mice. 

Acetylcholine is the endogenous neurotransmitter at cholinergic synapses and neuroeffector junctions in the central and peripheral nervous systems. The actions of acetylcholine are mediated through nicotinic and muscarinic cholinergic receptors, which transduce signals via distinct mechanisms. 

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