Acetylcholine receptors overstimulation

Another important example is the nicotinic acetylcholine receptor, which is activated by the agonist nicotine causing muscular fibrillation and paralysis. Indirect effects can also occur. For example, organophosphates and other acetylcholinesterase inhibitors increase the amount of acetylcholine and thereby overstimulate the receptor, leading to effects in a number of sites (see chap. 7). Alternatively, botulinum toxin inhibits the release of acetylcholine and causes muscle paralysis because muscular contraction does not take place (see chap. 7). 

The mushroom was also known as fly agaric because of its ability to attract and kill flies. Flies also have muscarinic acetylcholine receptors on their neurons after they ingest parts of the mushroom, the overstimulation of these receptors is apparently sufficient to kill them. But even if they somehow survive that fate, they re likely still doomed because of the... 

Acephate exerts its toxicity by inhibiting the enzyme acetylcholinesterase in the synapse and neuromuscular junctions, which leads to accumulation of the neurotransmitter acetylcholine and overstimulation of postsynaptic receptors. 

The previous discussion of amino acid catabolic disorders indicates that catabolic processes are just as important for the proper functioning of cells and organisms as are anabolic processes. This is no less true for molecules that act as neurotransmitters. To maintain precise information transfer, neurotransmitters are usually quickly degraded or removed from the synaptic cleft. An extreme example of enzyme inhibition illustrates the importance of neurotransmitter degradation. Recall that acetylcholine is the neurotransmitter that initiates muscle contraction. Shortly afterwards, the action of acetylcholine is terminated by the enzyme acetylcholinesterase. (Acetylcholine must be destroyed rapidly so that muscle can relax before the next contraction.) Acetylcholinesterase is a serine esterase that hydrolyzes acetylcholine to acetate and choline. Serine esterases have catalytic mechanisms similar to those of the serine proteases (Section 6.4). Both types of enzymes are irreversibly inhibited by DFP (diisopropylfluorophosphate). Exposure to DFP causes muscle paralysis because acetylcholinesterase is irreversibly inhibited. With each nerve impulse, more acetylcholine molecules enter the neuromuscular synaptic cleft. The accumulating acetylcholine molecules repetitively bind to acetylcholine receptors. The overstimulated muscle cells soon become paralyzed (nonfunctional). Affected individuals suffocate because of paralyzed respiratory muscles. 

Atropine acts as an antagonist of acetylcholine at muscarinic receptors, but not at nicotinic receptors. By acting as an antagonist, it can prevent overstimulation of muscarinic receptors by the excessive quantities of acetylcholine remaining in the synaptic cleft when AChE is inhibited. The dose of atropine needs to be carefully controlled because it is toxic. 

Acetylcholinesterase is a component of the postsynaptic membrane of cholinergic synapses of the nervous system in both vertebrates and invertebrates. Its structure and function has been described in Chapter 10, Section 10.2.4. Its essential role in the postsynaptic membrane is hydrolysis of the neurotransmitter acetylcholine in order to terminate the stimulation of nicotinic and muscarinic receptors (Figure 16.2). Thus, inhibitors of the enzyme cause a buildup of acetylcholine in the synaptic cleft and consequent overstimulation of the receptors, leading to depolarization of the postsynaptic membrane and synaptic block. 

Neurotransmission can be blocked pharmacologically at the level of the neuromuscular junction either by an antagonist which competes with acetylcholine at the binding site without activating the receptor or by an agonist which induce an overstimulation of the receptor and thereby a blockade of the transmission. 

The mechanism of toxicity for parathion is similar to that of chlorpyrifos. Following activation to the potent anticholinesterase paraoxon, acetylcholinesterase is inhibited within synapses and acetylcholine levels accumulate. This leads to overstimulation of cholinergic receptors of neurons, muscle cells, and end-organs culminating in cholinergic toxicity. 

Organophosphate and carbonate pesticides act by inhibiting the enzyme acetylcholinesterase, which hydrolyzes acetylcholine, a neurotransmitter. This inhibition in the CNS or peripheral nervous system prolongs the action at the neuron s synaptic receptors and produces clinically measurable overstimulation symptoms that include muscle weakness, perspiration, tremor, blurred vision, and salivationJ6l More than 90 different organophosphate pesticides have been identified J7l... 

The function of acetylcholinesterase (AChE) is to degrade the neurotransmitter acetylcholine (ACh). "niere is general agreement that the acute toxicity of OP is explained by irreversible inhibition of AChE activity at cholinergic synapses (Chambers and Levi, 1992 McDonough and Shih, 1997 Mileson etal., 1998 Pope, 1999 Taylor, 2001 Casida and Quistad, 2004). Inhibition of AChE (>70%) leads to accumulation of ACh at central and peripheral sites. In the brain, overstimulation of ACh receptors can lead to seizures. Inhibition of the breathing center in the brain results in asphyxiation. In the diaphragm muscle, overstimulation of... 

Like other nerve agents, VX works by disrupting the central nervous system. The neurotransmitter acetylcholine (ACh) passes messages across synapses (gaps between neurons). When its job is done, it is released by the receptor and has to be destroyed, otherwise the ACh build up would lead to overstimulation of the nervous system. This is done by the enzyme acetylcholinesterase (AChE). 

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