Nerve Acetylcholine

Motor nerves Acetylcholine Cutaneous pectoris and sartorius muscle Frog Johnston et al. 1983... 

How organophosphates are toxic to nerves. Acetylcholine is a neuro-transmitter chemical present in the ends of nerves. Acetylcholinesterase is an enzyme which breaks down acetylcholine so that it is no longer effective at causing muscle contraction. Organophosphates inhibit this enzyme allowing acetylcholine to accumulate. 

In normal transmission of a nervous impulse from nerve to nerve, acetylcholine is released into the synapse in order to excite the receiving neuron (Figure 5.10). Unless acetylcholine is rapidly broken down, the receiving nerve is constantly fired, resulting in uncoordinated muscle movement, nausea, dizziness, and eventually seizures and unconsciousness. The serine enzyme acetylcholinesterase is responsible for the expedient breakdown of the neurotransmitter acetylcholinesterase. 

Before further discussing the action of postsynaptic neurotoxins, it would be useful to review normal nerve transmission very briefly. When a normal nerve impulse (depolarization wave) passes through the axon and reaches the end of that axon, the calcium ion concentration is increased and the neurotransmitter, acetylcholine (ACh), is suddenly released from the vesicle at the end of the nerve. Acetylcholine moves across the synaptic crevice and reaches the acetylcholine receptor in the muscle. The AChR is composed of five subunits, a2,PyS. When two molecules of acetylcholine attach to the a-subunits, the AChR... 

Mode of Motion. Nicotine, anabasine, and imidocloprid affect the ganglia of the insect central nervous system, faciUtating transsynaptic conduction at low concentrations and blocking conduction at higher levels. The extent of ionisation of the nicotinoids plays an important role in both their penetration through the ionic barrier of the nerve sheath to the site of action and in their interaction with the site of action, which is befleved to be the acetylcholine receptor protein. There is a marked similarity in dimensions between acetylcholine and the nicotinium ion. 

Contraction of muscle follows an increase of Ca " in the muscle cell as a result of nerve stimulation. This initiates processes which cause the proteins myosin and actin to be drawn together making the cell shorter and thicker. The return of the Ca " to its storage site, the sarcoplasmic reticulum, by an active pump mechanism allows the contracted muscle to relax (27). Calcium ion, also a factor in the release of acetylcholine on stimulation of nerve cells, influences the permeabiUty of cell membranes activates enzymes, such as adenosine triphosphatase (ATPase), Hpase, and some proteolytic enzymes and facihtates intestinal absorption of vitamin B 2 [68-19-9] (28). 

The concept of discrete neurotransmitter recognition sites or receptors on nerve cells was based on work on systems physiology and dmg action (1). It was not until 1921 however, that it was shown that information could be transferred between neurons via a chemical, in this instance acetylcholine [51-84-3] (ACh), C H gN02 (1). 

Choline functions in fat metaboHsm and transmethylation reactions. Acetylcholine functions as a neurotransmitter in certain portions of the nervous system. Acetylcholine is released by a stimulated nerve cell into the synapse and binds to the receptor site on the next nerve cell, causing propagation of the nerve impulse. 

The influx of Ca(Il) across the presynaptic membrane is essential for nerve signal transmission involving excitation by acetylcholine (26). Calcium is important in transducing regulatory signals across many membranes and is an important secondary messenger hormone. The increase in intracellular Ca(Il) levels can result from either active transport of Ca(Il) across the membrane via an import channel or by release of Ca(Il) from reticulum stores within the cell. More than 30 different proteins have been linked to regulation by the calcium complex with calmoduhn (27,28). 

This makes choline an important nutritional substance. It is also of great physiological interest because one of its esters, acetylcholine [51-84-3] appears to be responsible for the mediation of parasympathetic nerve impulses and has been postulated to be essential to the transmission of all nerve impulses. Acetylcholine and other more stable compounds that simulate its action are pharmacologically important because of their powerful effect on the heart and on smooth muscle. Choline is used clinically in Hver disorders and as a constituent in animal feeds. 

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. 

In a monograph on ephedrine Gaddum has reviewed the differences in the action of adrenaline and ephedrine and has suggested that the latter has the same relation to adrenaline as physostigmine has to acetylcholine, that is, ephedrine inhibits the action of an enzyme system, which normally destroys adrenaline, or the substance closely resembling it, produced by adrenergic nerves. 

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)... 

While these functions can be a carried out by a single transporter isoform (e.g., the serotonin transporter, SERT) they may be split into separate processes carried out by distinct transporter subtypes, or in the case of acetylcholine, by a degrading enzyme. Termination of cholinergic neurotransmission is due to acetylcholinesterase which hydrolyses the ester bond to release choline and acetic acid. Reuptake of choline into the nerve cell is afforded by a high affinity transporter (CHT of the SLC5 gene family). 

ATP with acetylcholine and vasoactive intestinal peptide in some parasympathetic nerves... 

The PNS has two neurohormones (neurotransmitters) acetylcholine (ACh) and acetylcholinesterase (ACliE). ACh is a neurotransmitter responsible for die transmission of nerve impulses to effector cells of die parasympathetic nervous system. ACh plays an important role in die transmission of nerve impulses at synapses and myoneural junctions. ACh is quickly... 

Cholinergic blocking dragp inhibit die activity of acetylcholine in parasympadietic nerve fibers (see Chap. 24 for a description of die role of acetylcholine in the transmission of nerve impulses across parasympadietic nerve fibers). When die activity of acetylcholine is inhibited, nerve impulses traveling along parasympadietic nerve fibers cannot pass from die nerve fiber to die effector organ or structure ... 

Voluntary muscle contraction is initiated in the brain-eliciting action potentials which are transmitted via motor nerves to the neuromuscular junction where acetylcholine is released causing a depolarization of the muscle cell membrane. An action potential is formed which is spread over the surface membrane and into the transverse (T) tubular system. The action potential in the T-tubular system triggers Ca " release from the sarcoplasmic reticulum (SR) into the myoplasm where Ca " binds to troponin C and activates actin. This results in crossbridge formation between actin and myosin and muscle contraction. 

Neurohumoral transmitters are chemicals that facilitate the transmission of nerve impulses across nerve synapses and neuroeffector junctions. Acetylcholine is a neurohumoral transmitter that is present in the peripheral autonomic nervous system, in the somatic motor nervous system, and in some portions of the central nervous system. 

Peptides in the a-conotoxin family are inhibitors of nicotinic acetylcholine receptors. They were first isolated from C. geographus venom as components which cause paralysis in mice and fish when injected intraperitoneally (27). Early physiological experiments (28) indicated that a-conotoxins GI, GII, and GIA (see Table III) all act at the muscle end plate region. Mini end-plate potentials and end plate potentials evoked in response to nerve stimulation are inhibited in the presence of a-conotoxins in the nM to pM range. a-Conotoxin GI was subsequently shown to compete with rf-tubocurarine and a-bungarotoxin for the acetylcholine receptor (29). 

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