Neurotransmitters deactivation

Ephedrlne, 66 Epinephrine, 95, 241 clinical usage, 63 as neurotransmitter, 62 synthesis, 63 Epithiazide, 359 Eprazinone, 64 Ergosterol, 184 Erytriptamine, 317 Essential fatty acids, 26 Esterases, in drug deactivation, 14... 

The principal mechanism for the deactivation of released catecholamines is, however, not enzymatic destmction but reuptake into the nerve ending. The presynaptic membrane contains an amine pump—a saturable, high-affinity, Na" -dependent active-transport system that requires energy for its function. The recycled neurotransmitter is capable of being released again, as experiments with radiolabelled [ H]NE have shown, and can be incorporated into chromaffin granules as well. Many drugs interfere with neurotransmitter reuptake and metabolism, as discussed in subsequent sections. 

Serotonin is stored in synaptic vesicles and blood platelets in the form of an ATP complex in the ratio of 2 1. Very little is known about its release, but exocytosis is the assumed mechanism. The released neurotransmitter is deactivated primarily by reuptake, but a significant amount is metabolized by MAO to the corresponding indoleacetic acid. 

The most popular OTC sleep aids are those that contain antihistamines such as diphenhydramine or doxylamine (Table 3.1). As noted in Chapter 1, nerve cells in the brain communicate with each other by secreting chemicals called neurotransmitters. One such neurotransmitter that regulates sleep is histamine. When histamine is released by a nerve cell, it diffuses over to the target nerve cell and binds to specialized proteins called receptors located on the outer surface of the nerve cell. These receptors are specially designed to bind only histamine, and when they do, the target nerve cell will become either activated or deactivated. In the brain, histamine serves the function of keeping us awake, and when drugs such as antihistamines are taken, they block the ability of histamine receptors to bind histamine. 

Like barbiturates, benzodiazepines reduce the activity of the nervous system. They do this by acting on the type-A GABA (or GABA ) receptor, which is the protein that the neurotransmitter GABA activates when it is secreted by one nerve cell onto another (refer back to Ghapter 1 for an overview of how nerve cells communicate). When this receptor binds GABA, nerve cells become less active. Thus, like GABA, benzodiazepines deactivate nerve cells. 

Dopamine is one of more than fifty known neurotransmitters. It is manufactured in nerve cells in certain parts of the brain. When these nerve cells are stimulated, dopamine is released into the synapse. Normally, it is then deactivated by an enzyme called monoamine oxidase (MAO), or it is reabsorbed. 

The chemical messenger alters the conformational state of an integral membrane protein that operates as a channel for the movement of ions (e.g., Na+, K+, Ca2+, Cl") across the plasma membrane. Excitatory neurotransmitters such as glutamate, acetylcholine and ATP activate ligandgated ion channels that promote the entry of Na+ and Ca2+ ions to depolarize (activate) neurones. The inhibitory neurotransmitter -y-aminobutyrate (GABA), on the other hand, promotes the entry of Cl- ions that hyperpolarize (deactivate) neurons. 

A number of alkaloids are known whose structures are more or less similar to those of endogenous neurotransmitters. Targets can be the receptor itself, the enzymes which deactivate neurotransmitters, or transport processes, which are important for the storage of the neurotransmitters in synaptic vesicles. Alkaloids relevant here include (Table IV) brucine, ergot alkaloids, eseridine, serotonin, physostigmine, gelsemine, j8-carboline alkaloids, strychnine, yohimbine, berberine, bicuculline, bul-bocapnine, columbamine, coptisine, coralyne, corlumine, ephedrine, ga-... 

A second mechanism for removing neurotransmitters from the synapse is called rcuptake. Neurotransmitters arc taken back up into the terminal button after they have been released—hence the term reuptake. This is an economical mechanism of deactivating transmitters because the ncurotransmitter molecule is preserved intact and can be used again without the expense of energ) involved in the manufacture of new transmitters. Some drugs (notably cocaine) exert some of their action by blocking the reuptake process. 

Drugs alter neural transmission in several ways. For example, a drug may mimic a natural or endogenous neurotransmitter by activating receptor sites. Alternatively a drug may block a receptor site. Drugs can also affect the deactivation or release of neurotransmitters. 

Regardless of the mechanism involved, the overall result is the same. A change in receptor shape (or tertiary structure) leads eventually to the activation (or deactivation) of enzymes. Since enzymes can catalyse the reaction of a large number of molecules, there is once again an amplification of the original message such that a relatively small number of neurotransmitter molecules can lead to a biological result. 

Alternatively, the neurotransmitter/receptor interaction leads to the activation or deactivation of enzymes. In Chapter 5, this was represented as a direct process whereby the receptor and target enzyme are closely associated. In reality, the receptor and target enzyme are not directly associated and the interaction of receptor and neurotransmitter is the first step in a complex chain of events which involves several proteins and enzymes. 

Organophosphorus and carbamate insecticides are the two classes of anticholinesterase insecticides. All anticholinesterases inhibit nervous tissue acetylcholinesterase, the enzyme that deactivates the neurotransmitter acetylcholine (Ecobichon 1996). Poisoning causes accumulation of acetylcholine in the synaptic cleft, resulting in continuous electrical stimulation (Chambers 1992 Costa 1988). Described best by Chambers (1992), the mechanism of acute symptoms of poisoning occurs through three pathways ... 

The function of the enzyme is rapidly and efficiently to catalyze the hydrolysis of ACh (Eq. 8.2). The significance of rapid destruction of ACh is to deactivate the neurotransmitter after it binds to the receptors so as not to accumulate to levels that produce a continuous barrage of impulses by repetitive interactions. After all, the depolarization produced by the ACh-receptor binding must be terminated so that the excitability of the postsynaptic membrane and its permeability can be restored by repolarization. Inhibition of AChE levels would then exist in the vicinity of effector cells. Extreme inhibition, such as may occur following irreversible blockade of the enzyme, would lead to cholinergic intoxication with fatal results. 

Once the neurotransmitter substance has interacted with the receptor sites on the postsynaptic membrane it must be deactivated so that it does not continuously excite or inhibit the membrane. There are at least three deactivation processes—mass transport away from the synaptic gap, reuptake, and enzymic degradation. 

Many of these effects can be explained by an interference with a central signal cascade (Fig. 5.195). Adrenaline activates adenylylcyclase, which converts adenosine triphosphate (ATP) into cyclic 3 ,5 -adenosine monophosphate (cAMP). This is a secondary messenger, which is deactivated by a phosphodiesterase to adenosine monophosphate (AMP). Dephosphorylation with a 5 -nucleotidase releases the neuromodulator adenosine, which is enriched extracellularly in the waking state and is degraded during sleep. When adenosine binds in the presynaptic cleft to adenosine-Aj-receptors of the nerve cells, the release of most neurotransmitters, like glutamate, y-aminobutyric acid, norephedrine, serotonin and acetylcholine is inhibited. In addition, adenosine inhibits adenylylcyclase. 

Calcium-activated potassium channels. Calcium-activated potassium channels are important membrane proteins associated with a wide range of biological functions including smooth muscle neurotransmitter release, proliferation of white blood cells, red blood cell size, and many more. This channels functions by pumping out K ions when they detect Ca ions, resulting in hyperpolarisation due to subsequent calcium channel deactivation. 

Acetylcholine (ACh) is a natural neurotransmitter. After release from presynaptic nerve terminals and interaction with postsynaptic acetylcholine receptors, it is deactivated by acetylcholinesterase (AChE), which... 

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