Synaptic cleft neurotransmitter removal from

The communication between neurons occurs at either gap junctions (electrical synapses) or chemical synapses with release of neurotransmitters from a presynaptic neuron and their detection by a postsynaptic nerve cell (Fig. 17.1). Neurotransmitters not used in the synaptic cleft are removed promptly by either uptake into adjacent cells, reuptake in the presynaptic neuron, or are degraded by enzymatic systems. 

Unbound synaptic neurotransmitters, such as DA, 5-HT, NE, and others are taken back into the neuron by binding to protein transporters on the presynaptic neuronal membranes, which remove neurotransmitters from the synaptic cleft. Neurotransmitters also are inactivated by enzymatic degradation. 

Describe how neurotransmitters are removed from the synaptic cleft... 

Altered removal of a neurotransmitter from the synaptic cleft. The third mechanism by which drugs may alter synaptic activity involves changes in neurotransmitter reuptake or degradation. A very well known example of a drug in this category is Prozac (fluoxetine), which is used to treat depression. The complete etiology is unknown, but it is widely accepted that depression involves a deficiency of monoamine neurotransmitters (e.g., norepinephrine and serotonin) in the CNS. Prozac, a selective serotonin reuptake inhibitor, prevents removal of serotonin from the synaptic cleft. As a result, the concentration and activity of serotonin are enhanced. 

Many neurotransmitters are inactivated by a combination of enzymic and non-enzymic methods. The monoamines - dopamine, noradrenaline and serotonin (5-HT) - are actively transported back from the synaptic cleft into the cytoplasm of the presynaptic neuron. This process utilises specialised proteins called transporters, or carriers. The monoamine binds to the transporter and is then carried across the plasma membrane it is thus transported back into the cellular cytoplasm. A number of psychotropic drugs selectively or non-selectively inhibit this reuptake process. They compete with the monoamines for the available binding sites on the transporter, so slowing the removal of the neurotransmitter from the synaptic cleft. The overall result is prolonged stimulation of the receptor. The tricyclic antidepressant imipramine inhibits the transport of both noradrenaline and 5-HT. While the selective noradrenaline reuptake inhibitor reboxetine and the selective serotonin reuptake inhibitor fluoxetine block the noradrenaline transporter (NAT) and serotonin transporter (SERT), respectively. Cocaine non-selectively blocks both the NAT and dopamine transporter (DAT) whereas the smoking cessation facilitator and antidepressant bupropion is a more selective DAT inhibitor. 

The concentration of neurotransmitter in the synaptic cleft, which depends upon the rate of discharge of vesicles into the cleft and/or the rate of removal from the cleft or degradation within the cleft. 

It should be possible to treat the disease by increasing the concentration of the neurotransmitter in the synaptic cleft. There are, in principle, three ways in which this could be achieved, (i) Neurotransmitter synthesis could be increased, (ii) The rate of exocytosis could be increased, (iii) Removal of neurotransmitter from the synapse could be inhibited. Drugs that affect process (iii) have been developed. The tricyclic antidepressants and the specific serotonin (5-hydroxytryptamine) reuptake inhibitors (abbreviated to SSRIs) inhibit uptake of the neurotransmitter into the presynaptic on postsynaptic neurone. The most prescribed SSRI is fluoxetine (Prozac). 

Receptors are also located on the presynaptic membrane. These autc-reivptors regulate the release and synthesis of the neurotransmitter and are part of a feedback mechanism that aims to keep the activation or inhibition within the synapse for a discrete time interval and to terminate the signal transfer once the information has reached the adjacent cell via removal (mactivation) of the neurotransmitter from the synaptic cleft. 

To prepare a synapse to respond to another signal, the neurotransmitter must be removed quickly from the synaptic cleft. In some cases, the transmitter is taken up by the presynaptic neuron and repackaged in synaptic vesicles in other cases, it is broken down by extracellular enzymes. Acetylcholine, for example, is hydrolyzed rapidly to choline and acetate by the enzyme acetylcholinesterase. 

Tricyclics. Drugs in this category share a common three-ring chemical structure (hence the name tricyclic ). These drugs work by blocking the reuptake of amine neurotransmitters into the presynaptic terminal.61,67 Actively transporting amine neurotransmitters back into the presynaptic terminal is the method by which most (50 to 80 percent) of the released transmitter is removed from the synaptic cleft. By blocking reuptake, tricyclics allow the released amines to... 

These selective serotonin reuptake inhibitors (SSRIs) include fluoxetine (Prozac), sertraline (Zoloft), paroxetine (Paxil), fluvoxamine (Luvox), citalopram (Celexa), and, most recently, escitalopram (Lexapro see the appendix). These drugs block the removal of the neurotransmitter serotonin from the synaptic cleft. A number of other antidepressants are potent nonselective serotonin reuptake inhibitors (NSRIs). These include the atypical venlafaxine (Effexor) and the tricyclic clomipramine (Anafra-nil). Nefazodone (Serzone) has been withdrawn from the market due to liver damage. 

Neurotransmitters are removed by translocation into vesicles or destroyed in enzyme-catalysed reactions. Acetylcholine must be removed from the synaptic cleft to permit repolarization and relaxation. A high affinity acetylcholinesterase (AChE) (the true or specific AChE) catalyses the hydrolysis of acetylcholine to acetate and choline. A plasma AChE (pseudo-AChE or non-specific AChE) also hydrolyses acetylcholine. A variety of plant-derived substances inhibit AChE and there is considerable interest in AChE inhibitors as potential therapies for cognition enhancement and for Alzheimer s disease. Organophosphorous compounds alkylate an active site serine on AChE and the AChE inhibition by this mechanism is the basis for the use of such compounds as insecticides (and unfortunately also as chemical warfare agents). Other synthetics with insecticidal and medical applications carbamoylate and thus inactivate AChE (Table 6.4). 

As noted above, the arrival of an impulse at the synapse activates a cascade of events that culminates in the release of neurotransmitters into the synaptic cleft, the diffusion of neurotransmitters to membrane-bound receptors on a neighboring neuron or cell, and the removal of neurotransmitter molecules from the synaptic cleft. These events are readily disrapted by a number of toxicants and can lead to both subtle and severe functional deficits. 

In contrast to some hormones that have to travel considerable distances in order to stimulate their target cells, neurotransmitters have only to cross the gap or synaptic cleft, a distance of a few nanometres, from the nerve cell to the target cell. The release of TRH from the hypothalamus is triggered by the arrival of a neurotransmitter from an adjacent neurone. There are various types of neurone, sensory ones, intemeurones and motor neurones that collect and transmit information about the ambient temperature, light input to the eye, pain etc. to the brain, which may then transmit a message to motor neurones, for example, in order to effect removal of one s finger from a hot object. 

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. 

Information transfer in animals requires that after their release neurotransmitters must be quickly degraded or removed from the synaptic cleft. 

Following their release from a presynaptic cell, neurotransmitters must be removed or destroyed to prevent continued stimulation of the postsynaptic cell. Signaling can be terminated by diffusion of a transmitter away from the synaptic cleft, but this is a slow process. Instead, one of two more rapid mechanisms terminates the action of neurotransmitters at most synapses. 

With the exception of acetylcholine, all the neurotransmitters shown in Figure 7-41 are removed from the synaptic cleft by transport into the axon terminals that released them. Thus these transmitters are recycled Intact, as depicted in Figure 7-42 (step 5]). Transporters for GABA, norepinephrine, dopamine, and serotonin were the first to be cloned and studied. These four transport proteins are all Na -linked symporters. They are 60-70 percent Identical In their amino acid sequences, and each is thought to contain 12 transmembrane a helices. As with other Na symporters, the movement of Na into the cell down Its electrochemical gradient provides the energy for uptake of the neurotransmlt-ter. To maintain electroneutrality, CM often Is transported via an ion channel along with the Na and neurotransmitter. 

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