Tuesday 5 April 2011

Adrenergic Transmission

Adrenergic neurons transport a precursor amino acid; tyrosine, into the nerve ending, then synthesize the catecholamine transmitter, and finally store it in membrane-bound vesicles. In most sympathetic postganglionic neurons, norepinephrine is the final product. In the adrenal medulla and certain areas of the brain, some norepinephrine is further converted to epinephrine. In dopaminergic neurons, synthesis terminates with dopamine. Several processes in these nerve terminals are potential sites of drug action. One of these, the conversion of tyrosine to dopa, is the rate-limiting step in catecholamine transmitter synthesis. It can be inhibited by the tyrosine analog metyrosine. A high-affinity antiporter for catecholamines located in the wall of the storage vesicle; vesicular monoamine transporter, VMAT can be inhibited by the reserpine alkaloids. Reserpine causes depletion of transmitter stores. Another transporter; norepinephrine transporter, NET carries norepinephrine and similar molecules back into the cell cytoplasm from the synaptic cleft. NET is also commonly called uptake 1 or reuptake 1 and is partially responsible for the termination of synaptic activity. NET can be inhibited by cocaine and tricyclic antidepressant drugs, resulting in an increase of transmitter activity in the synaptic cleft.

































Release of the vesicular transmitter store from noradrenergic nerve endings is similar to the calcium-dependent process previously described for cholinergic terminals. In addition to the primary transmitter (norepinephrine), adenosine triphosphate (ATP), dopamine- -hydroxylase, and peptide cotransmitters are also released into the synaptic cleft. Indirectly acting and mixed sympathomimetics, eg, tyramine,amphetamines, and ephedrine, are capable of releasing stored transmitter from noradrenergic nerve endings by a calcium-independent process. These drugs are poor agonists (some are inactive) at adrenoceptors, but they are excellent substrates for monoamine transporters. As a result, they are avidly taken up into noradrenergic nerve endings by NET. In the nerve ending, they are then transported by VMAT into the vesicles, displacing norepinephrine, which is subsequently expelled into the synaptic space by reverse transport via NET. Amphetamines also inhibit monoamine oxidase and have other effects that result in increased norepinephrine activity in the synapse. Their action does not require vesicle exocytosis.
Norepinephrine and epinephrine can be metabolized by several enzymes. Because of the high activity of monoamine oxidase in the mitochondria of the nerve terminal, there is significant turnover of norepinephrine even in the resting terminal. Since the metabolic products are excreted in the urine, an estimate of catecholamine turnover can be obtained from laboratory analysis of total metabolites (sometimes referred to as "VMA and metanephrines") in a 24-hour urine sample. However, metabolism is not the primary mechanism for termination of action of norepinephrine physiologically released from noradrenergic nerves. Termination of noradrenergic transmission results from two processes, simple diffusion away from the receptor site (with eventual metabolism in the plasma or liver), and reuptake into the nerve terminal by NET or into perisynaptic glia or other cells.
  
Neurotransmitter Uptake Carriers

Several large families of transport proteins have been identified. The most important of these are the ABC (ATP-Binding Cassette) and SLC (SoLute Carrier) transporter families. As indicated by the name, the ABC carriers utilize ATP for transport. The SLC proteins are cotransporters and in most cases, use the movement of sodium down its concentration gradient as the energy source. Under some circumstances, they also transport transmitters in the reverse direction in a sodium-independent fashion.
NET, SLC6A2, the norepinephrine transporter, is a member of the SLC family, as are similar transporters responsible for the reuptake of dopamine (DAT, SLC6A3) and 5-HT (serotonin, SERT, SLC6A4) into the neurons that release these transmitters. These transport proteins are found in peripheral tissues and in the CNS wherever neurons utilizing these transmitters are located.
NET is important in the peripheral actions of cocaine and the amphetamines. In the CNS, NET and SERT are important targets of several antidepressant drug classes. The most important inhibitory transmitter in the CNS, -aminobutyric acid (GABA), is the substrate for at least three SLC transporters: GAT1, GAT2, and GAT3. GAT1 is the target of an antiseizure medication. Other SLC proteins transport glutamate, the major excitatory CNS transmitter.

Cotransmitters in Cholinergic & Adrenergic Nerves

As previously noted, the vesicles of both cholinergic and adrenergic nerves contain other substances in addition to the primary transmitter. Many of these substances are also primary transmitters in the nonadrenergic, noncholinergic nerves. They appear to play several roles in the function of nerves that release acetylcholine or norepinephrine. In some cases, they provide a faster or slower action to supplement or modulate the effects of the primary transmitter. They also participate in feedback inhibition of the same and nearby nerve terminals.

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