Neurotransmission at adrenergic neurons

Neurotransmission in adrenergic neurons closely resembles that already described for the cholinergic neurons , except that norepinephrine is the neurotransmitter instead of acetylcholine. Neurotransmission takes place at numerous bead-like enlargements called varicosities. The process involves five steps:synthesis, storage, release, and receptor binding of norepinephrine, followed by removal of the neurotransmitter from the synaptic gap

Figure: Synthesis and release of norepinephrine from the adrenergic neuron. (MAO = monoamine oxidase.)

1. Synthesis of norepinephrine:

Tyrosine is transported by a Na +-linked carrier into the axoplasm of the adrenergic neuron, where it is hydroxylated to dihydroxyphenylalanine (DOPA) by tyrosine hydroxylase.1 This is the rate-limiting step in the formation of norepinephrine. DOPA is then decarboxylated by the enzyme dopa decarboxylase (aromatic l-amino acid decarboxylase) to form dopamine in the cytoplasm of the presynaptic neuron. 

2. Storage of norepinephrine in vesicles:

Dopamine is then trans-ported into synaptic vesicles by an amine transporter system that is also involved in the reuptake of preformed norepinephrine. This carrier system is blocked by reserpine .Dopamine is hydroxylated to form norepinephrine by the enzyme, dopamine β-hydroxylase.

 [Note: Synaptic vesicles contain dopamine or norepinephrine plus adenosine triphosphate (ATP), and β-hydroxylase, as well as other cotransmitters.] In the adrenal medulla, norepinephrine is methylated to yield epinephrine, both of which are stored in chromaffin cells. On stimulation, the adrenal medulla releases about 80 percent epinephrine and 20 percent norepinephrine directly into the circulation

3. Release of norepinephrine: 

An action potential arriving at the nerve junction triggers an influx of calcium ions from the extracellular fluid into the cytoplasm of the neuron. The increase in calcium causes vesicles inside the neuron to fuse with the cell membrane and expel (exocytose) their contents into the synapse. This release is blocked by drugs such as guanethidine .

4. Binding to a receptor:

 Norepinephrine released from the synaptic vesicles diffuses across the synaptic space and binds to either postsynaptic receptors on the effector organ or to presynaptic receptors on the nerve ending. The recognition of norepinephrine by the membrane receptors triggers a cascade of events within the cell, resulting in the formation of intracellular second messengers that act as links (transducers) in the communication between the neurotransmitter and the action generated within the effector cell. Adrenergic receptors use both the cyclic adenosine monophosphate (cAMP) second-messenger system,2 and the phosphatidylinositol cycle,3 to transduce the signal into an effect.

5. Removal of norepinephrine:

Norepinephrine may
1) diffuse out of the synaptic space and enter the general circulation

2) be metabolized to O-methylated derivatives by postsynaptic cell membrane–associated catechol O-methyltransferase (COMT) in the synaptic space, or
 3) be recaptured by an uptake system that pumps the norepinephrine back into the neuron. The uptake by the neuronal membrane involves a sodium/potassium-activated ATPase that can be inhibited by tricyclic antidepressants, such as imipramine, or by cocaine (see Figure above). 

Uptake of norepinephrine into the presynaptic neuron is the primary mechanism for termination of norepinephrine's effects. 

6. Potential fates of recaptured norepinephrine: 

Once norepinephrine reenters the cytoplasm of the adrenergic neuron, it may be taken up into adrenergic vesicles via the amine transporter system and be sequestered for release by another action potential, or it may persist in a protected pool. Alternatively, norepinephrine can be oxidized by monoamine oxidase (MAO) present in neuronal mitochondria. The inactive products of norepinephrine metabolism are excreted in the urine as vanillylmandelic acid, metanephrine, and normetanephrine.

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