#Outline the production, release and fate of catecholamines at the sympathetic nerve terminal

#Production

1. Phenylalanine is converted to tyrosine in the liver
2. Tyrosine is transported into the axon via sodium dependent transport
3. Tyrosine is converted to L-DOPA via tyrosine hydroxylase
   • this is the slowest step in the pathway and is hence known as the rate limiting step
4. L-DOPA is converted to dopamine via dopa decarboxylase
5. VMAT-2 (vesicular monoamine transporter 2) packages dopamine into vesicles
6. Dopamine is converted to noradrenaline via dopamine β-hydroxylase (adds a hydroxyl group to the β-carbon)
7. In sympathetic nerves, this process ends here. However in chromaffin cells of the adrenal gland:
   • 20% of cells produce noradrenaline in small dense granules
   • 80% of cells produce noradrenaline which is methylated to adrenaline in larger, less dense granules
     • methylation is via phenylethanolamine-N-methyltransferase (PNMT)
   • metenkephalin (aka opioid growth factor - OGF) is also produced

#Release

1. An action potential propagates through a sympathetic neuron and depolarises the presynaptic axon terminal
2. → presynaptic voltage-gated N-type Ca channels open
3. → Ca2+ influx which activates SNARE proteins
4. SNARE proteins facilitate the exocytosis of the vesicles into synapse — mostly noradrenaline with a small amount of dopamine and adrenaline

#Fate

1. Reuptake

   • after release, catecholamines return to the presynaptic neuron where they may be metabolised or released again
   • reuptake of noradrenaline is via NET (norepinephrine transporter)
   • reuptake of dopamine is via DAT (dopamine transporter)

2. Neurotransmission

   • binds to postsynaptic adrenergic receptors, producing an effect in the target tissue
     • e.g. α1 → smooth muscle contraction
     • e.g. β1 → inotropy
     • e.g. β2 → smooth muscle relaxation
   • binds to presynaptic adrenergic receptors
     • α2 → ↓cAMP → negative feedback loop that inhibits further neurotransmission
     • β2 → ↑ cAMP → positive feedback loop that stimulates further neurotransmission

3. Diffusion away from the synaptic cleft

   • catecholamines diffuse into the bloodstream, after which they may be metabolised

4. Metabolism

   • at the nerve terminal (major pathway)
     • catecholamines are metabolised first by MAO which is bound to the outer mitochondrial membrane in the presynaptic nerve terminal
     • then diffuses into circulation where it is metabolised again by COMT, which is present in many tissues such as the liver, kidneys and vascular endothelium
     • MAO is also in present in other tissues such as gut, liver, kidneys and vascular endothelium
   • after diffusing away
     • catecholamines diffuse into the systemic circulation where they are metabolised by COMT and MAO in the various tissues where these enzymes exist, predominantly the liver

Catecholamine metabolism