M1i: Outline the production, release & fate of noradrenaline at the sympathetic nerve terminal

  • Catecholamine = an organic compound consisting of a catechol & an amino side chain
    • Catechol = benzene ring with 2 hydroxyl side groups at C3 and C4

Synthesis

  • Occurs in cytoplasm of adrenergic neurons & chromaffin cells of adrenal medulla
  • Formed from TYROSINE
  • Tyrosine can be dietary or from phenylalanine
    • TYROSINE → DOPA (Tyrosine hydroxylase) → rate limiting step
    • DOPA → DOPAMINE (DOPA decarboxylase)
  • Dopamine enters storage vesicles
    • DOPAMINE → NA (Dopamine-β-hydroxylase)
  • In the adrenal medulla only:
    • NA → Adrenaline (PNMT)
  • Catecholamines remain in vesicles until their release

Release

  • Repolarisation of nerve allows Ca2+ influx
  • Exocytosis of vesicles → releases NA into junctional space
    • Adrenal medulla → releases NA & Adrenaline
    • Post-ganglionic symp. neurons → Release NA
    • Sympathetic ganglia → interneurons use Dopamine as their NT

Inactivation

  • NA released from nerve terminal lasts ~10secs
  • It is removed by 3 mechanisms:

1) Reuptake

  • Back into nerve terminal
  • Here it can be:
    1. Stored in vesicles → for re-release
    2. Metabolised by MAO

2) Diffusion

  • Away from synaptic cleft
  • Eventually metabolised in plasma, lungs, liver

3) Metabolism

  • By tissue enzymes COMT & MAO
  • MAO formed on outer surface of mitochondria ∴ ‘intracellular enzyme’
  • MAO found in neurons which release NA, liver, kidney, intestinal mucosa
  • MAO deaminates removing the NH2
  • COMT is extraneuronal
  • Present in cytoplasm of liver, kidney, smooth m.
  • It methylates a hydroxyl group to produce normetanephrine
  • If normetanephrine is not metabolised it is deaminated by MAO to form VMA
  • NB: MAO inhibitors ↑[NA]+++, COMT inhibitors do not
Synthesis
Metabolism1