VPT 321: Veterinary Neuropharmacology (2+1) copy 1

SYNTHESIS OF CATECHOLAMINES

• The precursor for catecholamine synthesis is tyrosine

• Conversion of phenylalanine to tyrosine takes place in the liver.
• Conversion of tyrosine to DOPA and DOPA to dopamine takes place in the adrenergic neuronal cytoplasm.
• Dopamine gets converted to norepinephrine in the granules and norepinephrine to epinephrine in the adrenal medulla.
• Tyrosine hydroxylase is the rate limiting enzyme and its inhibition by alpha methyl-ρ-tyrosine results in depletion of catecholamines. All enzymes of catecholamine synthesis are rather non-specific and can act on closely related substrates. Tyrosine hydroxylase is activated by cAMP dependent protein kinases and inhibited by catecholamines.
• Storage within the granular vesicles is accomplished by complexation of the catecholamines with adenosine triphosphate and a specific protein, chromogranin. This complexation makes the amines inactive until their release. The vesicles also contain ascorbic acid and dopamine beta hydroxylase. Catecholamines are taken up from the cytoplasm into the granules by an active transport system that is ATP and Mg⁺⁺ dependent. This intragranular pool of norepinephrine is believed to be the principal source of the neurotransmitter that is released upon nerve stimulation.
• Release from the storage vesicles is calcium dependent exocytosis induced by depolarisation of the nerve ending. Drugs can also induce release by destruction of storage vesicles or displacement of catecholamines from the storage vesicles.
• Amines within, the cytoplasm may be taken up by the granules for storage or, they may be inactivated by a deaminating enzyme monoamine oxidase (MAO) that is located in the neuronal mitochondria. Intracytoplasmic dopamine may also be deaminated by MAO.
• Fate -The action of nerepinephrine may be terminated by (in descending order of importance) 
  • active reuptake into the nerve across the axoplasmic membrane   accounting for removal of NE upto 65% from the synaptic cleft. (uptake I)
  • diffusion from the cleft space via the extracellular fluid accounting for 15% of removal of NE (uptake II) 
  • metabolic breakdown by enzymes accounting for 20% of metabolism.
• Norepinephrine that has been taken back into the nerve may be restored in granules or it may be deaminated by MAO. Reuptake is an active mechanism and requires energy.
• Norepinephrine termination of action by enzymatic conversion accounts for 20 per cent of released norepinephrine. Initial inactivation involves two enzymes.
  • Monoamine oxidase (MAO) inactivates amines by conversion to aldehydes, which can subsequently be metabolized to carboxylic acids and alcohols. MAO is localised on the outer surface of the mitochondria and is present in neuronal and non-neuronal tissues. The reaction requires oxygen.
  • Catechol-O-methyl transferase (COMT) methylates m-hydroxyl group of catechols. COMT an extraneuronal enzyme that has a wide tissue distribution and broad substrate specificity.
• Catecholamines in the blood are metabolized in the liver by COMT and MAO. Aldehyde reductase and aldehyde dehydrogenase further metabolise the aldehydes formed by the deamination by MAO. Aldehyde reductase catalyses the formation of alcohol products and aldehyde derhydrogenase catalyse the formation of acid products. Products of the above enzymatic reactions can subserve as substrates for others. The major final products are 3-methyl-4-hydroxymandelic acid (VMA) or 3-methoxy-4-hydroxy-phenylethyleneglycol (MOPEG).