Catecholamine Synthesis, Storage, and Release

1. Aromatic L-amino acid decarboxylase (DOPA decarboxylase)

Tyrosine converted to DOPA by tyrosine hydroxylase which is a rate limiting step in pathway. Dopa in the presence of dopa decarboxylase is converted to dopamine. Methyldopa is then converted to alpha-methyldopamine (converted by dopamine ß hydroxylase to the "false transmitter" alpha-norepinephrine) & then to norepinephrine.

• Catecholamine Storage

  • In adrenergically innervated tissue: norepinephrine is localized in post-ganglionic nerve terminals

    • large dense core vesicles (corresponding to chromaffin granules)

    • small dense core vesicles (containing norepinephrine, ATP, and membrane-bound dopamine ß-hydroxylase

  • In the adrenal medulla, catecholamines are localized in chromaffin granules.

  • The most abundant catecholamine in the adrenal medulla is epinephrine.

  • The adrenal medulla has two cells types containing catecholamines:

    • one type contains mainly norepinephrine

    • the second type contains mainly epinephrine.

  • Epinephrine-containing cells express cytoplasmic phenylethanolamine-N-methyl transferase, allowing conversion of norepinephrine to epinephrine.

  • Norepinephrine:

1. synthesized in granules

2. diffuses out, is methylated in the cytoplasm to epinephrine

3. then reenters the chromaffin granules.

• About half of dopamine is formed in sympathetic neuronal cytoplasm is actively translocated into dopamine ß-hydroxylase-containing vesicles, where the final step, conversion to norepinephrine occurs.

• The remaining dopamine is converted to homovanillic acid.

• Reuptake

  • Following release from adrenergic nerve endings, termination of norepinephrine effect is mainly due to reuptake into presynaptic terminals.

  • In tissues with wide synaptic gaps and in blood vessels, the effect of released norepinephrine is ended by:

    1. enzymatic breakdown

    2. diffusion away from receptors

    3. extraneuronal uptake.

  • Neuronal norepinephrine reuptake requires two systems:

• A transport system that translocates norepinephrine from extraneuronal spaces into cytoplasm.

• A transport system that translocates norepinephrine from the cytoplasm into vesicles.

• Translocation of norepinephrine from extraneuronal spaces (uptake I) into the cytoplasm is blocked by:

1. Cocaine

2. Tricyclic antidepressants (e.g. imipramine)

Category: Pharmacology Notes