Endocrine lec6

• Adrenal medulla (A.M.)

  Part of the sympathetic nervous system where splanchic preganglionic nerve fibers terminate and innervate chromaffin cells that produce catecholamine hormones
• Components of the sympathoadrenal system


  • Parasympathetic nervous system with cholinergic pre- and postganglionic nerves
  • Sympathetic nervous system with cholinergic preganglionic and adrenergic postganglionic nerves
  • Adrenal medulla
• Catecholamines


  3,4 dihydroxyderivatives of phenylethylamine synthesized in chromaffin cells

  
• The major catecholamine product of the adrenal medulla is epinephrine, which constitutes about 80% of the catecholamines
• Most norepinephrine present in organs innervated by sympathetic nerves is made in situ and most of the rest is made in other nerve endings and reaches the target tissue via the circulation

  
• Catecholamine biosynthesis


  1. Ring hydroxylation

  2. Decarboxylation

  3. Side-chain hydroxylation

  4. N-methylation

  
• Tyrosine hydroxylase


  Rate-limiting enzyme in catecholamine biosynthesis, found in soluble and particle-bound forms in tissues that synthesize catecholamines

  
• DOPA decarboxylase


  Enzyme that converts L-dopa to dopamine, requires pyridoxal phosphate

  
• Dopamine beta-hydroxylase (DBH)


  Enzyme that catalyzes the conversion of dopamine to norepinephrine, present in the secretion granules of medullary cells

  
• Phenylethanolamine N-methyltransferase (PNMT)


  Enzyme that catalyzes the conversion of norepinephrine to epinephrine in the cytoplasm of adrenal medulla cells, induced by glucocorticoid hormones

  
• Secretory chromaffin granules


  • Capable of biosynthesis, uptake, storage and secretion of catecholamines
  • Also contain ATP, Mg2+, Ca2+, DBH, and the protein chromogranin A

  
• Catecholamine secretion


  1. Neural stimulation leads to fusion of granule membranes with plasma membrane, causing exocytotic release of norepinephrine and epinephrine

  2. Process is calcium-dependent and stimulated by cholinergic and beta-adrenergic agents

  
• Neural reuptake of catecholamines

  Important mechanism for conserving hormones and quickly terminating their activities
• COMT (catechol O-methyltransferase)


  Cytosolic enzyme that catalyzes the addition of a methyl group, usually at the 3-position on the benzene ring, producing metabolites like homovanillic acid, normetanephrine, and metanephrine

  
• MAO (monoamine oxidase)


  Oxidoreductase enzyme that deaminates monoamines, of two types: MAO-A in neural tissue and MAO-B in extra-neural tissues

  
• VMA is the end product of norepinephrine and epinephrine metabolism and usually increases if there is a tumor of the adrenal medulla (pheochromocytoma)
• The most important mechanism of the first step regulation involves feed back inhibition by the catecholamine.

  Its also inhibited by a series of tyrosine derivatives including α-methyltyrosine (this compound is occasionally used to treat catecholamine excess in pheochromocytoma).