BIOC 801 - Dr. Tischler Lecture 42 – April 14, 2005

1. BIOC 801 - Dr. Tischler Lecture 42 – April 14, 2005 ENDOCRINOLOGY: CATECHOLAMINES

2. NADP+ NADPH from phe, diet, or protein breakdown DHBR BH4 BH2 1 Tyrosine L-Dopa Tyrosine hydroxylase (rate-determining step) 2 Dopa decarboxylase H2O O2 pyridoxal phosphate CO2 3 H2O O2 ascorbate Dopamine Norepinephrine Dopamine hydroxylase PNMT Epinephrine 4 SAH SAM DPN OHase in neuro-scretory granules Parkinson’s disease: local deficiency of dopamine synthesis; L-dopa boosts production SAM from metabolism of Met PNMT specific to adrenal medulla Figure 1. Biosynthesis of catecholamines. BH2/BH4, dihydro/tetrahydrobiopterin; DHBR, dihydrobiopterin reductase; PNMT, phenylethanolamine N-CH3 transferase; SAH, S-adenosylhomocysteine; SAM, S-adenosylmethionine

3. Stress Chronic regulation Hypothalamus ACTH Cortisol Tyrosine L-Dopa Acute regulation DPN granule DPN  NE Neuron . . . . . . .. .. .. . . . . . . . . . . . . PNMT Epinephrine NE  promotes exocytosis acetylcholine E E E NE E E E E E NE Figure 2. Regulation of the release of catecholamines and synthesis of epinephrine in the adrenal medulla chromaffin cell. from adrenal cortex via intra-adrenal portal system induction Ca2+ E E E NE E neuro- secretory granules Adrenal Medulla Chromaffin Cell

4. COMT + MAO Epinephrine Vanillylmandelic acid Norepinephrine COMT + MAO Homovanillic acid Dopamine Neuronal re-uptake and degradation of catecholamines quickly terminates hormonal or neurotransmitter activity. Cocaine binds to dopamine receptor to block re-uptake of dopamine Dopamine continues to stimulate receptors of the postsynaptic nerve. Figure 3. Degradation of epinephrine, norepinephrine and dopamine via monoamine oxidase (MAO) and catechol‑O‑methyl-transferase (COMT)

5. Table 1. Classification of Adrenergic Hormone Receptors E = epinephrine; NE = norepinephrine Synthetic agonists: isoproterenol binds to beta receptors phenylephrine binds to alpha receptors (nose spray action) Synthetic antagonists: propranolol binds to beta receptors phentolamine binds to alpha receptors

6. NH2 HOOC Figure 4. Model for the structure of the 2-adrenergic receptor

7. Table 2. Metabolic and muscle contraction responses to catecholamine binding to various adrenergic receptors. Responses in italics indicate decreases of the indicated process (i.e., decreased flux through a pathway or muscle relaxation)

8. 1 or 2 receptor 2 receptor Gi Gs s  i        GTP GTP i s GTP GTP   X inactive adenylyl cyclase ACTIVE adenylyl cyclase ATP cyclic AMP inactive adenylyl cyclase Figure 5. Mechanisms of 1, 2, and 2 agonist effects on adenylyl cyclase activity

9. "FIGHT OR FLIGHT" RESPONSE • epinephrine/ norepinephrine major elements in the "fight or flight" response • acute, integrated adjustment of many complex processes in organs vital to the response (e.g., brain, muscles, cardiopulmonary system, liver) • occurs at the expense of other organs less immediately involved (e.g., skin, GI). • epinephrine: • rapidly mobilizes fatty acids as the primary fuel for muscle action • increases muscle glycogenolysis • mobilizes glucose for the brain by  hepatic glycogenolysis/ • gluconeogenesis • preserves glucose for CNS by  insulin release leading to reduced glucose uptake by muscle/ adipose • increases cardiac output • norepinephrine elicits responses of the CV system -  blood flow and  insulin • secretion.

10. [1] dissociation   [2]  GDP [3] [4] [5] GTPase degradation to VMA OP OP OP OP [6] OH OH ATP AMP phosphodiesterase activated PKA phosphorylates enzymes OP OH [7] Figure 6. Mechanisms for terminating the signal generated by epinephrine binding to a -adrenergic receptor epinephrine  GTP AC phosphorylation of -receptor by -ARK decreases activity even with bound hormone cAMP binding of -arrestin further inactivates receptor despite bound hormone insulin activation of protein phosphatase to dephosphorylate enzymes