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

2. DHBR NADP + NADPH from phe, diet, or protein breakdown Tyrosine L-Dopa H2OH2O O2O2 Tyrosine hydroxylase (rate-determining step) BH 2 BH 4 1 Dopa decarboxylase CO 2 Dopamine pyridoxal phosphate 2 Dopamine hydroxylase ascorbate H2OH2O Norepinephrine O2O2 3 PNMT SAM SAH Epinephrine 4 Figure 1. Biosynthesis of catecholamines. BH 2 /BH 4, dihydro/tetrahydrobiopterin; DHBR, dihydrobiopterin reductase; PNMT, phenylethanolamine N-CH 3 transferase; SAH, S-adenosylhomocysteine; SAM, S-adenosylmethionine Parkinson’s disease: local deficiency of dopamine synthesis; L-dopa boosts production PNMT specific to adrenal medulla SAM from metabolism of Met DPN OHase in neuro- scretory granules

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

4. Norepinephrine Epinephrine COMT + MAO Vanillylmandelic acid Figure 3. Degradation of epinephrine, norepinephrine and dopamine via monoamine oxidase (MAO) and catechol ‑ O ‑ methyl-transferase (COMT) 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. Dopamine Homovanillic acid COMT + MAO

5. Table 1. Classification of Adrenergic Hormone Receptors ReceptorAgonists Second Messenger G protein alpha 1 (  1 ) E>NEIP 3 /Ca 2+ ; DAGGqGq alpha 2 (  2 ) NE>E  cyclic AMP GiGi beta 1 (  1 ) E=NE  cyclic AMP GsGs beta 2 (  2 ) E>>NE  cyclic AMP GsGs 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. NH 2 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) Process  1 -receptor (IP 3, DAG)  2 -receptor (  cAMP)  1 -receptor (  cAMP)  2 -receptor (  cAMP) Carbohydrate metabolism  liver glycogenolysis No effect  liver/muscle glycogenolysis;  liver gluconeogenesis;  glycogenesis Fat metabolism No effect  lipolysis  lipolysis No effect Hormone secretion No effect  insulin secretion No effect  insulin and glucagon secretion Muscle contraction Smooth muscle - blood vessels, genitourinary tract Smooth muscle - some vascular; GI tract relaxation Myocardial -  rate, force Smooth muscle relaxation - bronchi, blood vessels, GI tract, genitourinary tract

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

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