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BIOC 801 - Dr. Tischler Lecture 42 – April 14, 2005 ENDOCRINOLOGY: CATECHOLAMINES NADP+ NADPH from phe, diet, or protein breakdown DHBR BH4 BH2 1 Tyrosine L-Dopa Tyrosine hydroxylase O2 (rate-determining step) H O 2 H2O DPN OHase in neuroscretory granules 3 ascorbate O2 Norepinephrine Dopamine hydroxylase PNMT SAM from metabolism of Met Epinephrine 4 SAM SAH 2 PNMT specific to adrenal medulla CO2 Dopa decarboxylase pyridoxal phosphate Dopamine Parkinson’s disease: local deficiency of dopamine synthesis; L-dopa boosts production Figure 1. Biosynthesis of catecholamines. BH2/BH4, dihydro/tetrahydrobiopterin; DHBR, dihydrobiopterin reductase; PNMT, phenylethanolamine N-CH3 transferase; SAH, S-adenosylhomocysteine; SAM, S-adenosylmethionine Stress Figure 2. Regulation of the release of catecholamines and synthesis of epinephrine in the adrenal medulla chromaffin cell. Chronic regulation Hypothalamus ACTH Cortisol Tyrosine L-Dopa Acute regulation from adrenal cortex via intraadrenal portal system DPN induction granule Neuron ..... .. ..... .. . ... acetylcholine Adrenal Medulla Chromaffin Cell DPN NE Ca2+ PNMT NE E E E NE E promotes exocytosis E EEE NE E E NE EE Epinephrine neurosecretory granules Epinephrine COMT + MAO Vanillylmandelic acid Norepinephrine COMT + MAO Dopamine Homovanillic acid 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) Table 1. Classification of Adrenergic Hormone Receptors Receptor Agonists Second Messenger G protein alpha1 (1) E>NE IP3/Ca2+; DAG Gq alpha2 (2) NE>E cyclic AMP Gi beta1 (1) E=NE cyclic AMP Gs beta2 (2) E>>NE cyclic AMP Gs 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 NH2 HOOC Figure 4. Model for the structure of the 2-adrenergic receptor 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) 1-receptor 2-receptor 1-receptor 2-receptor (IP3, DAG) ( cAMP) ( cAMP) ( cAMP) Process Carbohydrate liver metabolism glycogenolysis No effect 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 Smooth muscle - muscle blood vessels, some genitourinary vascular; tract GI tract relaxation Smooth muscle relaxation Myocardial bronchi, blood vessels, rate, force GI tract, genitourinary tract 1 or 2 receptor Gs 2 receptor Gi s GTP GTP inactive adenylyl cyclase ACTIVE adenylyl cyclase ATP GTP i s GTP i X inactive adenylyl cyclase cyclic AMP Figure 5. Mechanisms of 1, 2, and 2 agonist effects on adenylyl cyclase activity "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. Figure 6. Mechanisms for terminating the signal generated by epinephrine binding to a -adrenergic receptor [1] dissociation epinephrine [2] degradation to VMA GTP AC GDP [3] [5] GTPase [6] activated PKA phosphorylates enzymes OH [7] OP OP phosphorylation of -receptor by -ARK decreases activity even with bound hormone OH OH ATP cAMP AMP phosphodiesterase OP [4] OPOP binding of -arrestin further inactivates receptor despite bound hormone insulin activation of protein phosphatase to dephosphorylate enzymes