Catecholamines - Rivin

A catecholamine is a monoamine, an organic compound that has a catechol (benzene with two hydroxyl side groups at carbons 1 and 2) and a side-chain amine. Included among catecholamines are epinephrine (adrenaline), norepinephrine (noradrenaline), and dopamine. Release of the hormones epinephrine and norepinephrine from the adrenal medulla of the adrenal glands is part of the fight-or-flight response.

1. Catecholamines W. P. Rivindu H. Wickramanayake Group no. 04a 2 nd Year 2 nd Semester

2. C ompounds containing a catechol moiety (a benzene ring with two adjacent hydroxyl groups) and an amine side-chain .

3. T he most important Catecholamines are: 1) Noradrenaline (Norepinephrine ), - A transmitter released by sympathetic nerve terminals 2) Adrenaline (Epinephrine) - A hormone secreted by Chromaffin Cells the A drenal M edulla 3) Dopamine - The metabolic precursor of noradrenaline and adrenaline, also a transmitter/neuromodulator in the central nervous system ( Substantia Nigra & Ventral Tegmental Area in Brain ) 4 ) Isoproterenol (previously isoprenaline ), - A synthetic derivative of noradrenaline, not present in the body

4. Dopamine Epinephrine (Adrenaline) Norepinephrine (Noradrenaline)

5. These Hormones/Neurotransmitters  are not essential for  life. Are  required for adaptation to stress  (Acute & Chronic) also simply referred to as Fight or Flight . Major   element  for severe stress.

6. General Properties ; a) High Potency - Show highest potency in directly activating +/- activators b) Rapid Inactivation - Due to metabolism by Catechol-o- methylytransferase (COMT) & Monoamine Oxidase (MAO) - Have brief period of action when given parenterally & ineffective when given orally c) Poor Penetration into CNS - Catecholamines are Polar , not really penetrated into CNS

7. Biosynthesis of Catecholamines

8. First Step : Hydroxylation [ Tyrosine   hydroxylase] 1 . Produces L‐3,4‐dihydroxyphenylalanine (L‐DOPA).  2 . Is the rate  limiting enzyme. 3 . Iron‐containing protein[ferric state(Fe )]. 4 . Exists in soluble and particle forms. 5 . Uses molecular oxygen. 6 . Requires tetrahydrobiopterin (BH4). Tyrosine hydroxylase inhibitors 1 . Feedback inhibited by its products . 2 . Can be competitively inhibited by tyrosine  derivatives( α‐ methyltyrosine),  used  for treatment of  pheochromocytoma . 3 . Can also be inhibited by iron‐chelating agents  ( α , α ‐‐ bipyridine ).

9. Second Step : Decarboxylation [Aromatic  L‐amino acid ( DOPA)   decarboxylase] Synonyms : Tryptophan   decarboxylase & 5‐hydroxytryptophan  decarboxylase.  It  catalyzes several different  decarboxylation reactions: • L‐DOPA  to dopamine • 5‐HTP(5-hydroxytryptophan)  to serotonin • T ryptophan  to tryptamine 1. Soluble form. 2 . Requires  pyridoxal  phosphate(active form of Vit.B6). 3 . Is competitively inhibited by  α‐ methyl  DOPA. 4 . Can also be inhibited by halogenated compounds. 5. Anti‐hypertension   drugs (methyl DOPA,   3‐hydroxtyramine ,  α‐ methyl tyrosine,  metaraminol ) inhibits this enzyme .

10. Third Step : Hydroxylation [Dopamine‐ β‐ hydroxylase (DBH )] 1 . Converts  Dopamine  to N orepinephrine. 2 . Requires  Ascorbic   acid(Vitamin C)  as e‐ donor. 3 . Has Cu in active site.  4 . Use fumarate as  modulator. 5. Use O2. 6. Irreversible reaction. 7. Products are Water, Norepinephrine & Dehydroascorbate .

11. Fourth Step : Methylation [ Phenylethanolamine ‐N‐methyltransferase (PNMT )] 1 . Soluble in cytoplasm. 2 . Induced by glucocorticoids. 3 . Uses  S- Adenosyl Methionine(SAM),   methyl  donor . 4. Norepinephrine and S- adenosylmethionine (ado-Met ) form Epinephrine and S- adenosylhomocysteine (ado- Hcy ).

12. The  Regulation  of  C atecholamines   Synthesis 1 . Stimulated by  Splanchnic N erve . 2. Increases after  Acute   Stress  by  Activation  of  Enzymes . 3 . Enzymes are induced by  Chronic   Stress   (Corticoids ).

13. Function(s) : Outside the nervous system, norepinephrine and its methylated derivative, epinephrine , act as regulators of carbohydrate and lipid metabolism . Norepinephrine and epinephrine are released from storage vesicles in the adrenal medulla in response to fright, exercise, cold, and low levels of blood glucose . They increase the degradation of glycogen and triacylglycerol , as well as increase blood pressure and the output of the heart. These effects are part of a coordinated response to prepare the individual for emergencies, and are often called the “fight-or-flight” reactions.

14. The  Storage ,  Release  and  Uptake  of  C atecholamines • Storage  1 . Stored in the  Chromaffin   Granules 2 . Associated with ATP‐Mg2+ and Ca2 + • Release  1. By  Exocytosis (Ca2+‐dependent) 2 . Stimulated by  cholinergic and β‐adrenergic 3 . Inhibited by  α‐adrenergic • Uptake Neuronal  uptake of the hormone is necessary for: 1 . Conservation of the hormone 2 . Termination of signal

15. • α1  1 . Acts via  Calcium . 2 . Increases  G lycogenolysis . 3. Smooth  m uscle  c ontraction   ( blood vessels,  urinogenital tract). • α2 1 . Inhibits  cAMP formation. 2. Smooth muscle relaxation (GIT) 3 . Smooth muscle contraction  ( some vascular beds) 4 . Inhibits: a) Lipolysis b) Renin release c) Platelets aggregation d) Insulin secretion • β1   1 . Stimulates  cAMP formation 2 . Stimulates lipolysis 3 . Increases  mycocardial contraction  ( rate and force ) • β2 1 . Stimulates  cAMP formation 2 . Increases smooth muscle contraction  ( bronchi, blood  vessels, GIT and GUT) 3 . Increases: 1 . Hepatic gluconeogenesis 2 . Hepatic  glycogenolysis 3 . Muscle   glycogenolysis 4 . Release of insulin, glucagon and renin The  Catecholamines  Receptors

16. Continued ;

17. • Binding to β1 and β2 ; - Stimulates  G‐proteins coupled to adenylate cyclase . • Binding to  α2 ; - Inhibits adenylate cyclase . • Binding to  α1 ; - Is  coupled to phospholipase C, Increases P hosphoinsitol , DAG and Ca2+. The  Catecholamines  Mechanism of Signaling

18. 1 . Have very short t½ (10‐30 sec ) 2 . Less than 5% is excreted in  urine 3 . Catabolized by: 1 . Catechol‐o‐methyl transferase (COMT )  2 . Monoamine oxidase The  Catabolism  of  Catecholamines Termination of Action of Catecholamines 1. Re-uptake 2. Enzymatic degradation 3. Diffusion 4. Extra Synaptic Uptake

19. Catecholamine  Degradation COMT  = Catechol‐o‐methyl  transferase MAO   = Monoamine  oxidase DOPAC  = 3,4‐Dihydroxyphenylacetic  acid MHPG  = 3‐Methoxy‐4‐hydroxyphenylglycol  DHPG = 3,4  dihydroxyphenylglycol , 

20. References ; Pubmed - 1 Pubmed - 2 Pubmed - 3 Pubmed - 4 Pubmed - 5 Pubmed - 6 Guyton and Hall Textbook of Medical Physiology 13th Edition Guyton & Hall Physiology Review, 3e (Guyton Physiology)   3rd Edition by  John E. Hall PhD  ( Author) Textbook of Biochemistry with Clinical Correlations, 7th Edition by Thomas M. Devlin Pubmed - 7

21. Pubmed – 1 1 : Langer SZ. Presynaptic regulation of the release of catecholamines . Pharmacol Rev . 1980 Dec;32(4):337-62. PubMed PMID: 6267618. Pubmed – 2 1: Peyrin L, Dalmaz Y. [Peripheral secretion and inactivation of catecholamines (adrenaline , noradrenaline, dopamine)]. J Physiol (Paris). 1975;70(4): 353-433. French . PubMed PMID: 1221109. Pubmed – 3 1: Volavka J, Bilder R, Nolan K. Catecholamines and aggression: the role of COMT and MAO polymorphisms. Ann N Y Acad Sci. 2004 Dec;1036:393-8. Review. PubMed PMID : 15817751. Pubmed – 4 1: Devoto P, Flore G, Saba P, Frau R, Gessa GL. Selective inhibition of dopamine-beta-hydroxylase enhances dopamine release from noradrenergic terminals in the medial prefrontal cortex. Brain Behav . 2015 Sep 24;5(10):e00393. doi : 10.1002/brb3.393 . PubMed PMID: 26516613; PubMed Central PMCID: PMC4614051. Pubmed – 5 1: Mittal R, Debs LH, Patel AP, Nguyen D, Patel K, O'Connor G, Grati M, Mittal J,Yan D, Eshraghi AA, Deo SK, Daunert S, Liu XZ. Neurotransmitters: The Critical Modulators Regulating Gut-Brain Axis. J Cell Physiol. 2016 Aug 11. doi : 10.1002/jcp.25518 . [ Epub ahead of print] Review. PubMed PMID: 27512962. Pubmed – 6 1: Vuorenpää A, Jørgensen TN, Newman AH, Madsen KL, Scheinin M, Gether U. Differential Internalization Rates and Postendocytic Sorting of the Norepinephrine and Dopamine Transporters Are Controlled by Structural Elements in the N Termini. J Biol Chem. 2016 Mar 11;291(11):5634-51. doi : 10.1074/jbc.M115.702050 . PubMed PMID: 26786096; PubMed Central PMCID: PMC4786704. Pubmed – 7 1: Zhang WP, Ouyang M, Thomas SA. Potency of catecholamines and other L-tyrosine derivatives at the cloned mouse adrenergic receptors. Neuropharmacology. 2004 Sep;47(3 ):438-49. PubMed PMID: 15275833.

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