儿茶酚胺课件

CATECHOLAMINES NH2 HO CH2CH2HO NH2 HO CHCHHO ab HO HO OH HO CH2CHNH2HO OH HO CH2CHNH HO CH3 CATECHOL CATECHOLAMINE DOPAMINE (DIHYDROXYPHENYL- ETHYLAMINE) NOREPINEPHRINE (NORADRENALINE) EPINEPHRINE (ADRENALINE) CATECHOLAMINES NORADRENALINE POSTGANGLIONIC FIBRES OF SYMPATHETIC NERVOUS SYSTEM (ADRENERGIC FIBRES) FOUND IN HIGHEST CONCENTRATION IN HYPOTHALAMUS AND CERTAIN ZONES OF LIMBIC SYSTEM. MOST NORADRENERGIC NEURONES ARISE IN LOCUS COERULEUS. INHIBITORY IN ACTION. ALSO IN ADRENAL MEDULLA. DOPAMINE MAINLY IN CNS. FOUND IN BASAL GANGLIA ESP. CAUDATE NUCLEUS, NEOSTRIATUM, NUCLEUS ACCUMBENS, OLFACTORY TUBERCLE, CENTRAL NUCLEUS OF AMYGDALA, MEDIAN EMINENCE AND AND RESTRICTED FIELDS OF THE FRONTAL CORTEX. PREDOMINENT ACTION INHIBITORY ADRENALINE CHROMAFFIN CELLS OF THE ADRENAL MEDULLA. IN CNS FOUND IN MEDULLARY RETICULAR FORMATION CONNECTING TO A FEW PONTINE AND DIENCEPHALIC NUCLEI. NORADRENALINE DEFICIENCY BEHAVIOURAL DEPRESSION - EXCESS MANIA DOPAMINE EXCESS SCHIZZOPHRENIA & PSYCHOSES - DEFICIENCY PARKINSONS DISEASE HYPERTENSION - CATECHOLAMINE VASCULAR TONE BP NH2 HO CH2CH2HO OH HO CH2CHNH2HO OH HO CH2CHNH HO CH3 DOPAMINE (DIHYDROXYPHENYL- ETHYLAMINE) DOPAMINE-b-HYDROXYLASE (ASCORBIC ACID, O2, Cu2+ ) NOREPINEPHRINE (NORADRENALINE) PHENYLETHANOLAMINE-N- METHYL TRANSFERASE (S-ADENOSYLMETHIONINE) EPINEPHRINE (ADRENALINE) CHCH2 COOH NH2 CHCH2 COOH NH2 HO HO CHCH2 COOH NH2HO PHENYLALANINE TYROSINE DYHYDROXYPHENYLALANINE (DOPA) BIOSYNTHETIC PATHWAY PHENYLALANINE HYDROXYLASE (DIHYDROBIOPTERIN) TYROSINE HYDROXYLASE (TETRAHYDROPTERIDINE, O2, Fe 2+ ) 5 8x10-5 M IN BLOOD DOPA DECARBOXYLASE L-AROMATIC AMINOACID DECARBOXYLASE (PYRIDOXAL PHOSPHATE) NH2CH2CH2 OH CH2CHNH2 PHENYLETHANOLAMINEPHENYLETHYLAMINE DOPAMINE-b-HYDROXYLASE OH CH2CHNH2HONH2CH2CH2HO TYRAMINEOCTOPAMINE a-METHYLDOPA a-METHYLNOREPINEPHRINE FALSE NEUROTRANSMITTER TH P Ser40 TH DIACYLGLYCEROL PROTEIN KINASE C ATP ACase ATP35cAMP cAMPPK REGULATION OF TYROSINE HYDROXYLASE TETRAMER 59000 M.WT FEEDBACK INHIBITION BY CATECHOLAMINES N-TERMINAL REGULATORY DOMAIN TH P Ser40 PHOSPHORYLATION BY cAMPPK OR PKC ON SERINE 40 DECREASES Km FOR PTERIDINE COFACTOR (CATECHOLAMINE RELEASED) P TH Cal.Ca2+ KINASE Cal +Ca2+ Cal.Ca2+ Ca2+ Ser19 A P TH A ACTION POTENTIAL DEPOLARIZATION P TH A P ATP A TH P Ser40 TH DIACYLGLYCEROL PROTEIN KINASE C ATP ATP ATP ACase ATP35cAMP cAMPPK PHOSPHORYLATION ON SERINE 19 BY Ca2+-CAMODULIN PK RESULTS ON BINDING OF ACTIVATOR PROTEIN AND INCREASE IN THE Vmax OF THE ENZYME. DUAL PHOSPHORYLATION RESULTS IN FULLY ACTIVE ENZYME STORAGE CHROMAFFIN GRANULES LARGE VESICLES NORADRENALINE (2 POOLS) DOPAMINE-b- HYDROXYLASE ATP Ca2+/Mg 2+ ATPase POLYOPIOID PRECURSORS CHROMOGRANIN (GLYCOSYLATED/ SULPHATED PROTEIN) NE:ATP 12:1 EPI:ATP 4:1 SMALL VESICLES NO CHROMOGRANIN NO DOPAMINE-b-HYDROXYLASE NO OPIOID PEPTIDES ONE POOL NE NEURONAL CELL X NERVE TERMINAL MICROTUBULES COLCHICINE P TH Cal.Ca2+ KINASE Cal +Ca2+ Cal.Ca2+ Ca2+ Ser19 A P TH A ACTION POTENTIAL DEPOLARIZATION P TH A P ATP A TH P Ser40 TH DIACYLGLYCEROL PROTEIN KINASE C ATP ATP ATP A2 ATP35cAMP ADENOSINE cAMPPK V V TUBULIN MAP-2 CATECHOLAMINEATP METABOLISM 1. MONOAMINE OXIDASE -COOH MAO ALDEHYDE -CH-NH2 -CHO DEHYDROGENASE AMINEALDEHYDE ALDEHYDE REDUCTASE -CH2OH OH HO CH2CHNH2HO 2. CATECHOL-O-METHYL TRANSFERASE OH CH3O CH2CHNH2HO COMT S-ADENOSYLMETHIONINE 3. REUPTAKE INTO PRESYNAPTIC TERMINAL ACTIVE TRANSPORT LINKED TO Na+/K+ ATPase DRUG ACTION TYROSINETYROSINE DOPA DOPAMINE NENE NEMAO NE NE NE a2a b POST- SYNAPTIC EFFECTOR CELL 1 2 3 4 5 6 7 8 9 10 1. UPTAKE BLOCKED BY AROMATIC AMINO ACIDS 2. a-METHYL-p-TYROSINE INHIBITOR TYROSINE HYDROXYLASE 3. NON-SPECIFIC ENZYMES FALSE NEUROTRANSMITTERS a-METHYL DOPA TO a-METHYLNOREPINEPHRINE 4. INHIBITION OF STORAGE RAUWOLFIA ALKALOIDS (RESERPINE) 5. DISPLACEMENT OF CATECHOLAMINE GUANETHIDINE 6. MAO INHIBITORS PARGYLLINE & TRANYLCYPROMINE 7. INHIBITION OF RELEASE BRETYLIUM 8. INHIIBTION OF RE-UPTAKE TRICYCLIC ANTIDEPRESSANTS, COCAINE E.G. IMIPRAMINE, AMITRYPTYLINE 9. FACILITATION OF UPTAKE LITHIUM 10. ADRENERGIC RECEPTOR BLOCKERS AND SYMPATHOMIMETIC AGONISTS ADRENAL MEDULLA ACTIVE IN RESPONSE TO COLD, STRESS, FEAR, ANGER, LOW BLOOD SUGAR, CEREBRAL ANOXIA, ASPHYXIA, LOW BLOOD PRESSURE SYMPATHETIC NERVE STIMULATION ACETYL CHOLINE NICOTINIC RECEPTOR Na+ ENTRY DEPOLARISATION VOLTAGE-DEPENDENT Ca2+ CHANNELS INTRACELLULAR Ca2+ ADRENERGIC AGONISTS OH HO CH2CHNH+ HO CH3 CH3 ISOPROTERENOL b (ISOPRENALINE) OH CHCHNH2 HO CH3 PHENYLEPHRINE a OH HO CH2CHNH HO CH3 EPINEPHRINE MIXED ANTAGONISTS ba PROPRANOLOLPHENTOLAMINE BUTOXAMINE (b2)PHENOXYBENZAMINE METOPROLOL (b1)ERGOT ALKALOIDS BUPRANOLOL (b3)PRAZOCIN (a1) YOHIMBINE (a2) DISTRIBUTION a1 RECEPTORS POSTSYNAPTIC EFFECTOR SITES ON SMOOTH MUSCLE, GLAND CELLS, LIVER ETC. a2 RECEPTORS EXIST ON NERVE TERMINALS (PRE-SYNAPTIC FEEDBACK INHIBITION OF NOREPINEPHRINE RELEASE). POST-SYNAPTIC SITES IN NUMEROUS TISSUES INCLUDING CEREBRAL CORTEX, PLATELETS, UTERUS, LIVER ETC. b1-RECEPTORS PREDOMINENTLY IN CARDIAC ANDADIPOSE TISSUE. PRE-SYNAPTIC FIBRES IN CNS, RBCs. b2-RECEPTORS SMOOTH MUSCLE AND GLAND CELLS. MOST COMMON b3-RECEPTORS - ATYPICAL RECEPTORS. ADIPOSE TISSUE, LIVER AND HEART DIFFERENT TISSUES MAY POSSESS b1, b2 AND b3 RECEPTORS E.G. LIVER, ADIPOSE TISSUE. FLIGHT OR FRIGHT RESPONSE SYSTEM ACTION RECEPTOR LIVER GLYCOGENOLYSIS a1 GLYCOGEN SYNTHESIS b2 & b3 GLUCONEOGENESIS UREAGENESIS MUSCLE GLYCOGENOLYSIS b2 GLYCOGEN SYNTHESIS ADIPOSE LIPOLYSIS b1 & b3 TISSUE LIPOGENESIS b1 & b3 LIPOLYSIS a2 PANCREAS INSULIN SECRETION b2 INSULIN SECRETION a2 HEART RATE & FORCE b1 BLOOD CONSTRICTION a1 VESSELS DILATION b2 GUT CONSTRICTION a1 SPHINCTERS DILATION b2 CATECHOL- RELEASE b1 AMINE RELEASE a2 RELEASE b-RECEPTORS ATP 35cyclic AMP ACTIVATES ADENYLATE CYCLASE R2C2 + 4cAMP 2C + (R2.4cAMP) PYRUVATE KINASE PYRUVATE KINASE GLYCOGEN SYNTHASE GLYCOGEN