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HuBio 543 September 25, 2007

HuBio 543 September 25, 2007. Neil M. Nathanson K-536A, HSB 3-9457 nathanso@u.washington.edu Introduction to the Sympathetic Nervous System. Catecholamines. NH. HO. +. 2. HO. Catechol Plus Amine. OH. H. OH. H. NH. HO. HO. C. C. C. C. NH. CH. 2. 3. HO. HO. H.

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HuBio 543 September 25, 2007

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  1. HuBio 543September 25, 2007 Neil M. Nathanson K-536A, HSB 3-9457 nathanso@u.washington.edu Introduction to the Sympathetic Nervous System

  2. Catecholamines NH HO + 2 HO Catechol Plus Amine OH H OH H NH HO HO C C C C NH CH 2 3 HO HO H H H H Epinephrine Norepinephrine H H H OH CH 3 NH NH HO C C C C CH HO 2 CH HO HO H 3 H H H Dopamine Isoproterenol

  3. Adrenergic Innervation of Vasculature

  4. ADRENERGIC TRANSMISSION Tyrosine TH Tyrosine DOPA DDC Dopamine MAO DA ++ Ca ++ Ca DßH NE NE NE Transp. NE AdR COMT

  5. ++ Ca ++ Ca SYNTHESIS OF EPINEPHRINE IN THE ADRENAL MEDULLA TH Tyrosine DOPA DDC Dopamine PMNT DA NE EPI DßH NE EPI EPI

  6. CAT ACh + CoA Ch + AcCoA NE NE NE ACh ACh ACh TERMINATION OF SYNAPTIC TRANSMISSION NE ACh Re-Up NE ACh Ch +Ac AdR AChE AChR

  7. Metabolism of Catecholamines OH H OH O MAO NH C C HO 2 HO C C OH HO HO H H H H 3,4- Dihydroxymandelic acid Norepinephrine OH H OH H COMT H3CO NH NH HO C C C C 2 2 HO HO H H H H Norepinephrine Normetanephrine

  8. ADRENERGIC TRANSMISSION Tyrosine TH Tyrosine DOPA DDC Dopamine MAO DA ++ Ca ++ Ca DßH NE NE NE Transp. NE AdR COMT

  9. Drugs that act on adrenergic terminals • Inhibit reuptake of NE into terminal- cocaine, tricyclic antidepressants • Induce release of NE from terminal- amphetamine, tyramine • Inhibit uptake of DA & NE into vesicle- reserpine • Block release of NE- bretylium • Displace NE from vesicle- guanethidine • Inhibit TH activity- a-methyltyrosine • Inhibit DDC activity- carbidopa • Inhibit MAO activity- pargyline • (Inhibit COMT activity- tolcapone)

  10. NE NE Presynaptic Receptors Inhibit NE Release From Terminals NE ß1- AdR NE X X NE a2- AdR NE

  11. The Subtypes of Adrenergic Receptors a: EPI > NOR >>ISO ß: ISO > EPI > NE

  12. Beta- Adrenergic Receptors Mediate Positive Chronotropic Effect 80 Isoproterenol Norepinephrine 60 40 Change in HR. BPM 20 0 Dose, µg/kg 0.1 100 0. 01 0.001 1 10

  13. Even More Subtypes of Adrenergic Receptors a: EPI > NOR >>ISO ß: ISO > EPI > NE a1: contraction of smooth muscle (incl. VSM) a2: presynaptic receptors ( decrease NE release) ß1: in heart and juxtaglomerular cells (and some fat cells) ß2: relaxation of smooth muscle (and in heart) ß3: some fat cells NOTE ON ß2: (1) mediate relaxation of skeletal muscle vasculature (2) P’cologically administered NE is not effective

  14. Specificity of Agonists at Targets and Receptors E NE I Contraction of VSM (a1-AdR) I Relaxation of Airways (ß2-AdR) E NE I E NE Increase in HR (ß1-AdR) Concentration of Drug

  15. Hormone/Transmitter g b a Effector GTP BANG GDP Receptors G-Proteins Effectors 9 adrenergic R 20 a 4 PLC-ß 5 mAChR 5 ß 10 AC 12 g PDE (≥ 100?) K channels (GIRK ) Na, Ca channels IP3 Receptors PI-3-kinases Rho-GEF, Ras-GEF Tyrosine Kinases (src)

  16. Regulator of G-protein Signaling

  17. The basic functions of G-proteins as family: mediates stimulation of adenylyl cyclase (ß-AdR) ai family: mediates inhibition of adenylyl cyclase activates GIRK (M2, M4 mAChR; 2-AdR) aq family: activate certain forms of PLC (M1, M3, M5 mAChR; 1-AdR) (and others as well)

  18. Beta-adrenergic receptors stimulate adenylyl cyclase Norepinephrine Adenylyl Cyclase G-protein ATP (Gs) cAMP cAMP-dependent protein kinase (PKA) Increased phosphorylation

  19. ß- ARR Iso Iso Ad. Ad. g g b Cyc. b a a Cyc. ß- ARR P GRK Regulation of Receptor Signaling by G-protein- Coupled Receptor Kinase (GRK) and ß-Arrestin Receptor is uncoupled from G-protein and targeted for internalization and down-regulation

  20. 40 30 ß-Receptors In Heart 20 10 0 ISO- Treated ISO, Withdrawn Control Chronic Isoproterenol Decreases Cardiac Beta-AdR #

  21. Chronic Isoproterenol Decreases Cardiac Beta-AdR Functional Responsiveness Increase In Contractile Force Control Isoproterenol, Withdrawn (OR) Increase In Adenylyl Cyclase Isoproterenol Treated Concentration of Isoproterenol

  22. 200 150 ß-Receptors In Heart 100 50 0 T3- Treated T4- Treated Control Thyroid Hormones Increase Cardiac Beta-AdR #

  23. Decreased number of cardiac ß-AdR in ventricles of patients with heart failure Controls Heart Failure (Receptor #)

  24. Decreased function of cardiac ß-AdR in ventricles of patients with heart failure

  25. Differential coupling of ß1 and ß2- AdR • ß1-AdR only couple to the stimulatory G-protein Gs • ß2-AdR can couple to both Gs & the inhibitory G-protein Gi • In heart failure, levels of ß1-AdR decrease and levels of Gi increase • Therefore, ß2-AdR has less stimulatory and more inhibitory effects in a failing heart than in a non-failing heart • Failing heart has increased expression and activity of GRK, which increases ß1 desensitization and degradation and also increases coupling of ß2 to Gi • The decreased level of ß1-AdR and increased ß2-AdR coupling to Gi both contribute to decreased ß-adrenergic stimulation of contractility in failing heart

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