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Beta Adrenergic Signaling in Heart

Beta Adrenergic Signaling in Heart. Roles of local signaling complexes. The Long QT Syndrome: Dysfunction in Ventricular Repolarization. Keating & Sanguinetti, Cell , 2001. Decrease in K Channel Activity or Increase in Na Channel Activity Can Prolong ADP (QT Interval).

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Beta Adrenergic Signaling in Heart

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  1. Beta Adrenergic Signaling in Heart • Roles of local signaling complexes

  2. The Long QT Syndrome: Dysfunction in Ventricular Repolarization Keating & Sanguinetti, Cell, 2001.

  3. Decrease in K Channel Activity or Increase in Na Channel Activity Can Prolong ADP (QT Interval)

  4. LQTS: Genetic Linkage to Multiple Ion Channel Genes

  5. AP Prolongation Can Trigger Arrhythmias

  6. Triggers Are Gene-specific Circ 2001;103:89-95

  7. -AdrenergicStimulation Shortens AP Duration (Kass & Wiegers, J Physiol. 1982)

  8. b-AR Regulation of Cardiac AP:A Balance of Inward and Outward Current • L-type Calcium Channel current Increased • Slow IKs potassium channel Current Increased

  9. KCNQ1 (KvLQT-1) KCNE1 (Splawski et al, Circ102;1178-85, 2000) KCNQ1 KCNQ1+KCNE1 50 pA/pF 200 pA/pF 0.5 s Molecular Architecture of IKS Channel Revealed Through LQTS studies (minK)

  10. Receptor stimulation to Local Signaling

  11. Adaptor Proteins: Channel Microsignaling Domains: Macromolecular Complexes

  12. Calcium Channel Complex

  13. Channels as Macromolecular Signaling Complexes • Signaling Microdomains exapnd diversity of receptor-mediated cellular responses • Disruption of Microdomains in disease can unbalance physiological responses

  14. K Channel Complex

  15. cAMP control 5 Iso 8Br-cAMP 4 5 10 control OA+8Br-cAMP 8Br-cAMP 8 3 OA Increase of tail IKs 6 9 2 Tail current (pA/pF) 5 4 5 7 2 1 0 0 -40 -20 0 20 40 60 80 mouse CHO cell Pre-pulse potential (mV) Functional regulation in TG+ Myocytes but not in CHO cells: Phosphatase and Kinase activity

  16. KCNQ1 forms a macromolecular complex Human Heart

  17. RyR macromolecular complexes are held together by leucine/isoleucine zippers (LZs) Marx, et al., (2001). The Journal of Cell Biology, 153:699-708.

  18. A leucine zipper motif in KCNQ1 C-terminus : Coordination of protein-protein interactions (LZm = V595A/L602A)

  19. The KCNQ1 Macromolecular Complex

  20. LZ mutation ablates functional up regulation KCNQ1+ E1+Y LZm KCNQ1+E1+Y

  21. Disruption of Macromolecular Complexes in Disease

  22. AP Prolongation Can Trigger Arrhythmias

  23. State-dependent Block of Ion Channels by drugs • The Modulated Receptor Hypothesis • Hille, B. (1977). Local anesthetics: hydrophilic and hydrophobic pathways for the drug-receptor reaction. Journal of General Physiology69, 497-515.

  24. KPQ Y1795 I II III IV + + + + + + + + + + + + + + + + + + + + + + + + + + + + COOH NH2

  25. Na+ Na+ Na+ X Closed Open Inactivated Na+ channel open state inactivation

  26. Wild-Type (WT) Y179C (YC) DKPQ 50ms Chandra, R., et. al., (1998) Am. J. Physiol. 274, H1643-H1654.

  27. Binding Sites of LA’s in Na channels:Vladimir Yarov-Yarovoy, Jancy C. McPhee, Diane Idsvoog, Caroline Pate, Todd Scheuer, and William A. Catterall J. Biol. Chem., Vol. 277, Issue 38, 35393-35401, September 20, 2002

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