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Beta Adrenergic Signaling in Heart Roles of local signaling complexes.

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Presentation on theme: "Beta Adrenergic Signaling in Heart Roles of local signaling complexes."— Presentation transcript:

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  -Adrenergic Stimulation Shortens AP Duration (Kass & Wiegers, J Physiol. 1982)

8  -AR Regulation of Cardiac AP: A Balance of Inward and Outward Current L-type Calcium Channel current Increased Slow I Ks potassium channel Current Increased

9 KCNE1KCNQ1 (KvLQT-1) KCNQ1+KCNE1 200 pA/pF KCNQ1 0.5 s 50 pA/pF (Splawski et al, Circ102;1178-85, 2000) (minK) Molecular Architecture of I KS Channel Revealed Through LQTS studies

10 Receptor stimulation to Local Signaling

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14 Adaptor Proteins: Channel Microsignaling Domains: Macromolecular Complexes

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17 Calcium Channel Complex

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

20 K Channel Complex

21 Functional regulation in TG + Myocytes but not in CHO cells: Phosphatase and Kinase activity

22 Human Heart KCNQ1 forms a macromolecular complex

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

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

25 The KCNQ1 Macromolecular Complex

26 KCNQ1+ E1+YLZm KCNQ1+E1+Y LZ mutation ablates functional up regulation

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28 Disruption of Macromolecular Complexes in Disease

29 AP Prolongation Can Trigger Arrhythmias

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31 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 Physiology 69, 497-515.

32 NH 2 COOH ++++++++++++++ ++++++++++++++ ++++++++++++++ ++++++++++++++ IIIIVIII  KPQ Y1795

33 Na + X Closed Open Inactivated Na+ channel open state inactivation

34 50ms  KPQ Chandra, R., et. al., (1998) Am. J. Physiol. 274, H1643-H1654. Wild-Type (WT)Y179C (YC)

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36 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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