Beta Adrenergic Signaling in Heart Roles of local signaling complexes.

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Presentation transcript:

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)

LQTS: Genetic Linkage to Multiple Ion Channel Genes

AP Prolongation Can Trigger Arrhythmias

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

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

 -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

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

Receptor stimulation to Local Signaling

Adaptor Proteins: Channel Microsignaling Domains: Macromolecular Complexes

Calcium Channel Complex

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

K Channel Complex

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

Human Heart KCNQ1 forms a macromolecular complex

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

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

The KCNQ1 Macromolecular Complex

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

Disruption of Macromolecular Complexes in Disease

AP Prolongation Can Trigger Arrhythmias

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,

NH 2 COOH IIIIVIII  KPQ Y1795

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

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

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, , September 20, 2002