Beta Adrenergic Signaling in Heart

	Roles of local signaling complexes

The Long QT Syndrome:
Dysfunction in Ventricular Repolarization

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

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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

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Receptor stimulation to Local Signaling

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Adaptor Proteins:

	Channel Microsignaling Domains: Macromolecular Complexes

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Calcium Channel Complex

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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

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Disruption of Macromolecular Complexes in Disease

AP Prolongation Can Trigger Arrhythmias

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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.

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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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