Regulation of Ion Channels by Drugs and Hormones

	Roles of local signaling complexes
	Lessons from Investigation of Human Disease
	Pharmacology Unique to Voltage-Gated Ion channels

Adrenergic Regulation of Cardiac Electrical Activity:
 Lessons from Human Disease

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:

	Molecular Basis for Receptor/Substrate Diversity:  Channel as 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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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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Use-Dependent Block

	Pulse-dependent channel availability depends on recovery from inactivation;
	Drug-Bound Channels recovery slower than drug-free channels;
	Channels are not available for excitation when drug-bound.

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Block Develops During Repetitive electrical Activity

	Block During Depolarization (systole)
	Unblock During Repolarization (Diastole)

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Targeting Different Channels for Distinct Therapeutic Goals:

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