Molecular Determinants of Na+ and K+ Channel Regulation in Heart: Ion Channels as Targets of Neurohormones and Drugs

Electrical System of the Heart

Ion Channels in Heart

-Adrenergic Stimulation Shortens AP Duration

(Kass & Wiegers, J Physiol. 1982) 10-9 10-8 10-7 10-6 10-5 Normalized change in ICa Normalized change in IKs (Kass & Wiegers, J Physiol. 1982) [Noradrenaline] (M) 10-9 10-8 10-7 10-6 10-5

Targeting Proteins

AKAPS

A B KCNE1 KCNQ1 KCNQ1+KCNE1 (Splawski et al, Circ102;1178-85, 2000) 200 pA/pF 0.5 s 50 pA/pF B A (Splawski et al, Circ102;1178-85, 2000)

The KCNQ1 Macromolecular Complex

LZ mutation ablates functional up regulation wtKCNQ1+KCNE1(E1)+yotiao(Y) LZm KCNQ1+E1+Y

State-Dependent Block Na Channels as models of drug targets

Voltage-Gated Sodium Channels

Na Channel Stucture

Gating and S4 Segments

Molecular Determinants of Inactivation

Inherited Mutations and Cardiac Arrhythmias

Lessons from Rare Genetic Disorders

Mutations of inactivation gate alter inactivation Dins1795 NH2 E1784K D1790G COOH + KPQ IFM I II III IV A1924T

Clinical studies: linking sympathetic nerve stimulation to Long-Sydrome (LQT-1) Genotype-phenotype correlation in the long-QT syndrome: gene-specific triggers for life-threatening arrhythmias. Schwartz PJ, et al. Circulation 2001 Jan 2;103(1):89-95.   "LQT1 patients experienced the majority of their events (62%) during exercise, and only 3% occurred during rest/sleep. "

J Am Coll Cardiol 2001 Feb;37(2):562-8 A founder mutation of the potassium channel KCNQ1 in long QT syndrome: implications for estimation of disease prevalence and molecular diagnostics. Piippo K, Swan H, Pasternack M, Chapman H, Paavonen K, Viitasalo M, Toivonen L, Kontula K. Department of Medicine, University of Helsinki, Finland.

Mutation G589D ablates channel regulation G589D KCNQ1+E1+Y

Drugs Can Induce LQT