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

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Molecular Determinants of Na and K Channel
Regulation in HeartIon Channels as Targets of
Neurohormones and Drugs
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Electrical System of the Heart
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Ion Channels in Heart
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?-Adrenergic Stimulation Shortens AP Duration
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Normalized change in ICa
Normalized change in IKs
(Kass Wiegers, J Physiol. 1982)
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Targeting Proteins
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AKAPS
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LZ mutation ablates functional up regulation
wtKCNQ1KCNE1(E1)yotiao(Y)
LZm KCNQ1E1Y
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State-Dependent Block

• Na Channels as models of drug targets

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Voltage-Gated Sodium Channels
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Na Channel Stucture
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Gating and S4 Segments
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Molecular Determinants of Inactivation
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Inherited Mutations and Cardiac Arrhythmias
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Lessons from Rare Genetic Disorders
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A1924T
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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 2103(1)89-95.   "LQT1
patients experienced the majority of their events
(62) during exercise, and only 3 occurred
during rest/sleep. "
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J Am Coll Cardiol 2001 Feb37(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.
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Mutation G589D ablates channel regulation
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Drugs Can Induce LQT