electrical system of the heart
DESCRIPTION
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. 10 -9. 10 -8. 10 -7. 10 -6. 10 -5. [Noradrenaline] (M). - PowerPoint PPT PresentationTRANSCRIPT
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Molecular Determinants of Na+ and K+ Channel Regulation in Heart:
Ion 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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[Noradrenaline] (M)10-9 10-8 10-7 10-6 10-5(Kass & Wiegers, J Physiol. 1982)
Nor
mal
ized
cha
nge
in I C
aN
orm
aliz
ed c
hang
e in
I Ks
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Targeting Proteins
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AKAPS
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KCNE1KCNQ1
KCNQ1+KCNE1
200 pA/pF
KCNQ1
0.5 s
50 pA/pF
B
A
(Splawski et al, Circ102;1178-85, 2000)
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The KCNQ1 Macromolecular Complex
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-40 -20 0 20 40 60 800
50
100 control cAMPOA
IKs.
tail
(pA
/pF)
(mV)-40 -20 0 20 40 60 80
0
50
100
(pA/
pF)
(mV)
wtKCNQ1+KCNE1(E1)+yotiao(Y) LZm KCNQ1+E1+Y
LZ mutation ablates functional up regulation
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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
Mutations of inactivation gate alter inactivation
Dins1795NH2
E1784K
D1790G
COOH
++++++++++++
++++++++++++
++++++++++++
++++++++++++
KPQIFM
I II III IV
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h H 1 K P Q
-8 0 -4 0 4 0 8 0
-1 00
-5 0pA
m V
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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 2;103(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 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.
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-40 -20 0 20 40 60 800
50
100
(pA
/pF)
(mV)
G589D KCNQ1+E1+Y
Mutation G589D ablates channel regulation
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Drugs Can Induce LQT