K 812 16 Oct 07 Long QT Syndrome

K 812 16 Oct 07 Long QT Syndrome 16 Oct 07 1

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K+ currents and channels in the heart 16 Oct 07 4

1 = Ito (transient outward) 2 = IKr (delayed rectifier – r) 16 Oct 07 3 = IKs (delayed rectifier – s) 4 = IK 1 (inward rectifier) 5

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KV channel biophysical properties activation (conductance) curve I/Imax 1. 0 I Ohm’s Law steady-state I-V -80 16 Oct 07 0. 5 V = IR and g = 1/R 0 40 V IK = g. K (Em - EK) 9

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KV channel biophysical properties fully-activated relationship I -80 IK = g. K (Em - EK) • K current - voltage-dependent • K selective – Nernst equilibrium potential 16 Oct 07 0 40 V Nernst equilibrium potential 11

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Block with E-4031 (dofetilide) 16 Oct 07 Class III Antiarrhythmic – blocks IKr (HERG) 15

Superior Vena Cava SA Node Atrium AV Node Purkinje Tricuspid Valve Mitral Valve Ventricle R T ECG P Q S 16 Oct 07 PR 16 QRS

16 Oct 07 Long QT syndrome - QT > 450 ms 17

Long QT syndrome associated genes LQT 1 IKs (a) KVLQT 1 a KV 7. 1 potassium LQT 2 IKr (a) HERG KV 11. 1 potassium LQT 3 INa (a) SCN 5 A Na. V 1. 5 sodium LQT 4 Ankyrin B not a channel LQT 5 IKs (b) Min K potassium LQT 6 IKr (b) Mi. RP potassium LQT 7 IK 1 KCNJ 2 Kir 2. 1 potassium LQT 8 ICa (a) CACNA 1 c Ca. V 1. 2 calcium LQT 9 LQT 10 16 Oct 07 INa (b) Caveolin 3 not a channel SCN 4 B sodium 18

A boy with congenital Long QT syndrome that becomes “torsades de pointes”. Q T QT interval > 0. 6 s 16 Oct 07 19

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Long-QT Syndrome-Associated Missense Mutations in the Pore Helix of the HERG Potassium Channel Fu-De Huang; Jun Chen; Monica Lin; Mark T. Keating; Michael C. Sanguinetti Circulation. 2001; 104: 1071 16 Oct 07 23

Location of LQTS-associated missense mutations in pore helix of HERG channel subunit Huang, F. -D. et al. Circulation 2001; 104: 1071 -1075 16 Oct 07 Copyright © 2001 American Heart Association 24

Representative currents recorded from oocytes expressing WT or mutant HERG channels Huang, F. -D. et al. Circulation 2001; 104: 1071 -1075 16 O 07 25

Anatomy of a current waveform in a single CHO-h. ERG cell. An example of whole-cell h. ERG current is shown here. From a holding potential of -80 m. V, the voltage is first stepped to -50 m. V for 500 ms. This step to a voltage in which h. ERG channels are not opened is important for leak subtraction. From -50 m. V the voltage is stepped to +20 m. V for 2 seconds. At this voltage, h. ERG channels open and steady-state current is observed. From +20 m. V, the voltage is stepped back down to -50 m. V. An immediate increase in h. ERG current amplitude is observed for the following reasons. The inactivation rate constant is faster than the deactivation rate constant. This means that inactivation is quickly removed, but there are many channels that have not proceeded to the closed state from the opened 16 Oct 07 state. This results in the observed "rebound" or tail current. Typically, this tail current amplitude is measured and the leak current measured at -50 m. V is subtracted out. 26

Chemiluminescence of single oocytes expressing HA-tagged WT HERG or mutant HERG channel subunits Huang, F. -D. et al. Circulation 2001; 104: 1071 -1075 16 Oct 07 Copyright © 2001 American Heart Association 27

Properties of currents induced by coexpression of WT and mutant HERG channel subunits Huang, F. -D. et al. Circulation 2001; 104: 1071 -1075 16 Oct 07 28

Voltage dependence of HERG channel activation and inactivation Huang, F. -D. et al. Circulation 2001; 104: 1071 -1075 16 Oct 07 29

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