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

2. 16 Oct 072

3. 3

4. 4 K + currents and channels in the heart

5. 16 Oct 075 2 = I Kr (delayed rectifier – r) 3 = I Ks (delayed rectifier – s) 1 = I to (transient outward) 4 = I K1 (inward rectifier)

6. 16 Oct 076

7. 7

8. 8

9. K V channel biophysical properties I V -8040 0 steady-state I-V activation (conductance) curve 0.5 1.0 I/I max I K = g K (E m - E K ) V = IRg = 1/R Ohm’s Law and 9

10. 16 Oct 0710

11. 16 Oct 0711 K V channel biophysical properties I V -8040 0 K current - voltage-dependent K selective – Nernst equilibrium potential Nernst equilibrium potential fully-activated relationship I K = g K (E m - E K )

12. 16 Oct 0712

13. 16 Oct 0713

14. 16 Oct 0714

15. 16 Oct 0715 Block with E-4031 (dofetilide) Class III Antiarrhythmic – blocks I Kr (HERG)

16. 16 Oct 0716 Superior Vena Cava SA Node Atrium AV Node Purkinje Tricuspid Valve Mitral Valve Ventricle ECG P PRQRS Q R S T

17. 16 Oct 0717 Long QT syndrome - QT > 450 ms

18. 16 Oct 0718 LQT 1 I Ks (  ) KVLQT1aK V 7.1potassium LQT 2 I Kr (  ) HERGK V 11.1potassium LQT 3 I Na (  ) SCN 5ANa V 1.5sodium LQT 4Ankyrin Bnot a channel LQT 5 I Ks (  ) Min Kpotassium LQT 6 I Kr (  ) MiRPpotassium LQT 7I K1 KCNJ2K ir 2.1potassium LQT 8 I Ca (  ) CACNA1cCa V 1.2calcium LQT 9Caveolin 3not a channel LQT 10 I Na (  ) SCN 4Bsodium Long QT syndrome associated genes

19. 16 Oct 0719 A boy with congenital Long QT syndrome that becomes “torsades de pointes”. QT QT interval > 0.6 s

20. 16 Oct 0720

21. 16 Oct 0721

22. 16 Oct 0722

23. 16 Oct 0723 Circulation. 2001;104:1071 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

24. Copyright ©2001 American Heart Association Huang, F.-D. et al. Circulation 2001;104:1071-1075 Location of LQTS-associated missense mutations in pore helix of HERG channel subunit 16 Oct 0724

25. Huang, F.-D. et al. Circulation 2001;104:1071-1075 Representative currents recorded from oocytes expressing WT or mutant HERG channels 16 O 0725

26. 16 Oct 0726 Anatomy of a current waveform in a single CHO-hERG cell. An example of whole-cell hERG current is shown here. From a holding potential of -80 mV, the voltage is first stepped to -50 mV for 500 ms. This step to a voltage in which hERG channels are not opened is important for leak subtraction. From -50 mV the voltage is stepped to +20 mV for 2 seconds. At this voltage, hERG channels open and steady-state current is observed. From +20 mV, the voltage is stepped back down to -50 mV. An immediate increase in hERG 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 state. This results in the observed "rebound" or tail current. Typically, this tail current amplitude is measured and the leak current measured at -50 mV is subtracted out.

27. Copyright ©2001 American Heart Association Huang, F.-D. et al. Circulation 2001;104:1071-1075 Chemiluminescence of single oocytes expressing HA-tagged WT HERG or mutant HERG channel subunits 16 Oct 0727

28. Huang, F.-D. et al. Circulation 2001;104:1071-1075 Properties of currents induced by coexpression of WT and mutant HERG channel subunits 16 Oct 0728

29. Huang, F.-D. et al. Circulation 2001;104:1071-1075 Voltage dependence of HERG channel activation and inactivation 16 Oct 0729

30. 16 Oct 0730