16 Oct 07 K 812 16 Oct 07 Long QT Syndrome 1. 16 Oct 072.

16 Oct 07

K 812

16 Oct 07

Long QT Syndrome

1

16 Oct 07 2

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16 Oct 07 4

Channel Inward rectifier IK1 Kir2.1 Transient outward Ito KV4.2 / KV4.3 Delayed rectifier IK slow IKs KV7.1 rapid IKr KV11.1 HERG ultrarapid IKur KV1.5

K+ currents and channels in the heart

16 Oct 07 5

0

2

3

1

4

2 = IKr (delayed rectifier – r)

3 = IKs (delayed rectifier – s) 1 = Ito (transient outward)

4 = IK1 (inward rectifier)

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16 Oct 07

KV channel biophysical properties

I

V-80 400

steady-state I-V

activation (conductance) curve

0.5

1.0

I/I m

ax

IK = gK (Em - EK)

V = IR g = 1/R

Ohm’s Lawand

9

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16 Oct 07 11

KV channel biophysical properties

I

V-80 400

• K current - voltage-dependent• K selective – Nernst equilibriumpotential

Nernst equilibrium potential

fully-activated relationship

IK = gK (Em - EK)

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16 Oct 07 15

Block with E-4031 (dofetilide)

Class III Antiarrhythmic – blocks IKr (HERG)

16 Oct 07 16

Superior Vena Cava

SA Node

Atrium

AV Node

Purkinje

Tricuspid Valve

Mitral Valve

Ventricle

ECGP

PR QRS

Q

R

S

T

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

16 Oct 07 18

LQT 1 IKs () KVLQT1a KV7.1 potassium

LQT 2 IKr () HERG KV11.1 potassium

LQT 3 INa () SCN 5A NaV1.5 sodium

LQT 4 Ankyrin B not a channel

LQT 5 IKs () Min K potassium

LQT 6 IKr () MiRP potassium

LQT 7 IK1 KCNJ2 Kir2.1 potassium

LQT 8 ICa () CACNA1c CaV1.2 calcium

LQT 9 Caveolin 3 not a channel

LQT 10 INa () SCN 4B sodium

Long QT syndrome associated genes

16 Oct 07 19

A boy with congenital Long QT syndrome that becomes “torsades de pointes”.

Q T

QT interval > 0.6 s

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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

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 07 24

Huang, F.-D. et al. Circulation 2001;104:1071-1075

Representative currents recorded from oocytes expressing WT or mutant HERG channels

16 O 07 25

16 Oct 07 26

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.

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 07 27

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 07 28

Huang, F.-D. et al. Circulation 2001;104:1071-1075

Voltage dependence of HERG channel activation and inactivation

16 Oct 07 29

16 Oct 07 30