Post on 18-Dec-2015
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)
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
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)
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 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
16 Oct 07 23
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