Research

MARKOV IKr

Cellular consequences of HERG mutations in Long-QT Syndrome

Clancy, C. E. and Y. Rudy (2001). "Cellular consequences of HERG mutations in the long QT syndrome: precursors to sudden cardiac death." Cardiovasc Res 50(2): 301-13.

A variety of mutations in HERG, the major subunit of the rapidly activating component of the cardiac delayed rectifier IKr, have been found to underlie the congenital Long-QT syndrome, LQT2. LQT2 may give rise to severe arrhythmogenic phenotypes leading to sudden cardiac death. We attempt to elucidate the mechanisms by which heterogeneous LQT2 genotypes can lead to prolongation of the action potential duration (APD) and consequently the QT interval on the ECG. We develop Markovian models of wild-type (WT) and mutant IKr channels and incorporate these models into a comprehensive model of the cardiac ventricular cell.

Formulation of the wild-type and mutant IKr channels are provided below.

IKr formulation
IKr   = G Kr * P(O) * (V m -E K )
P(O) = open probability of I Kr
G Kr = 0.0135 * ([K + ] o ) 0.59
E K = (R*T/F) * ln([K + ] o /[K + ] i )

Wild-type rate constants
C1 ==> O or C1 ==> I 
aa =  65.5*e-3  * exp (0.05547153*(v-36))
C2 ==> C1 
a in =  2.172
C3 ==> C2 
a =  55.5 *e-3 * exp (0.05547153*(v-12))
C2 ==> C3
b =   2.357*e-3 * exp (-0.036588*(v)) 
C1 ==> C2
b in =  1.077
O ==> C1
bb =  2.9357*e-3 * exp (-0.02158*(v)) 
I ==> O
ai =  0.439 * exp (-0.02352*(v+25)) * 4.5/[K + ] o
O ==> I 
bi =  0.656 * exp (0.000942*(v)) * (4.5/ [K + ] o ) 0.3
I ==> C1 
mu =  (ai * bb * aa)/(aa *bi)

T474I rates
C1 ==> O 
aa =  65.5*e-3 * exp (0.05547153*(v+25)) 
C3 ==> C2 
a =  55.5*e-3 * exp (0.05547153*(v+6))

R56Q rates
C2 ==> C3 
b =  2.357*e-3 * exp (-0.036588*(v)) * 10.5 
O ==> C1
bb =  2.9357*e-3 * exp (-0.02158*(v))* 6.3

N629D rates
O ==> I 
bi = 0.0
N629D loss of selectivity
Na:K permeability (P Na /P K ) = 0.65
E K = (R*T/F) * ln([K + ] o + P Na /P K * [Na + ] o / [K + ] i   + P Na /P K * [Na + ] i )

Syntax note:     e-n is 10 -n      exp (n) is e n

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