readme.html

<pre>
This is the readme.txt for the models associated with the paper.

Clancy CE, Rudy Y. Cellular consequences of HERG mutations in the long QT 
syndrome:precursors to sudden cardiac death. Cardiovasc Res 2001;50:301-313.

Abstract:
BACKGROUND: A variety of mutations in HERG, the major subunit of the rapidly 
activating component of the cardiac delayed rectifier I(Kr), have been found
to underlie the congenital Long-QT syndrome, LQT2. LQT2 may give rise to 
severe arrhythmogenic phenotypes leading to sudden cardiac death.
OBJECTIVE: 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. 
METHODS: We develop Markovian models of wild-type (WT) and mutant I(Kr)
channels and incorporate these models into a comprehensive model of the 
cardiac ventricular cell. RESULTS: Using this virtual transgenic cell model, 
we describe the effects of HERG mutations on the cardiac ventricular action
potential (AP) and provide insight into the mechanism by which each defect 
results in a net loss of repolarizing current and prolongation of APD.
CONCLUSIONS: This study demonstrates which mutations can prolong APD
sufficiently to generate early afterdepolarizations (EADs), which may trigger
life-threatening arrhythmias. The severity of the phenotype is shown to 
depend on the specific kinetic changes and how they affect I(Kr) during the
time course of the action potential. Clarifying how defects in HERG can lead
to impaired cellular electrophysiology can improve our understanding of the 
link between channel structure and cellular function.
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<a href="http://rudylab.wustl.edu/research/cell/methodology/markov/clancy_herg.htm">
Rudy lab site reference to model </a>

Model:
C1<==>C2<==>C3<==>O<==>I

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 
---------------------------------------------------------------------
To run the models:
XPP: start with the command

xppaut IERG_Mar.ode

Mouse click on Initialconds, and then (G)o.
This makes a trace similar to fig 4B (0mV) of the paper.
To obtain the other traces in figure 4B you can press
the Param button on the top of the XPP screen.  Enter
a new vtest (e.g. one of -30, -20, ... 30, 40) and click
Go.

To run as a series of voltage-clamp studies, click Range over, 
change to 'vtest', 
and then select voltage protocol from 
Steps (8) , Start (-30) and End (40).

Regarding xpp program, please contact with 
Bard Ermentrout's website http://www.pitt.edu/~phase/
describes how to get and use xpp (Bard wrote xpp).

These model files were submitted by:

Dr. Sheng-Nan Wu, Han-Dong Chang, and Jiun-Shian Wu
Dept Physiol
Natl Cheng Kung U Med Coll
Tainan 70101, Taiwan

snwu@mail.ncku.edu.tw
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