Clancy-Rudy Markovian Model of Ion Channels 2001
Catherine
Lloyd
Bioengineering Institute, University of Auckland
Model Status
This CellML model represents the IKrR56Q mutant epicardial cell. For more details on the curation status of this model please see this separate notes document.
Model Structure
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.
The original paper reference is cited below:
Cellular consequences of HERG mutations in the long QT syndrome: precursors to sudden cardiac death, Colleen E. Clancy and Yoram Rudy, 2001,
Cardiovascular Research, 50, 301-313. PubMed ID: 11334834
cell diagram of the Clancy-Rudy model showing ionic currents, pumps and exchangers within the sarcolemma and the sarcoplasmic reticulum
A schematic diagram describing the current flows across the cell membrane that are captured in the Clancy-Rudy model.
cardiac
Markovian Model
electrophysiology
keyword
Cellular consequences of HERG mutations in the long QT syndrome: precursors to sudden cardiac death (IKrR56Q Mutant Epicardial Cell)
The University of Auckland, Bioengineering Research Group
Catherine
Lloyd
May
Catherine
Lloyd
May
Catherine
Lloyd
May
Catherine
Lloyd
May
The model for cardiac i_Na includes three closed states (C3, C2 and
C1) an open, conducting state (O) and fast and slow inactivation
states (IF and Is, respectively). P_i is the probability of a
channel occupying a particular state (i), which is determined by a
system of linear first order differential equations.
The Clancy-Rudy Markovian Model of Wild-Type Ikr Channels in a Cardiac
Ventricular Cell, 2001
Ventricular Myocyte
Mammalia
In 1999, Viswanathan, Shaw and Rudy published a paper which updated
the original Luo-Rudy II Model. It describes how the slow component
of the time-dependent potassium current has two activation gates,
one fast (Xs1) and one slow (Xs2). This paper is referenced below.
Yoram
Rudy
2002-02-25
Changed the model name so the model loads in the database easier.
In 1995, Zeng, Laurita, Rosenbaum and Rudy published a paper which
updated the original Luo-Rudy II Model. It describes two distinct
delayed rectifier potassium currents, i_Kr and i_Ks. They also
identified a second "T-type" calcium channel. This paper is
referenced below.
2002-01-21
Catherine
Lloyd
May
In 2000, Faber and Rudy published a paper which updated the original
Luo-Rudy II Model. It describes an additional, sodium-activated
potassium current. This paper is referenced below.
updated curation status, removed publication link from documentation
Catherine
Lloyd
May
10318671
Cardiovascular Research
2009-06-05T15:17:33+12:00
2002-07-18
2002-01-06
In 1997, Shaw and Rudy published a paper which modified the
original Luo-Rudy II Model by adding an ATP-dependent potassium
current. This paper is referenced below.
2002-02-20
Updated metadata to conform to the 16/1/02 CellML Metadata 1.0
Specification.
Changed equations after checking them with the mathml validator.
Autumn
Cuellar
A
2001-10-08T00:00:00+00:00
Added more metadata.
2003-04-05
Catherine
Lloyd
May
10777735
c.lloyd@auckland.ac.nz
2001-05-01
Changed equations of the fast_sodium_current from Hodgkin-Huxley type
to Markovian.
2002-02-28
Autumn
Cuellar
A.
Made MathML id's unique
2001-10-19
Corrected beta_K1 differential equation.
Peter
Villiger
J
Catherine
Lloyd
May
9349389
Removed document type definition as this is declared as optional
according to the W3C recommendation.
7788872
2001-10-24
Cellular consequences of HERG mutations in the long QT syndrome: precursors to sudden cardiac death
50
301
313
James
Lawson
Richard
11334834
The use of a Markovian model to represent i_Na deviates from the
traditional Hodgkin-Huxley approach used in many ionic models
(including Luo-Rudy II). The Markovian scheme represents distinct
channel states and coupling between these states, which allowed
Clancy and Rudy to relate state-specific kinetic properties of ion
channels to the electophysiological behaviour of the whole cell.
Made changes to some of the metadata, bringing them up to date with
the most recent working draft (26th September) of the Metadata
Specification.
Catherine Lloyd
The University of Auckland
The Bioengineering Research Group
Catherine
Lloyd
May
Corrected units.
This is the CellML description of Clancy and Rudy's mathematical Markovian model of the wild-type cardiac delayed rectifier current (Ikr). They incorporate this into a comprehensive model of the cardiac ventricular cell, which is based on the modified Luo-Rudy II Model. The use of a Markovian model to represent IKr deviates from the traditional Hodgkin-Huxley approach.
2001-12-10
Altered some of the connections.
2005-04-20
Colleen
Clancy
E