Modelling HERG-KCNE2 Functional Interaction
Catherine
Lloyd
Bioengineering Institute, University of Auckland
Model Structure
The protein products of the genes HERG and KCNE2 form the subunits of the rapid delayed rectifier potassium channel (IK,r). Mutations in KCNE2 have been associated with acquired long-QT syndrome and ventricular fibrillation, whilst mutations in the HERG gene have been associated with the inherited form of the disease. The mechansisms underlying the KCNE mutation-induced cardiac arrhythmias are not clear. An improved understanding of the functional interactions between the two gene products could facilitate the development of superior therapeutic approaches for particular lesions in either HERG or KCNE2.
In the study described here, Mazhari et al. characterise the functional effects of KCNE2 coexpression with HERG. They develop a Markov state model of both HERG and HERG-KCNE2 coassembly (see below), and use this model to elucidate mechanisms of interaction. In addition, ion channel gating models provide a quantitative description of gating behaviour and they provide clues to channel strcture. In order to predict the consequences of HERG-KCNE2 interactions for action potential repolarisation, the Markov state model was embedded within the Winslow et al. Canine Ventricular Cell Model, 1999.
The model has been described here in CellML (the raw CellML description of the Mazhari et al. 2001 model can be downloaded in various formats as described in ).
The complete original paper reference is cited below:
Molecular Interactions Between Two Long-QT Syndrome Gene Products, HERG and KCNE2, Rationalized by In Vitro and In Silico Analysis, Reza Mazhari, Joseph L. Greenstein, Raimond L. Winslow, Eduardo Marban, and H. Bradley Nuss, 2001,
Circulation Research
, 89, 33-38. (Full text (HTML) and PDF versions of the article are available on the Circulation Research website.) PubMed ID: 11440975
reaction diagram
State diagram of the HERG and HERG+hKCNE2 Marcov model. C1, C2, and C3 are closed states. O is the open state, and I is the inactivated state.
While coexpression of HERG and KCNE2 alters both the kinetics and density of the ionic current, including these effects in the Winslow et al. action potential model predicts that only changes in current density significantly affect repolarisation. Therefore the main functional consequence of KCNE2 on action potential morphology is through modulation of IK,r density. The mutations associated with long-QT syndrome that result in only modest changes of gating kinetics may be an epiphenomena or alternatively, they may modulate action potential repoalrisation via interactions with alternative pore-forming potassium channel alpha subunits.
kcne2
long-QT syndrome
hreg
cardiac myocyte
electrophysiology
long-qt syndrome
cardiac
cardiac myocytes
The University of Auckland, Bioengineering Institute
c.lloyd@auckland.ac.nz
11440975
open state
O
Richard
Winslow
L
closed state 2
C2
closed state 3
C3
closed state 1
C1
Eduardo
Marban
The University of Auckland
The Bioengineering Institute
Reza
Mazhari
2007-06-05T09:44:00+12:00
Mazhari et al's model of the molecular interactions between two long-QT
syndrome gene products, HERG and KCNE2.
cardiac myocytes
Catherine
Lloyd
May
inactivated state
I
Catherine
Lloyd
May
The new version of this model has been re-coded to remove the reaction element and replace it with a simple MathML description of the model reaction kinetics. This is thought to be truer to the original publication, and information regarding the enzyme kinetics etc will later be added to the metadata through use of an ontology.
The model runs in the PCEnv simulator but gives a flat output.
keyword
Molecular Interactions Between Two Long-QT Syndrome Gene Products,
HERG and KCNE2, Rationalized by In Vitro and In Silico Analysis
89
33
38
2001-07-06 00:00
Catherine Lloyd
H
Nuss
Bradley
This is the CellML description of Mazhari et al's model of the molecular interactions between two long-QT syndrome gene products, HERG and KCNE2.
This model can be run in PCEnv but it gives a flat output. I suspect it needs to be embedded within a whole cell model in order to give a reasonable output.
2003-05-23T00:00:00+00:00
Circulation Research
Joseph
Greenstein
L