Page 50 - YORAM RUDY BOOK FINAL

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However, there is greater preference energetically for open-pore conformations with greater

number of activated (high) voltage sensors, increasing their open-pore probability. Thus, the
simulations support the mechanism of sequential gating in channel activation. 5. Integration of
the molecular structure-based I dynamics into the ORd model of human ventricular myocyte
Ks
revealed that I is more effective than KCNQ1 in shortening the APD at fast rate and that
Ks
modulation of KCNQ1 by KCNE1 is crucial for normal rate-dependent AP repolarization.

The computational approaches described above provide a framework for linking a channel
structural molecular movement during gating to its electrophysiological function as a carrier of

transmembrane ionic current. The next section examines how alterations in function of ion
channels by genetic mutations affect the whole-cell action potential, giving rise to a cardiac
arrhythmia phenotype.

2.9. Linking Ion-Channel Mutations to the Whole-Cell Electrophysiological Phenotype

Abnormal repolarization of the cardiac action potential provides a substrate for life
threatening cardiac arrhythmias. Mutations in genes that encode cardiac ion channels can lead

to altered channel function, which in turn perturbs the action potential. While certain mutations
affect conduction, repolarization is more susceptible because of its dependence on a delicate
balance between multiple currents. The function of mutated channels is studied experimentally
in expression systems (e.g., Xenopus oocyte), away from the cellular environment where they

function and interact to generate the action potential. In this section, a computational approach is
used to integrate the information from isolated preparations into the functioning cardiac cell and
to relate the molecular-level findings to the whole-cell electrophysiology and to clinical
phenotypes. Examples are provided of mutations in the SCN5A gene that encodes the sodium

channels (I ) and in HERG that encodes the rapid delayed rectifier potassium channels (I ).
Na
Kr
Clinically, the mutations are linked to the hereditary long QT syndrome (LQT) that presents as
prolongation of the QT interval on the ECG (see section 4.3). LQT is associated with life-
threatening cardiac arrhythmias and sudden death. LQT mutations in SCN5A are classified as

LQT3 and in HERG as LQT2. KCNQ1 mutations that alter I , such as E160K presented in the previous
Ks
section, are classified as LQT1 and are the most common LQT mutations. Because mutations alter
structural elements of the ion-channel protein and specific kinetic states and inter-state
transitions of the channel, single-channel based Markov models are used in the simulations.

The ΔKPQ Mutation in SCN5A and LQT3

The ΔKPQ mutation is a deletion of three amino acids from a highly conserved region of

the III-IV linker between transmembrane domains III and IV of the channel α-subunit (Figure 2.5).
The III-IV linker is involved in fast inactivation of the I channel. Experiments in expression systems
Na
show that the ΔKPQ defect leads to two modifications of channel function: (1) faster activation and
recovery from inactivation and (2) transient complete loss of inactivation. 124,125,126,127