Page 56 - Cardiac Electrophysiology | A Modeling and Imaging Approach

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Figure 2.36. HERG mutations. A. Structure of cardiac HERG showing locations of mutations
discussed here. Kinetic changes caused by the mutations are summarized below the structure.
B. Markovian model of I .
Kr

T474I is a point mutation in the S2-S3 linker; it shifts the activation curve to more negative

potentials (in experiments V was shifted by -27.3 mV relative to wild-type). Experiments also
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showed reduction of macroscopic current density. R56Q is another point mutation; it is located
in the Per-Arnt-Sim (PAS) domain of the N-terminus, which in the wild-type interacts with the

channel to slow the rate of deactivation. Mutations in this region accelerate channel deactivation.
N629D alters the channel kinetics in two ways: (1) loss of inactivation and (2) loss of K selectivity,
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allowing the channel to conduct other monovalent cations (in particular Na ).
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