Abstract
Rationale: Understanding the roles of ion currents is crucial to predict the action of pharmaceuticals and mutations in different scenarios, and thereby to guide clinical interventions in the heart, brain and other electrophysiological systems. Our ability to predict how ion currents contribute to cellular electrophysiology is in turn critically dependent on our characterization of ion channel kinetics - the voltage-dependent rates of transition between open, closed and inactivated channel states. Objective: The hERG potassium channel plays a fundamental role in controlling electrical activity in the heart and many other tissues. There is a well-established link between hERG mutations, or block by pharmaceuticals, and increased arrhythmic risk. We present a new method for rapidly exploring and characterizing ion channel kinetics, applying it to the hERG channel as an example, with the aim of generating a quantitatively predictive representation of the ion current. Methods & Results: We fit a mathematical model to currents evoked by a novel 8 second sinusoidal voltage clamp in CHO cells over-expressing hERG1a. The model is then used to predict over 5 minutes of recordings in the same cell in response to further protocols: a series of traditional square step voltage clamps, and also a novel voltage clamp comprised of a collection of physiologically-relevant action potentials. We demonstrate that we can make predictive cell-specfic models that outperform the use of averaged data from a number of different cells, and thereby examine which changes in gating are responsible for cell-cell variability in current kinetics. Conclusions: Our technique allows rapid collection of consistent and high quality data, from single cells, and produces more predictive mathematical ion channel models than traditional approaches. The approach will be widely applicable to other voltage-gated ion currents both in the heart and other electrophysiological systems.
Highlights
1471-Pos Board B380 Molecular Mechanisms of Human-ether-a-go-go-related channel (hERG) Potassium Channel Interactions with Ivabradine: Importance of the Lipophilic Route Sergei Noskov, Henry Duff, Laura Perissinotti, Jiqing Guo, Meruyert Kudaibergenova
Human-ether-a-go-go-related channel is a voltage gated potassium channel expressed in heart and brain. hERG is notorious for its interaction with various medications blocking Kþ transport, thereby prolonging action potentials and resulting in an arrhythmias
ZKCNH6a channels produced a characteristic resurgent current in response to an action potential voltage waveform that was similar to that observed from hERG channels. zKCNH6a channels displayed a sensitivity to blocker compounds that was similar to hERG channels: dofetilide (5 mM) and terfenadine (5 mM) produced 8352% (n=5) and 7452% (n=5) block of zKCNH6a channels, respectively, and 8954% (n=5) and 8254% (n=5) block of hERG channels, respectively
Summary
1471-Pos Board B380 Molecular Mechanisms of hERG Potassium Channel Interactions with Ivabradine: Importance of the Lipophilic Route Sergei Noskov, Henry Duff, Laura Perissinotti, Jiqing Guo, Meruyert Kudaibergenova. 1468-Pos Board B377 External Protons Accelerate Deactivation of hERG Channels by Destabilizing the Relaxed State of the Voltage-Sensor Yu Shi, Samrat Thouta, Tom Claydon. These data suggest that the relaxed state of the voltage sensor is destabilized by external protons and that this contributes to faster deactivation gating in hERG channels. A number of reports have shown that hydrogen can reduce HERG current by a mechanism that does not involve an effect on channel deactivation and which likely involves pore block.
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