Phan, Kevin (2017) Probing the molecular and structural basis of voltage sensor gating in Kv11.1 ion channels. Masters thesis, Victor Chang Cardiac Research Institute. Faculty of Medicine, UNSW.
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2017 Kevin Phan _Masters Thesis UNSW VCCRI.pdf Download (4MB) | Preview |
Abstract
Congenital mutations in the cardiac Kv11.1 channel can cause long QT syndrome type 2 (LQTS2), a heart rhythm disorder associated with sudden cardiac death. Mutations act either by reducing protein expression at the membrane, and/or by perturbing the intricate gating properties of Kv11.1 channels. A number of clinical LQTS2-associated mutations have been reported in the first transmembrane segment (S1) of Kv11.1 channels but the role of this region of the channel is largely unexplored. In part this is due to problems defining the extent of the S1 helix, as a consequence of its low sequence homology with other Kv family members. Here we used NMR spectroscopy and electrophysiological characterization to show that the S1 of Kv11.1 channels extends seven helical turns, from Pro405 to Phe431, and is flanked by unstructured loops. Functional analysis suggests that pre-S1 loop residues His402 and Tyr403 play an important role in regulating the kinetics and voltage dependence of channel activation and deactivation. Multiple residues within the S1 helix also play an important role in fine-tuning the voltage dependence of activation, regulating slow deactivation, and modulating C-type inactivation of Kv11.1 channels. We demonstrate that for Kv11.1, activation and deactivation processes are not simple reversal transitions, but rather deactivation and inactivation processes are likely to be coupled. Analyses of LQTS2-associated mutations in the pre-S1 loop or S1 helix of Kv11.1 channels demonstrate perturbations to both protein expression and most gating transitions. Thus S1 region mutations would reduce both the action potential repolarizing current passed by Kv11.1 channels in cardiac myocytes, as well as the current passed in response to premature depolarizations that normally helps protect against the formation of ectopic beats.
| Item Type: | Thesis (Masters) |
|---|---|
| Additional Information: | SUPERVISORS: Vandenberg, Jamie, Victor Chang Cardiac Research Institute, Faculty of Medicine, UNSW; Perry, Matthew, Victor Chang Cardiac Research Institute, Faculty of Medicine, UNSW |
| Subjects: | R Medicine > R Medicine (General) |
| Depositing User: | Repository Administrator |
| Date Deposited: | 09 Nov 2017 23:07 |
| Last Modified: | 09 Nov 2017 23:09 |
| URI: | https://eprints.victorchang.edu.au/id/eprint/664 |
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