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The effect of inter-helix loop length and composition on the voltage sensitivity of jShak1 and mouse Kv1.2 Open Access


Other title
voltage sensitivity
Kv channels
Loop length
Type of item
Degree grantor
University of Alberta
Author or creator
Sharmin, Nazlee
Supervisor and department
Gallin, Warren (Department of Biological Sciences)
Examining committee member and department
French, Robert ( Department of Physiology & Pharmacology, University of Calgary)
Ali, Declan (Department of Biological Sciences)
Light, Peter (Department of Pharmacology)
Tierney, Keith (Department of Biological Sciences)
Gallin, Warren (Department of Biological Sciences)
Department of Biological Sciences
Physiology, Cell, and Developmental Biology
Date accepted
Graduation date
Master of Science
Degree level
The mechanism by which voltage-gated potassium ion (Kv) channels respond to changes in membrane polarization is one of the most widely studied yet least understood aspects of Kv channels. The voltage sensing S4 helix contains 4-7 basic residues that form an electrostatic interaction network with the acidic residues in the S2 and S3 helices to stabilize the open and the closed state in response to voltage change. Previous studies have demonstrated the importance of S3-S4 loop length and composition in shaping the voltage response of Kv channels. In this thesis, I have undertaken a series of mutagenesis experiments on the mouse Kv1.2 (V50 approximately -13 mV) and a jellyfish Kv1 channel jShak1 (V50 approximately +26 mV) to evaluate how the S3-S4 loop affects the voltage sensitivity and regulates the interaction within the VSD in two different channel backgrounds. I have mutated the S3-S4 loop by changing the length and composition and have mutated an acidic residue on the S2 helix that stabilizes the open state by forming salt bridges with basic residues of the S4 helix. In most Kv1 family channels this residue is glutamate (E226 in mouse, E283 in D. melanogaster Shaker), but in the jellyfish channel it is asparagine (N227). I have also made pairwise combinations of the loop-mutants and the S2 mutants to evaluate how their effects interact. Our study found that the effects of the loop mutations on the two channels are significantly different, both in terms of loop length and composition, indicating that the loops affect the propensity for channel opening through factors other than simple constraints on relative movement of S3 and S4. Mutations in the S2 residue reveal the packing of the helices in the two channels differs significantly - in the mouse Kv1.2 mutations of E226 to shorter and less charged residues creates an omega pore through the voltage sensing domain, whereas mutation of N227 in jShak1 leads to strong interactions between the effects of shortening the S3-S4 loop and increasing the size of the residue 227 side-chain, indicating a tighter packing of the helices in jShak1 than in mouse Kv1.2.
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