Defense Date


Document Type


Degree Name

Master of Science



First Advisor

Carlos A. Villalba-Galea


It is commonly assumed that the voltage dependence for activation of voltage-gated channels is an intrinsic characteristic of the protein that remains unchanged during electrical activity. However, sporadic reports have suggested otherwise by showing that voltage dependence changes in a use-dependent manner resulting in a voltage dependence shift towards negative potentials (Bezanilla et al., 1982; Bruening-Wright and Larsson, 2007; Kuzmenkin et al., 2004; Labro et al., 2012; Larsson and Elinder, 2000; Olcese et al., 1997; Piper et al., 2003; Shirokov et al., 1992). Although the mechanism underlying the shift in voltage dependence remains unclear, this process seems to have two components. The first stage has been proposed to be related to the stabilization of the open conformation of the pore domain (Labro et al., 2012). The second stage seems to involve the stabilization of the activated state of the voltage sensing domain (VSD) (Labro et al., 2012; Lacroix et al., 2011) through a process known as VSD relaxation (Villalba-Galea, 2012; Villalba-Galea et al., 2008). This latter process has been proposed to be an intrinsic property of the VSD in which the domain is stabilized in an active-like state referred to as the relaxed state. Yet, the underlying mechanism remains unknown. This project expands upon the hypothesis that the movement of the fourth transmembrane (S4) segment of the VSD can induce conformational changes using the loop connecting the third and fourth transmembrane segments (S3-S4 loop) to couple VSD activation to VSD relaxation. Using the Drosophila potassium-selective, voltage-gated channel Shaker as a model, I show here that mutations in the S3-S4 loop of the VSD modulate the time constant of deactivation of the conductance and cause an apparent partial immobilization of the sensing charges of the VSD. These results hint, for the first time, at a mechanism for VSD relaxation. Particularly, these results indicate that the S3-S4 loop is intimately involved in the mechanism of coupling VSD activation to VSD relaxation.


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Date of Submission

August 2013

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