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The Inactivation Mechanisms of Shaker IR and Kv2.1 Potassium Channels: Lessons from Pore Mutation

Jamieson, Quentin
http://rave.ohiolink.edu/etdc/view?acc_num=case1396357775

Abstract Details

2014, Doctor of Philosophy, Case Western Reserve University, Physiology and Biophysics.
Voltage-gated potassium channels have enchanted electrophysiologists for over 60 years since the pioneering work of Hodgkin and Huxley. Potassium channel inactivation is interesting biophysically since it comprises multiple distinct molecular mechanisms that can be characterized. However, inactivation is also interesting physiologically since it can impact the excitability of tissues as diverse as central neurons, pancreatic beta cells, and photoreceptors. Elucidating the molecular mechanisms underlying slow inactivation in Shaker IR and Kv2.1 channels has been the focus of this thesis. A single point mutation in Shaker IR (T449) has been shown to affect the kinetics of slow inactivation up to 100-fold. Originally, this effect was ascribed to C-type inactivation but Shaker is now known to possess two forms of slow inactivation: C-type (preferential open-state inactivation) and U-type (preferential closed-state inactivation). C-type inactivation occurs via outer-pore constriction while the mechanism of U-type inactivation remains unknown. This thesis uses established techniques of electrophysiology, pharmacology, and mutagenesis to demonstrate that mutants of Kv2.1 outer pore residue Y380 (homologous to Shaker T449) undergo U-type inactivation alone, and that mutants of Shaker T449 affect C-type inactivation alone. The study also hypothesizes that Kv2.1 channels lack C-type inactivation as it exists in Shaker IR and that C- and U-type inactivation have different molecular mechanisms. Furthermore, this study advances pore mutation as yet another tool (in addition to pharmacological and electrophysiological approaches) to help separate C- from U-type inactivation in channels with complex slow inactivation. In both Shaker and Kv2.1 channels, slow inactivation in wild-type and mutant channels was characterized with a 12-state Markov model concluding that C-type inactivation is not exclusive open-state inactivation and U-type inactivation is not exclusive closed-state inactivation.
Stephen Jones, Ph.D. (Advisor)
Witold Surewicz, Ph.D. (Committee Chair)
William Schilling, Ph.D. (Committee Member)
Diana Kunze, Ph.D. (Committee Member)
Corey Smith, Ph.D. (Committee Member)
Isabelle Deschênes, Ph.D. (Committee Member)
Sudha Chakrapani, Ph.D. (Committee Member)
230 p.
Applied Mathematics; Biology; Biomedical Research; Biophysics; Experiments; Molecular Biology; Neurosciences; Physiology
slow inactivation; potassium channels; kinetic models; shaker; excitability; electrophysiology; mutagenesis; modeling

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Citations

  • Jamieson, Q. (2014). The Inactivation Mechanisms of Shaker IR and Kv2.1 Potassium Channels: Lessons from Pore Mutation [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1396357775

    APA Style (7th edition)

  • Jamieson, Quentin. The Inactivation Mechanisms of Shaker IR and Kv2.1 Potassium Channels: Lessons from Pore Mutation. 2014. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1396357775.

    MLA Style (8th edition)

  • Jamieson, Quentin. "The Inactivation Mechanisms of Shaker IR and Kv2.1 Potassium Channels: Lessons from Pore Mutation." Doctoral dissertation, Case Western Reserve University, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=case1396357775

    Chicago Manual of Style (17th edition)

case1396357775
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This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.