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Divalent Effects on Permeatin and Gating of T-type calcium channels

Lopin, Kyle V
http://rave.ohiolink.edu/etdc/view?acc_num=case1364042187

Abstract Details

2013, Doctor of Philosophy, Case Western Reserve University, Physiology and Biophysics.
Cells carefully regulate their intracellular ion composition and their membrane potential. Voltage gated calcium channels change both of these properties by allowing Ca2+ to enter the cell, causing membrane depolarization and the entry of Ca2+ which acts as important signaling molecule. Much research over the last few decades has gone into discovering the different types of voltage gated calcium channels and their permeation and gating properties. Many models have been proposed to explain how ions permeate through calcium channels. The second chapter of this thesis uses a 2 binding site 3 barrier model of permeation to fit a wide range of permeation data previously collected from a1G T-type calcium channels. Using this model of permeation we were able to fit permeation and block data well over a wide range of concentrations and voltages for four different ions (Ca2+, Ba2+, Mg2+, Na+). T-type calcium channels are expressed in a wide range of cells in a diverse set of tissue types. In the third chapter of this thesis, electrophysiological measurements were made of the effects of block and permeation of Fe2+ on a1G channels and the model of permeation was extended to this physiological ion to examine the role that calcium channels can play in iron overload condition and in cadmium toxicity. Fe2+ entry through calcium channels has potentially deleterious consequences as this entry is unregulated and in iron overload condition where cells have an impaired iron efflux mechanism, calcium channels may play a role in increasing the labile iron pool inside a cell. This labile iron pool is unbound iron that is redox active and can cause oxidative damage to proteins and lipids. We observed currents through a1G calcium channels carried by Fe2+ showing that a1G calcium channels can allows ferrous iron (Fe2+) to enter into cells. Rates of Fe2+ entry in physiological concentrations of Fe2+ using the extended model of permeation showed that a1G calcium channels can be a mechanism for non transferrin bound iron entry. The fourth chapter of this thesis focuses on the permeation and blocking properties of Cd2+ on a1G channels. Cd2+ is known to have cytotoxic effects and while the exact mechanism of Cd2+ toxicity is still being elucidated, cadmium is increasingly contaminating the environment leading to increased exposure to humans. Electrophysiology experiments show that Cd2+ permeates extremely well through the T-type calcium channel and only incompletely block the channel. The model of permeation was extended again for a1G channels to include Cd2+, and it was able to fit the data collected in Cd2+ and to predict the transport rate of Cd2+ through the channels in Cd2+ concentrations seen in populations exposed to environmental containment. The calculated rates of Cd2+ entry showed that in Cd2+ exposure, a1G calcium channels can be a mechanism for Cd2+ entry into cells.
Stephen Jones, PhD (Advisor)
Witold Surewicz, PhD (Committee Chair)
William Schilling, PhD (Committee Member)
Corey Smith, PhD (Committee Member)
David Friel, PhD (Committee Member)
164 p.
Biophysics; Physiology
T-Type; Calcium Channels; iron; cadmium; Erying rate theory; Permeation

Recommended Citations

Citations

  • Lopin, K. V. (2013). Divalent Effects on Permeatin and Gating of T-type calcium channels [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1364042187

    APA Style (7th edition)

  • Lopin, Kyle. Divalent Effects on Permeatin and Gating of T-type calcium channels. 2013. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1364042187.

    MLA Style (8th edition)

  • Lopin, Kyle. "Divalent Effects on Permeatin and Gating of T-type calcium channels." Doctoral dissertation, Case Western Reserve University, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=case1364042187

    Chicago Manual of Style (17th edition)

case1364042187
573
© 2013, some rights reserved.Creative Commons License Divalent Effects on Permeatin and Gating of T-type calcium channels by Kyle V Lopin is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License. Based on a work at etd.ohiolink.edu.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.