Type
Text
Type
Dissertation
Advisor
White, Thomas | Valiunas, Virginijus | Brink, Peter | El-Magharabi, Raafat | Verselis, Vytautas.
Date
2015-12-01
Keywords
Biophysics | atrial fibrillation, connexins, currents, electrical, gap junctions, permeability
Department
Department of Physiology and Biophysics.
Language
en_US
Source
This work is sponsored by the Stony Brook University Graduate School in compliance with the requirements for completion of degree.
Identifier
http://hdl.handle.net/11401/76753
Publisher
The Graduate School, Stony Brook University: Stony Brook, NY.
Format
application/pdf
Abstract
Abstract of the Dissertation Biophysical properties of Cx40 mutants as they relate to Atrial Fibrillation by Ana Santa Cruz Doctor of Philosophy in Physiology and Biophysics Stony Brook University 2015 Gap junctions (GJs) are integral membrane proteins and are the only known cellular structures that allow a direct cell-to-cell transfer of signaling molecules by forming densely packed arrays of hydrophilic channels that bridge the opposing membranes of neighboring cells. A gap junction channels is formed with two hexameric connexons. Each connexon is comprised of six connexin subunits. Cell-to-cell action potential propagation in the heart is mediated through gap junction channels that are located in regions called intercalated discs found at lateral cell to cell borders in cardiomyocytes. The three Cx40 mutations (A96S, M163V and G38D) are associated with atrial fibrillation and retain the ability to form functional channels. This dissertation is motivated by questions such as how these mutations could be changing the biophysical and expression properties of the channels compared to wild type (WT) Cx40. In our first aim, we showed that all three mutations exhibited a similar macroscopic coupling and also similar voltage dependencies comparable to WT Cx40. We also showed that the unitary conductance of G38D channels was higher than the WT Cx40. The A96S and M163V mutants exhibited unitary conductances comparable to the WT. In the second aim, we showed that the M163 and G38D mutations exhibited a higher LY (Lucifer yellow) permeability when compared with WT, while the A96S permeability is very similar to WT. A96S and M163V exhibited a higher EthBr (Ethidium bromide) permeability when compared with wild type and G38D is almost impermeable. Finally in our third aim, we showed that all the mutants are able to reach the membrane and form plaques. The results of our work show that even when the three mutations exhibited a similar total conductance and voltage dependence the permeability of the mutations to LY and EthBr is different when compared with WT. An important role of Cx is their ability to form intracellular channels capable of supporting intercellular exchange of molecules up to 1,000 Da. The change in permeability properties of the mutations could be implicated in the mechanism of atrial fibrillation and reentry arrhythmias. | 118 pages
Recommended Citation
santa cruz garcia, ana b, "Biophysical properties of Cx40 mutants as they relate with Atrial fibrillation" (2015). Stony Brook Theses and Dissertations Collection, 2006-2020 (closed to submissions). 2633.
https://commons.library.stonybrook.edu/stony-brook-theses-and-dissertations-collection/2633