Ca2+ activated signaling pathways coordinate contraction in the heart, but these pathways cause disease upon excessive activation. Intracellular Ca2+ activates the multifunctional Ca2+ and calmodulin dependent protein kinase II (CaMKII) and activated CaMKII increases Ca2+ entry, by a feed-forward process, through voltage-gated (CaV1.2) Ca2+ channels in cardiac myocytes. Timothy Syndrome an autosomal dominant, monogenic disease that induces cellular Ca2+ overload in cardiomyocytes, due to a loss of voltage dependent inactivation of ICa. Based on the proarrhythmic properties of CaMKII, I hypothesized that excess ICa in Timothy Syndrome would activate CaMKII and that CaMKII would serve as a positive feedback and proarrhythmic signal. A ventricular myocyte model of TS showed significant increases in CaMKII activity and a cellular proarrhythmic phenotype that included action potential prolongation, increased ICa facilitation and afterdepolarizations. A highly specific CaMKII inhibitor, and not an inactive control peptide, reversed the dynamic ICa facilitation increases, normalized the action potential duration and prevented afterdepolarizations in TS ventricular myocytes. The ability of CaMKII to phosphorylate the CaV1.2 C-terminus was also examined.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-11172008-100413 |
| Date | 02 December 2008 |
| Creators | Thiel, William Howard |
| Contributors | Brian Wadzinski, Dan Roden, Roger Colbran, Alfred George |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu/available/etd-11172008-100413/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Vanderbilt University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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