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Title page for ETD etd-11172008-100413


Type of Document Dissertation
Author Thiel, William Howard
Author's Email Address william.thiel@gmail.com
URN etd-11172008-100413
Title Proarrhythmic defects in Timothy Syndrome require calmodulin kinase II
Degree PhD
Department Pharmacology
Advisory Committee
Advisor Name Title
Alfred George Committee Chair
Brian Wadzinski Committee Member
Dan Roden Committee Member
Roger Colbran Committee Member
Keywords
  • CaMKII
  • Calcium Channel
  • cardiology
  • arrhythmia
Date of Defense 2008-09-19
Availability unrestricted
Abstract
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.
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