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ORCID
https://orcid.org/0000-0002-0084-9341
Access Type
Open Access Thesis
Document Type
thesis
Degree Program
Molecular & Cellular Biology
Degree Type
Master of Science (M.S.)
Year Degree Awarded
2022
Month Degree Awarded
September
Abstract
Ca2+/calmodulin-dependent protein kinase II (CaMKII) is involved in Ca2+signaling throughout the body. CaMKII is enriched in the hippocampus and required for learning and memory formation. Four highly conserved genes encode CaMKII in vertebrates: A, B, G, and D. All CaMKII variants are constituted of a kinase domain, regulatory segment, variable linker, and hub domain. These domains comprise an individual subunit which oligomerize together via the hub domain to form multimeric holoenzymes. These four genes are most variable in the linker domain due to extensive alternative splicing. The variable linker significantly impacts the activation of CaMKIIA. Herein, I attempt to develop an in vitro assay which resembles physiological activation of CaMKII via Ca2+ oscillations. I provide preliminary data which indicate that alternative splicing of the variable linker in CaMKIIA modulates the Ca2+ frequency dependent autonomy of these variants. Additionally, neuronal CaMKII variants of CaMKIIA and CaMKIIB decode Ca2+ oscillations into different levels of autonomous activity. Lastly, I assess the impacts of three de novo mutations (Q274P, R275H, and F294S) on Ca2+/CaM sensitivity in CaMKIID by providing data that these 3 mutants increase the sensitivity of CaMKIId to Ca2+/CaM and that Q274P and F294S mutants display Ca2+/CaM independent activity.
DOI
https://doi.org/10.7275/31142560
First Advisor
Margaret Stratton
Second Advisor
Peter Chien
Third Advisor
Rafael Fissore
Recommended Citation
Dunn, Matthew J., "Determining CaMKII Variant Activities and Their Roles in Human Disease" (2022). Masters Theses. 1229.
https://doi.org/10.7275/31142560
https://scholarworks.umass.edu/masters_theses_2/1229