Date of Completion

4-2-2015

Embargo Period

3-29-2016

Keywords

Kalirin-7, Dendritic Spine, Postsynaptic Density, Phosphoinositide, Phosphorylation, GEF, Rac1

Major Advisor

Dr. Betty A. Eipper

Associate Advisor

Dr. Richard E. Mains

Associate Advisor

Dr. Kimberly L. Dodge-Kafka

Associate Advisor

Dr. Eric S. Levine

Field of Study

Biomedical Science

Degree

Doctor of Philosophy

Open Access

Open Access

Abstract

Through studies of a single RhoGEF, Kalirin-7, the work presented herein provides insight into several of the key mechanisms underlying postsynaptic neurotransmission in the central nervous system. Much of this work has focused on the significance of non-enzymatic functions of Kal7, highlighting the importance of spatial and temporal control of multi-domain proteins and the postsynaptic protein/ lipid interactome. Our work on Kalrn promoter usage and phosphorylation (Chapters 5 & 6) expands upon our understanding of synaptic protein diversity and regulation. Additionally, Kalrn promoter switching has implications for the poorly-understood mechanisms by which cytoskeletal dynamics and membrane trafficking are coordinated at the postsynaptic density (PSD). Combined with our biochemical characterization of the Sec14 domain (Chapter 4), our exploration of Kalrn promoter usage also touches upon the importance of synaptic lipid metabolism. Thus, by enhancing our knowledge of the functions and regulatory mechanisms of Kal7, we highlight the extraordinary intricacies of postsynaptic signaling and the necessity for precise control of multiple cellular events. Furthermore, we provide a large body of evidence to support the notion that large, multi-domain proteins serve diverse roles at the synapse, which are crucial for normal brain function.

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