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dc.contributor.authorMason, Amanda King
dc.date.accessioned2012-03-07T18:22:30Z
dc.date.available2012-03-07T18:22:30Z
dc.date.issued2008
dc.identifier.urihttp://hdl.handle.net/10713/1010
dc.descriptionUniversity of Maryland, Baltimore. Molecular Medicine. Ph.D. 2008en_US
dc.description.abstractThe inwardly rectifying family of potassium (Kir)2.x channels underlie the strong inward rectifier potassium current and set the resting membrane potential and conductance in many excitable and non-excitable cells. Differential expression and regulation of Kir2.X isoforms have been suggested to underscore cell-specific regulation of membrane excitability, but the mechanisms are unclear. In this dissertation, I explore whether Kir2.1 and Kir2.3 are controlled by channel-specific endocytic and postendocytic trafficking mechanisms. I found that unique interactions with clathrin adaptor proteins differentially regulate the cell surface density of Kir2.1 and Kir2.3. A novel diisoleucine motif, unique to the carboxyl-terminus of the Kir2.3 channel, interacts with the clathrin adaptor AP-2, and siRNA-mediated suppression of the AP-2 alpha subunit attenuates internalization of Kir 2.3. By contrast, a separate AP-2 "YXXphi" trafficking signal coordinates internalization of Kir2.1. Degradative pathways also diverge between the Kir2.1 and Kir2.3 channels, specifically targeting the Kir2.1 channel to the lysosomal compartment. In summary, while both channels depend on interaction with clathrin adaptor proteins for trafficking, the interaction motifs and ultimate fates of the channels differ. Overall, the results suggest that intricate endocytic and post-endocytic regulatory control parallels the complicated biosynthetic regulatory mechanisms to ensure accurate physiological control of the Kir channels.en_US
dc.language.isoen_USen_US
dc.subjectBiology, Physiologyen_US
dc.titleMolecular mechanisms of endocytic and post-endocytic trafficking regulating Kir2.x channelsen_US
dc.typedissertationen_US
dc.contributor.advisorWelling, Paul A.
dc.identifier.ispublishedYes
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