Show simple item record

dc.contributor.authorSutherland-Deveen, Morganen
dc.date.accessioned2018-07-05T19:02:54Z
dc.date.available2018-07-05T19:02:54Z
dc.identifier.urihttp://hdl.handle.net/1974/24301
dc.description.abstractThe human ether-à-go-go-related gene (hERG) encodes the pore-forming alpha subunit of the channel that conducts the rapidly activating delayed rectifier potassium current (IKr) in the heart. Reductions in IKr cause long QT syndrome (LQTS), which predisposes individuals to potentially fatal arrhythmias that can be triggered by stress. One potential link between stress and hERG function is protein kinase C (PKC) activation. However, PKC regulation of hERG is complex and seemingly conflicting results have been reported. In the present study, both acute and chronic effects of PKC activation were investigated using phorbol 12-myristate 13-acetate (PMA) on hERG channels expressed in human embryonic kidney (HEK) 293 cells. Western blot analyses demonstrate that chronic PKC activation increases expression of intracellular and membrane-bound hERG protein. However, the increased channel abundance is accompanied by a decrease in hERG current (IhERG) after chronic PMA treatment. Furthermore, patch clamp data reveal that acute PKC activation reduces IhERG, and this effect is dependent on the presence of the N-terminus of the channel. Upon truncation of the N-terminus of hERG, chronic activation of PKC increases both hERG protein expression and current. The increase in hERG protein is partially mediated by reduced degradation of mature hERG channels. This results from increased phosphorylation of neural precursor cell expressed developmentally down-regulated protein 4 subtype 2 (Nedd4-2), an E3 ubiquitin ligase that mediates hERG degradation. These findings demonstrate that PKC regulates hERG in a balanced manner, increasing expression while decreasing current.en
dc.language.isoengen
dc.relation.ispartofseriesCanadian thesesen
dc.rightsQueen's University's Thesis/Dissertation Non-Exclusive License for Deposit to QSpace and Library and Archives Canadaen
dc.rightsProQuest PhD and Master's Theses International Dissemination Agreementen
dc.rightsIntellectual Property Guidelines at Queen's Universityen
dc.rightsCopying and Preserving Your Thesisen
dc.rightsThis publication is made available by the authority of the copyright owner solely for the purpose of private study and research and may not be copied or reproduced except as permitted by the copyright laws without written authority from the copyright owner.en
dc.subjecthERGen
dc.subjectProtein Kinase Cen
dc.subjectPhorbol Esteren
dc.subjectRegulationen
dc.subjectIKren
dc.titleDifferential Regulation of hERG Current and Expression by Activation of Protein Kinase C Using Phorbol Ester Treatmenten
dc.typethesisen
dc.description.degreeM.Sc.en
dc.contributor.supervisorZhang, Shetuanen
dc.contributor.departmentBiomedical and Molecular Sciencesen
dc.degree.grantorQueen's University at Kingstonen


Files in this item

Thumbnail

This item appears in the following Collection(s)

Show simple item record