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dc.contributor.authorSangoi, Matthewen
dc.date2016-09-06 09:52:20.314
dc.date.accessioned2016-09-06T20:23:35Z
dc.date.issued2016-09-06
dc.identifier.urihttp://hdl.handle.net/1974/14840
dc.descriptionThesis (Master, Biomedical & Molecular Sciences) -- Queen's University, 2016-09-06 09:52:20.314en
dc.description.abstractThe human ether-a-go-go-related gene (hERG) encodes the voltage-gated K+ channel, hERG (Kv11.1). This channel passes the rapidly-activating delayed rectifier K+ current (IKr), which is important for cardiac repolarization. A reduction in IKr due to loss-of-function mutations or drug interactions causes long QT syndrome (LQTS), which can lead to cardiac arrhythmias and sudden cardiac death. The density of hERG channels in the plasma membrane is a key determinant of normal physiological function, and is balanced by trafficking to and from the cell surface. Many LQTS-associated hERG mutations result in a trafficking deficiency of otherwise functional channels. Thus, elucidating mechanisms of hERG regulation at the plasma membrane is useful for the prevention and treatment of LQTS. We previously demonstrated that M3 muscarinic receptor activation increases mature hERG expression through a Gq protein-dependent protein kinase C (PKC) pathway. In addition to conventional Gq protein-coupling, M3 receptors recruit β-arrestins upon agonist binding. Traditionally known for their role in receptor desensitization and internalization, β-arrestins also act as adaptor proteins to facilitate G protein-independent signaling. In the present work, I investigated the exclusive effect of β-arrestin signaling on hERG expression by utilizing an arrestin-biased M3 designer receptor (M3D-arr) exclusively activated by clozapine-N-oxide (CNO). By expressing M3D-arr in hERG-HEK cells and treating with CNO under various conditions, I found that M3D-arr activation increased mature hERG expression and current. Within this paradigm, M3D-arr recruited β-arrestin to the plasma membrane, and promoted the PI3K-dependent activation of Akt. I further found that the activated Akt acted through phosphatidylinositol 3-phosphate 5-kinase (PIKfyve) and Rab11 to facilitate endosomal recycling of hERG channels to the plasma membrane.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.rightsCreative Commons - Attribution - CC BYen
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.subjectβ-arrestin signallingen
dc.subjectCardiac Electrophysiologyen
dc.subjectPI3Ken
dc.subjectAkten
dc.subjectKv11.1en
dc.subjectRab11en
dc.subjectPIKfyveen
dc.subjectPotassium Channelen
dc.subjectLong QT Syndromeen
dc.subjectM3 Muscarinic Receptorsen
dc.subjecthERGen
dc.subjectDesigner Receptorsen
dc.titleβ-Arrestin-Mediated Regulation of the Human Ether-a-go-go-Related Gene (hERG) Potassium Channelen
dc.typethesisen
dc.description.restricted-thesisThe work comprising this thesis is in the process of being published in a peer-reviewed scientific journal. It is preferred that the work remains confidential until publication is finalized.en
dc.description.degreeM.Sc.en
dc.contributor.supervisorZhang, Shetuanen
dc.contributor.departmentBiomedical and Molecular Sciencesen
dc.embargo.terms1825en
dc.embargo.liftdate2021-09-05
dc.degree.grantorQueen's University at Kingstonen


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