Biophysical Investigation of Short QT Syndrome-associated Mutation in Voltage-gated Potassium Channels IKs and KCNQ1

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dc.contributor.advisor Plant, Leigh
dc.contributor.author Park, Juhee
dc.date.accessioned 2015-05-18T14:53:29Z
dc.date.available 2015-05-18T14:53:29Z
dc.date.issued 2015
dc.identifier.uri http://hdl.handle.net/10192/30573
dc.description.abstract Short QT Syndrome (SQTS) is a potentially fatal cardiac arrhythmia, characterized by a reduced QT interval in the electrocardiogram. A gain-of-function mutation, V307L, observed in the voltage-gated potassium channel KCNQ1 gene in a SQTS patient has implicated this disease as a cardiac channelopathy. In the heart, KCNQ1 (Q1) subunits assemble with accessory subunits, KCNE1 (E1), to produce the IKs channel, which passes slow outwardly rectifying potassium current that contributes to the cardiac action potential repolarization. To understand the effect of the V307L mutation on the biophysical properties of IKs and Q1 channels, we used whole-cell patch clamp to investigate the channel gating and total internal reflection fluorescence (TIRF) microscopy to visualize the channel expression at the membrane. Electrophysiological studies indicated that the V307L mutation makes the transition from closed to open state more favorable for IKs channels, but not for Q1 channels, by shifting the half-maximal activation voltage and accelerating the activation kinetics. TIRF microscopy illustrated that the V307L mutation decreased the IKs (but not Q1) channel density. In conclusion, we propose two testable mechanisms for E1-dependent gain-of-function phenotype associated with the V307L mutation. The V307L mutation in the pore of Q1 may introduce a partially open state or decrease the energetic barrier to the voltage sensing domain movement upon depolarization of the membrane. These models illustrate how the V307L mutation may result in increased K+ efflux associated with expedited cardiac action potential repolarization and highlight the significance of the 307 site in IKs and Q1 gating.
dc.description.sponsorship Brandeis University, Graduate School of Arts and Sciences
dc.format.mimetype application/pdf
dc.language English
dc.language.iso eng
dc.publisher Brandeis University
dc.relation.ispartofseries Brandeis University Theses and Dissertations
dc.rights Copyright by Juhee Park 2015
dc.subject SQTS
dc.subject KCNQ1
dc.subject KCNE1
dc.subject IKs
dc.subject ion channel
dc.subject patch clamp
dc.subject TIRF
dc.title Biophysical Investigation of Short QT Syndrome-associated Mutation in Voltage-gated Potassium Channels IKs and KCNQ1
dc.type Thesis
dc.contributor.department Department of Biochemistry
dc.degree.name MS
dc.degree.level Masters
dc.degree.discipline Biochemistry
dc.degree.grantor Brandeis University, Graduate School of Arts and Sciences
dc.description.esploro 2


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