Advisor

Jonathan Abramson

Date of Award

1-31-2017

Document Type

Dissertation

Degree Name

Doctor of Philosophy (Ph.D.) in Applied Physics

Department

Physics

Physical Description

1 online resource (viii, 100 pages)

DOI

10.15760/etd.3360

Abstract

The cardiac ryanodine receptor (RyR2) plays a key role in excitation-contraction coupling (ECC). Mutations in RyR2 are known to be linked to the arrhythmogenic disorder, catecholaminergic polymorphic ventricular tachycardia (CPVT), a deadly disease which is characterized by a leak of calcium from sarcoplasmic reticulum and a decrease in calmodulin (CaM) binding. A novel drug, 84F2, shown to inhibit arrhythmias in RyR2-R176Q heterozygous CPVT mouse hearts (2.5 µg/kg), decrease spark frequency in cells derived from CPVT mice (IC50 = 35 nM), and inhibit RyR2 single channel activity at low nanomolar concentrations (IC50 = 8 nM). When CaM is added back to RyR2, 84F2's ability to inhibit channel activity is suppressed approximately 250 fold. A metabolite of 84F2, 78F3, is shown to also be active in the inhibition of RyR2. We propose that 84F2 decreases arrhythmias by binding to the CaM deficient RyR2, but does not affect normal ECC when CaM is present. This work characterizes for the first time a class of drugs whose inhibitory affects are dependent upon the removal of CaM from RyR2.

Persistent Identifier

http://archives.pdx.edu/ds/psu/19609

Available for download on Wednesday, January 31, 2018

Included in

Physics Commons

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