Real Time Screening for GIRK1/4 Channel Blockers

University Of South Carolina At Columbia, Columbia SC

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Abstract

DESCRIPTION (provided by applicant): Atrial fibrillation (AF) is the most commonly occurring cardiac arrhythmia and is responsible for significant morbidity, mortality and health care costs. The incidence of AF is expected to increase markedly with the aging population. However, the use of conventional anti-arrhythmic drugs for treating AF has been limited due to their pro- arrhythmic actions. One novel target for AF drug therapy is the acetylcholine-activated K+ channel (IK,Ach). This channel is a member of the super-family of proteins known as the G protein-coupled inward rectifier K+ (GIRK) channels and is composed of the GIRK1/4 subunits. IK,Ach opens upon binding of acetylcholine to the cardiac muscarinic (M2) receptor and mediates vagal effects on heat rate and atrial excitation. Recent studies indicate that IK,Ach is constitutively active in AF, thus enhancing atrial excitability. The goal of this project is to develop a high throughput-screening (HTS) assay for identifying new drugs that inhibit IK,Ach. The hypothesis to be tested in this project is that membrane potential-sensitive dyes can be used as a HTS sensor in screening for IK,Ach blockers in immortalized cardiac cell lines. In Aim #1 methods for the measurement and analysis of IK,Ach, using a fluorescent imaging plate reader (FLIPR), will be established. In Aim #2 a high density HTS assay will be developed and screened with a library of ion channel blockers. New compounds identified in the assay will be tested in an isolated rat heart model of AF. Overall, the long term goal of work in the laboratory is to develop novel therapeutic strategies for treating cardiac arrhythmias. PUBLIC HEALTH RELEVANCE: Atrial fibrillation (AF) is the most commonly occurring cardiac arrhythmia and is responsible for significant morbidity, mortality and health care costs. The incidence of AF is expected to increase markedly with the aging population. The goal of this project is to identify new drugs for treating AF.