Advancing the health and well-being of animals and people


Principal Investigator:   Huai-hu Chuang

Department of Biomedical Sciences
Contact Information: Email: hac29@cornell.edu; Phone: 607-253-4303
Sponsor: American Heart Association – Founders Affiliate
Grant Number: 12GRNT9750008
Title: Stimulatory Mechanisms of RGS Proteins on G-Protein Activated Potassium Current GIRK
Annual Direct Cost: $60,000
Project Period: 01/01/2012-12/31/2014

DESCRIPTION (provided by applicant): The physiological cardiac rhythm is controlled by the autonomic nervous system. In a healthy heart, parasympathetic nerves release acetylcholine (ACh), a neurotransmitter that activates inward rectifier potassium channels (KACh) to slow down the heartbeat. However, in diseased hearts, ACh produces paradoxical effects to precipitate atrial tachyarrhythmia by prematurely converting atria back to the excitable state in a period normally refractory to electric triggers before the start of next cardiac cycle. In a severe case, it leads to atrial fibrillation (AF), irregular atrial contraction that creates turbulent blood flow and increases risks of blood coagulation. Blood clots in atria, if accidentally entering circulation, can occlude arteries, compromise blood supplies to major organs and cause strokes and heart attacks, the main leading causes of death in US. Better medical control of atrial arrhythmia will thus reduce clinical mortality or morbidity of cardiovascular diseases. Thanks to its restriction of expression to only atria, KACh is a good candidate for management of AF compared to other ion channels more widely present in the heart. Drugs selectively targeting KACh will be less likely to suppress ventricular functions or induce other life-threatening ventricular arrhythmia. Activation of KACh by acetylcholine involves intracellular communication between transmitter or hormone receptors and potassium channels via signal transducer G-proteins. Consequently, there are multiple potential molecular sites for pharmacological intervention of KACh. We will dissect the mechanism involved in the G-protein activation step of KACh currents, with a focus on the stimulation by a special class of regulator proteins (RGS proteins). Using the Xenopus oocyte expression system, we aim at identifying (1) specific structural elements within G-proteins and (2) molecular compositions of RGS required for the stimulation of receptor-K channel coupling. (3) We will define rate-limiting reactions of the coupling process. At the end, we expect to provide the framework for designing methods to specifically control neurotransmitter-induced KACh currents, but not other autonomic control of cellular processes by ACh, thereby facilitating the development of safer antiarrhythmic drugs that selectively target atrial myocytes with aberrant KACh while sparing normal ones that coexist as a mixed population in the diseased heart.