Cardiac arrhythmias remain a major cause of death and disability, affecting both genders and all age groups. Treatment is mostly empirical, with unpredictable outcomes in many cases. The disease processes that lead to irregular heart rhythms often involve alterations in the molecular structure and function of ion channels, which constitute the elementary "building blocks" of the cardiac excitatory process. These changes can be due to mutations, remodeling by disease processes and/or environmental factors, or unwanted effects of drugs. Promising new approaches to the treatment of cardiac arrhythmias and prevention of sudden cardiac death, including molecular and gene therapy and rational drug design, require knowledge of processes and mechanisms at the molecular level of ion-channel proteins and their integrated effects on whole-cell excitation. The overall objective of the proposed project is to provide mechanistic understanding of the relationships between the dynamic molecular structure of cardiac ion- channel proteins during their gating process and their function as charge carriers during the whole-cell action potential (AP). Processes to be studied include the alteration of the channel structure-function properties by mutations and their modulation by cellular signaling pathways (?- adrenergic and CaMKII). Specifically, we will focus on the slow delayed rectifier K+ channel, IKs, and its role in AP repolarization and arrhythmogenic repolarization abnormalities. The approach is based on computational biology methods (combination of molecular dynamics simulations and models of cardiac cell electrophysiology) together with experimental data. ? Specific aims are: (1) To construct a structural molecular model of IKs by incorporating its ?- subunit (KCNE1) into the -subunit (KCNQ1) model that we have developed previously, and to study the functional consequences of KCNE1 co-assembly with KCNQ1 in terms of channel activation gating, the macroscopic IKs current, and the whole-cell AP, including effects of clinically occurring mutations in KCNE1. (2) To study at the molecular level the mechanism of IKs regulation by ?-adrenergic stimulation and explain its effects on IKs current and the whole-cell AP, including consequences of clinical mutations that alter this regulation.
Cardiac arrhythmias are a major cause of death and disability, with estimated 400,000 cases of sudden death annually in the US (7 million worldwide) and many more cases of severely compromised quality of life. These cardiac rhythm disorders affect both genders and all age groups. The proposed studies are aimed at elucidating molecular processes and mechanisms that underlie irregular heart rhythms, in order to provide a rational basis for the development of mechanism-based strategies for improved diagnosis, prevention and treatment.
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