Molecular basis and proarrhythmic role of enhanced small conductance Ca2+ activated K+ channels in patients with atrial fibrillation

• Applicant: Professor Dr. Dobromir Dobrev
• Subject Area: Pharmacology ; Cardiology, Angiology
• Term: from 2017 to 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 349202494

Atrial fibrillation (AF) is a frequent arrhythmia increasing morbidity and mortality. Current antiarrhythmic drugs have suboptimal efficacy and potentially severe adverse effects. There is a clear need for the identification of new atrial selective targets for AF therapy, since this produces less unwanted ventricular effects. Although atrial selective small conductance Ca2+ activated K+ channels (SK channels) have emerged as a potential target for anti AF therapy, their precise function and specific contribution to AF mechanisms in the human atrium is not established. The role of potentially increased SK channel current (ISK) in atrial arrhythmogenesis is complex. It might favour reentry by abbreviating action potential duration (APD), but can also be antiarrhythmic by reducing automaticity/triggered activity through membrane hyperpolarization/reduced excitability. Based on our previous work highlighting a central role for AF related Ca2+ handling abnormalities in atrial cardiomyocytes and our preliminary work on ISK dysregulation in AF patients, we hypothesize that enhanced ISK provides a link between Ca2+ dependent triggered activity (SR Ca2+ leak) and reentry (shorter APD), playing a critical role in the formation of the proarrhythmic substrate supporting AF maintenance. Therefore, the primary goal of this application is to discover and dissect the cellular and molecular mechanisms of enhanced ISK in AF and to delineate the precise contributions of ISK to APD shortening and arrhythmia mechanisms in AF patients. As an initial step we will exploit molecular biology techniques to validate the expression of SK channel isoforms and their regulatory proteins, identify the cellular and molecular determinants of SK channel trafficking and establish potential abnormalities in the complex organization and local regulation of SK channels that could alter Ca2+ dependent channel gating in AF patients. Then we will functionally assess the Ca2+ concentration response relationship of ISK including contribution of Ca2+ influx vs. internal Ca2+ release, explore the role of different actin based and microtubule driven trafficking pathways and test the effects of AF relevant atrial rates on the regulation of ISK in AF patients. Finally we will refine the contribution of ISK to human atrial AP and dissect the proarrhythmic (contribution to the reentrant substrate by causing APD shortening) and anti arrhythmic (protection against afterdepolarization mediated focal ectopic [triggered] activity) consequences of pharmacological ISK modulation in AF patients. Combined the proposed experiments will provide molecular and functional insights into the ISK determinants, their remodeling and regulation in AF. Ultimately, the insights from this work should facilitate the identification of novel therapeutic targets in AF patients.

• DFG Programme: Research Grants