Development of pharmacological tools to study the kv4.3 channelosome in atrial fibrillation

Ion channels are macromolecular complexes present in the plasma membrane and in intracellular organelles of the cells, where they play important functions, such as smooth muscle contraction or secretion of hormones. The dysfunction of these channels results in several disorders named channelopathies, which represent a challenge for study and treatment.[1] We are focused on voltage-gated potassium channels, specifically on KV4.3 and its role in atrial fibrillation (AF). KV4.3 channel is expressed in smooth muscle, heart and brain. Its activation generates outward currents operating at subthreshold membrane potentials as recorded from myocardial cells (ITO, transient outward current). KV4.3 plays a key role in AF, the most common cardiac arrhythmia, with an estimated prevalence in the general population of 1.5–2%. However, current antiarrhythmic drugs for AF prevention have limited efficacy and considerable potential for adverse effects.[2] To reproduce the ITO currents, KV4.3 channels need to assemble with other subunits, forming channelosome. KChIPs (Potassium Channel Interacting Proteins), which belong to the calcium binding protein superfamily, forms the KV4.3 channelosome, along with other proteins.[3] To study the complex interaction of KV4.3 channelosome and the development of modulators, the interplay of different techniques is central to advance knowledge. In this regard, the development of novel KChIPs modulators and fluorescent biosensors constitutes invaluable pharmacological tools to unravel the KV4 channelosome and its role in AF.[3] In this communication, we will describe preliminary results towards the identification of new pharmacological tools to study the KChIPs/KV4 interaction.