Kv Channel Interacting Proteins (KChIPs) as calcium sensors for Kv4 channels

• Applicant: Professor Dr. Robert Bähring
• Subject Area: Anatomy and Physiology
• Term: from 2019 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 424246803

Potassium channels control the resting membrane potential and membrane excitation in very different cell types, as reflected by the huge number of potassium channel types and subfamilies. Voltage-gated potassium channels (Kv channels), particularly those of the Kv4 subfamily, are critically involved in cardiomyocyte repolarisation and the controlled spread of excitation in the dendritic trees of neurons. The Kv4 channels in the membrane of cardiomyocytes and neuronal dendrites form complexes with Kv Channel Interacting Proteins (KChIPs). KChIPs belong to the Neuronal Calcium Sensor (NCS) family of calcium-binding EF-hand proteins. Both in cardiomyocytes and in neurons local fluctuations in cytoplasmic calcium are central to normal cell function and plasticity. However, a rise in cytoplasmic calcium above the normal range may lead to pathophysiological processes and eventually to cell death. From the time when the KChIPs were discovered as being specific β-subunits of Kv4 channels, the role of a calcium sensor for Kv4 channels has been attributed to the KChIPs, based on the fact that they belong to the NCS protein family. Hints on such a role do exist in the literature. However, it has not been studied in detail and it remains unproven whether calcium-dependent conformational changes of the KChIPs influence Kv4/KChIP complex formation or whether in an existing Kv4/KChIP complex calcium-dependent conformational changes of the KChIPs are directly transmitted to the Kv4 channel. Therefore, the aim of the present research proposal is the molecular elucidation of the role of KChIPs as calcium sensors for Kv4 channels during physiologic and pathophysiologic calcium fluctuations. Fluorescence measurements with epitope-tagged Kv4 α- und KChIP β-subunits as well as electrophysiological measurements of Kv4/KChIP-mediated currents in the presence of different cytoplasmic calcium concentrations, combined with the use of KChIPs with mutated calcium binding sites, should provide valuable information regarding this issue.

• DFG Programme: Research Grants