Voltage-gated Ion Channels

Membrane transport is essential to many areas of cellular life. The movement of ions across the cell membrane is carried out by ion channels which play crucial roles in many physiological processes such as electrical signaling in the brain, muscular contraction, generation of the heartbeat, and hormone secretion. The importance of this class of membrane proteins is also reflected by the fact that many diseases are caused by inherited mutations in ion channel genes, so-called channelopathies, and that 15% of currently used drugs target ion channels.

Research in our lab employs molecular modeling and molecular dynamics simulations to study the structure-activity relationships in ion channels. Specifically, we aim to predict all possible ligand binding sites in ion channels and design selective molecules that will modulate ion channel activity. We are particularly interested in the KCNQ1 channel, which has an important function in the regulation of the heartbeat, and cyclic nucleotide-gated (CNG) channels, which play a key role in photoreceptor signal transduction. Using an integrative computational and experimental approach, we have studied the effect of mutations in KCNQ1 and modeled the molecular details of the interaction between KCNQ1 and its β-subunit KCNE1. In addition, we are performing drug discovery studies in CNG channels with the aim to find a selective inhibitor for rod CNG channels, which could lead to therapeutic options in the treatment of retinitis pigmentosa.

Amino acid variations of the ion channel KCNQ1 which change the channel half-maximal activation voltage (V1/2). The location of residues that are substituted in the KCNQ1 variants are shown as spheres and colored according to their V1/2 change.

Molecular dynamics simulation of the potassium ion permeation process through the KCNQ1 ion channel.

Selected Publications:

  • Pliushcheuskaya P, Kesh S, Kaufmann E, Wucherpfennig S, Schwede F, Künze G, Nache V. Similar Binding Modes of cGMP Analogues Limit Selectivity in Modulating Retinal CNG Channels via the Cyclic Nucleotide-Binding Domain. ACS Chem Neurosci. 2024. 15(8):1652-1668. doi: 10.1021/acschemneuro.3c00665
  • Melancon K, Pliushcheuskaya P, Meiler J, Künze G. Targeting ion channels with ultra-large library screening for hit discovery. Front Mol Neurosci. 2024. 16:1336004. doi: 10.3389/fnmol.2023.1336004
  • Pliushcheuskaya P, Künze G. Recent Advances in Computer-Aided Structure-Based Drug Design on Ion Channels. Int J Mol Sci. 2023. 24(11):9226. doi: 10.3390/ijms24119226
  • Phul S, Kuenze G, Vanoye CG, Sanders CR, George AL Jr, Meiler J. Predicting the functional impact of KCNQ1 variants with artificial neural networks. PLoS Comput Biol. 2022. 18(4):e1010038. doi: 10.1371/journal.pcbi.1010038
  • Kuenze G, Vanoye CG, Desai RR, Adusumilli S, Brewer KR, Woods H, McDonald EF, Sanders CR, George AL Jr, Meiler J. Allosteric mechanism for KCNE1 modulation of KCNQ1 potassium channel activation. Elife. 2020. 9:e57680. doi: 10.7554/eLife.57680
  • Taylor KC, Kang PW, Hou P, Yang ND, Kuenze G, Smith JA, Shi J, Huang H, White KM, Peng D, George AL, Meiler J, McFeeters RL, Cui J, Sanders CR. Structure and physiological function of the human KCNQ1 channel voltage sensor intermediate state. Elife. 2020. doi: 10.7554/eLife.53901
  • Kuenze G, Duran AM, Woods H, Brewer KR, McDonald EF, Vanoye CG, George AL Jr, Sanders CR, Meiler J. Upgraded molecular models of the human KCNQ1 potassium channel. PLoS One. 2019. 14(9):e0220415.  doi: 10.1371/journal.pone.0220415
  • Huang H, Kuenze G, Smith JA, Taylor KC, Duran AM, Hadziselimovic A, Meiler J, Vanoye CG, George AL Jr, Sanders CR. Mechanisms of KCNQ1 channel dysfunction in long QT syndrome involving voltage sensor domain mutations. Sci Adv. 2018. 4(3):eaar2631. doi: 10.1126/sciadv.aar2631

Collaborations:

Dr. Vasilica Nache, Institute of Physiology II, University Hospital Jena, Friedrich-Schiller University Jena