Biophysical studies of ion channels

One of our main research interests is ion channels. Our goal is to understand the mechanisms of ion permeation, gating, ligand modulation, and post-translational modification across physiologically important ion channels, including voltage-gated, ligand-gated, and pH-gated ion channels. To date, we have demonstrated that the plasticity of the selectivity filter is a key factor for efficient non-selective cation permeation in the NaK channel. This was achieved using a combination of atomistic MD simulations, high-resolution X-ray crystallography, and solid-state NMR spectroscopy together with our collaborators [1-3]. Additionally, we were the first to reveal the ion permeation mechanisms of monovalent and divalent Ca²⁺ ions in human AMPA receptors, which are also non-selective cation channels [4,5].

Regarding potassium channels, we have shown in collaboration with experimental labs that the selectivity filter functions as the main gate in various two-pore-domain potassium (K2P) channels [6]. We identified a class of negatively charged activators (NCAs) that bypass specific gating mechanisms but act as master keys to open K⁺ channels gated at their selectivity filter. This includes many K2P channels, voltage-gated hERG (human ether-à-go-go-related gene) channels, and calcium (Ca²⁺)-activated big-conductance potassium (BK)-type channels [7]. Recently, we provided atomistic insights into the selectivity filter gating mechanism and the physiological regulation of TREK K2P channels by phosphorylation (Figure 1) [8]. These projects have been supported by two DFG grants over seven years as part of the DynIon RU2518 research unit, as well as an ongoing grant “K2PGate” from the Leibniz Collaborative Excellence program.

Schematic illustration of TREK K2P channel inactivation.

Figure 1. Schematic illustration of TREK K2P channel inactivation by phosphorylation [8].

References:

[1] Shi, C.; He, Y.; Hendriks, K.; de Groot, B. L.; Cai, X.; Tian, C.*; Lange, A.*; Sun, H.* A single NaK channel conformation is not enough for non-selective ion conduction, Nat. Commun. 2018, 9(1), 717. doi:10.1038/s41467-018-03179-y

[2] Minniberger, S.; Abdolvand, S.; Braunbeck, S.; Sun, H.*, Plested, A. J. R.* Asymmetry and ion selectivity properties of bacterial channel NaK mutants mimicking ionotropic glutamate receptors, J. Mol. Biol., 2023, 435(6), 167970. doi:10.1016/j.jmb.2023.167970

[3] Roy, R. N.; Hendriks, K.; Kopec, W.; Abdolvand, S.; Weiss, K. L.; de Groot, B. L.; Lange, A.; Sun H.; Coates, L. Structural plasticity of the selectivity filter in a nonselective ion channel. IUCrJ 2021, 8(3), 421-430. doi:10.1107/S205225252100213X

[4] Biedermann, J.; Braunbeck, S.; Plested, A. J. R.*; Sun H.* Nonselective cation permeation in an AMPA-type glutamate receptor, PNAS 2021, 118(8), e2012843118. doi:10.1073/pnas.2012843118

[5] Schackert, F. K.; Biedermann, J.; Song, C.; Plested, A. J. R.; Carloni, P.*; Sun, H.* Mechanism of calcium permeation in a glutamate receptor ion channel, J. Chem. Inf. Model., 2023, 63(4), 1293-1300. doi:10.1021/acs.jcim.2c01494

[6] Schewe, M.; Nematian-Ardestani, E.; Sun, H.; Musinszki, M.; Cordeiro, S.; Bucci, G.; de Groot, B. L.; Tucker, S. J.; Rapedius, M.; Baukrowitz, T. A non-canonical voltage sensor controls gating in K2P K+ channels, Cell 2016, 164(5), 937-949. doi:10.1016/j.bpj.2015.11.1502

[7] Schewe, M.#; Sun, H.#; Mert, Ü.; Mackenzie, A.; Pike, A. C. W.; Schulz, F.; Constantin, C.; Vowinkel, K. S.; Conrad, L. J.; Kiper, A. K.; Gonzalez, W.; Musinszki, M.; Tegtmeier, M.; Pryde, D. C.; Belabed, H.; Nazare, M.; de Groot, B. L.; Decher, N.; Fakler, B.; Carpenter, E. P.; Tucker, S. J.; Baukrowitz, T. A pharmacological master key mechanism that unlocks the selectivity filter gate in K+ channels, Science 2019, 363(6429), 875-880. doi:10.1016/j.bpj.2018.11.1635

[8] Türkaydin, B.; Schewe, M.*; Riel, E. B.; Schulz, F.; Biedermann, J.; Baukrowitz, T.*; Sun, H.*, Atomistic mechanism of coupling between cytosolic sensor domain and selectivity filter in TREK K2P channels. Nat. Commun., 2024, 15, 4628, doi:10.1038/s41467-024-48823-y