Biophysical pharmacology of ion channels

Principal Investigator: Prof. Dr. med. Ralf Hausmann

The work group is interested in the following research topics:

• Molecular function and biophysics of voltage- and ligand-gated ion channels
• Ligand-recognition and ion permeation in ligand-gated ion channels
• Molecular dynamics of ion conduction in ligand-gated ion channels (in collaboration with Jun.-Prof. Dr. med. Jan-Philipp Machtens, Institute of Clinical Pharmacology of RWTH Aachen University and Computational Neurophysiology (ICS-4) of Forschungszentrum Jülich)
• Drug screening of ion channels
• Biophysical and pharmacological characterization of pain-related variants in voltage-gated sodium channels

The research focus of the group is the molecular function and biophysics of voltage- and ligand-gated ion channels. We are interested in understanding the dynamic molecular mechanisms responsible for the activation and switching behavior as well as ion permeation, conductance and selectivity of ligand-gated and voltage-gated ion channels. In addition, we perform drug screening on ligand-gated and voltage-gated ion channels to identify the molecular determinants of subtype-specific drug interactions and to understand how P2X receptors (a class of ligand-gated ion channels) and NaV channels (a class of voltage-gated ion channels) can be selectively targeted by drugs. Another topic is the biophysical characterization and drug screening of pain-related mutations (variants) in voltage-gated sodium channels (NaV) with the aim of enabling variant-specific precision therapy in selected pain patients in the future.

The above-mentioned scientific fields of interest are studied using a variety of molecular biology, pharmacological and electrophysiological methods. These include among others site directed mutagenesis, heterologous expression of ion channels in Xenopus laevis oocytes or mammalian cells (e.g. HEK293, 1321N1 astrocytoma cells), two-electrode voltage-clamp (TEVC) and patch-clamp electrophysiology, automated patch-clamp (high-throughput electrophysiology in 384-well format) for high throughput screening of compound libraries and molecular dynamics simulations (in collaboration with Jun.-Prof. Dr. Jan-Philipp Machtens, RWTH Aachen and Forschungszentrum Jülich).

Research projects that are currently in progress

(for details please click on link):

Molecular Dynamics Guided Analysis of Ligand Activation, Ion Permeation and Subtype-specific Ligand Interactions in P2X Receptors

Screening of approved drugs regarding their P2X3 receptor activity

Biophysical characterization of heterologously expressed pain-related Na_V mutants

EISonION - Electrical Impedance Spectroscopy for drug screening on Ligand-gated ION channels

Precision medicine for pain patients: Precision²Treat
 

Publications

Please find below a selection of publications covering the scientific field of interest. A more complete list of publications can be found here.

Kriegeskorte S, Bott R, Hampl M, Korngreen A, Hausmann R^*, Lampert A^* (2023) Cold and warmth intensify pain-linked sodium channel gating effects and persistent currents. J Gen Physiol. 155(9):e202213312. https://www.ncbi.nlm.nih.gov/pubmed/37531097/

Grohs L, Cheng L, Cönen S, Haddad BG, Bülow A, Toklucu I, Ernst L, Körner J, Schmalzing G, Lampert A, Machtens JP, Hausmann R (2023) Diclofenac and other non-steroidal anti-inflammatory drugs (NSAIDs) are competitive antagonists of the human P2X3 receptor. Front Pharmacol. 14:1120360.
https://www.ncbi.nlm.nih.gov/pubmed/37007008/

Weinhausen S, Nagel J, Namasivayam V, Spanier C, Abdelrahman A, Hanck T, Hausmann R, Müller CE (2022) Extracellular binding sites of positive and negative allosteric P2X4 receptor modulators. Life Sci. 311(Pt A):121143. https://www.ncbi.nlm.nih.gov/pubmed/36328074/

Rühlmann AH, Körner J, Hausmann R, Bebrivenski N, Neuhof C, Detro-Dassen S, Hautvast P, Benasolo CA, Meents J, Machtens JP, Schmalzing G, Lampert A (2020) Uncoupling sodium channel dimers restores the phenotype of a pain-linked Na(v) 1.7 channel mutation. Br J Pharmacol. 177(19):4481-4496. 
https://www.ncbi.nlm.nih.gov/pubmed/32663327/

Thull S, Neacsu C, O'Reilly AO, Bothe S, Hausmann R, Huth T, Meents J, Lampert A (2020) Mechanism underlying hooked resurgent-like tail currents induced by an insecticide in human cardiac Nav1.5. Toxicol Appl Pharmacol. 397:115010. https://www.ncbi.nlm.nih.gov/pubmed/32302602/

Obrecht AS, Urban N, Schaefer M, Rose A, Kless A, Meents JE, Lampert A, Abdelrahman A, Muller CE, Schmalzing G and Hausmann R (2019) Identification of aurintricarboxylic acid as a potent allosteric antagonist of P2X1 and P2X3 receptors. Neuropharmacology 158:107749. https://www.ncbi.nlm.nih.gov/pubmed/31461640

Kaluza L, Meents JE, Hampl M, Rosseler C, Hautvast PAI, Detro-Dassen S, Hausmann R, Schmalzing G and Lampert A (2018) Loss-of-function of Nav1.8/D1639N linked to human pain can be rescued by lidocaine. Pflugers Archiv: European journal of physiology 470:1787-1801. https://www.ncbi.nlm.nih.gov/pubmed/30099632

Stephan G, Huang L, Tang Y, Vilotti S, Fabbretti E, Yu Y, Norenberg W, Franke H, Goloncser F, Sperlagh B, Dopychai A, Hausmann R, Schmalzing G, Rubini P and Illes P (2018) The ASIC3/P2X3 cognate receptor is a pain-relevant and ligand-gated cationic channel. Nature communications 9:1354. https://www.ncbi.nlm.nih.gov/pubmed/29636447

Kowalski M^*, Hausmann R^*, Schmid J, Dopychai A, Stephan G, Tang Y, Schmalzing G, Illes P and Rubini P (2015) Flexible subunit stoichiometry of functional human P2X2/3 heteromeric receptors. Neuropharmacology 99:115-130. ^*these authors contributed equally https://www.ncbi.nlm.nih.gov/pubmed/26184350

Hausmann R, Bahrenberg G, Kuhlmann D, Schumacher M, Braam U, Bieler D, Schlusche I and Schmalzing G (2014) A hydrophobic residue in position 15 of the rP2X3 receptor slows desensitization and reveals properties beneficial for pharmacological analysis and high-throughput screening. Neuropharmacology 79:603-615. https://www.ncbi.nlm.nih.gov/pubmed/24452010