Biophysical pharmacology of ion channels

Principal Investigator: Priv.-Doz. 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 ligand-gated ion channels
  • Functional characterization of pain-related mutants in voltage-gated sodium channels

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, fluorescence based high throughput screening of compound libraries (in collaboration with Prof. Dr. Michael Schaefer, University of Leipzig) 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

Functional characterization of heterologously expressed pain-related NaV mutants
 

Publications

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

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

Stephan G, Kowalski-Jahn M, Zens C, Schmalzing G, Illes P and Hausmann R (2016) Inter-subunit disulfide locking of the human P2X3 receptor elucidates ectodomain movements associated with channel gating. Purinergic Signal 12:221-233. https://www.ncbi.nlm.nih.gov/pubmed/26825305

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

Hausmann R, Gunther J, Kless A, Kuhlmann D, Kassack MU, Bahrenberg G, Markwardt F and Schmalzing G (2013) Salt Bridge Switching from Arg290/Glu167 to Arg290/ATP Promotes the Closed-to-Open Transition of the P2X2 Receptor. Molecular pharmacology 83:73-84. https://www.ncbi.nlm.nih.gov/pubmed/23041661

Baqi Y*, Hausmann R*, Rosefort C, Rettinger J, Schmalzing G and Mueller CE (2011) Discovery of Potent Competitive Antagonists and Positive Modulators of the P2X2 Receptor. Journal of Medicinal Chemistry 54:817-830. *these authors contributed equally https://www.ncbi.nlm.nih.gov/pubmed/21207957

Wolf C, Rosefort C, Fallah G, Kassack MU, Hamacher A, Bodnar M, Wang H, Illes P, Kless A, Bahrenberg G, Schmalzing G and Hausmann R (2011) Molecular determinants of potent P2X2 antagonism identified by functional analysis, mutagenesis, and homology docking. Molecular pharmacology 79:649-661. https://www.ncbi.nlm.nih.gov/pubmed/21191044