Computational Neurophysiology (Jan-Philipp Machtens)
Über
We combine all-atom molecular simulations, machine learning, and computational structure prediction, together with quantitative functional experiments (e.g., patch-clamp electrophysiology, time-resolved fluorescence spectroscopy), to understand information processing in the brain under both normal and pathologic conditions at atomic resolution.
Forschungsthemen
We investigate structure–dynamics–function relationships of important membrane proteins involved in neuronal signal processing and transmission such as voltage- or light-gated ion channels, neurotransmitter transporters, and receptors.
We currently focus on:
- transport mechanisms of SLC1 glutamate transporters
- molecular sound amplification in the inner ear by SLC26A5 (prestin)
- voltage-gated sodium channels in neuropathic pain
- developing light-gated ion channels as novel optogenetic tools
- developing machine-learning and multiscale methods to investigate voltage-dependent transport proteins
Members
Kovermann P, Machtens JP, Ewers D, Fahlke C (2010) A conserved aspartate determines pore properties of anion channels associated with excitatory amino acid transporter 4 (EAAT4). The Journal of biological chemistry 285, 23676-23686
Leinenweber A, Machtens JP, Begemann B, Fahlke (2011) Regulation of glial glutamate transporters by C-terminal domains. The Journal of biological chemistry 286, 1927-1937
Machtens JP, Kovermann P, Fahlke C (2011) Substrate-dependent gating of anion channels associated with excitatory amino acid transporter 4. The Journal of biological chemistry 286, 23780-23788
Machtens JP, Fahlke C, Kovermann P (2011) Noise analysis to study unitary properties of transporter-associated ion channels. Channels 5, 468-472
Hotzy J, Machtens JP, Fahlke C (2012) Neutralizing Aspartate 83 Modifies Substrate Translocation of Excitatory Amino Acid Transporter 3 (EAAT3) Glutamate Transporters. The Journal of biological chemistry 287, 20016-20026
Ewers D, Becher T, Machtens JP, Weyand I, Fahlke C (2013) Induced fit substrate binding to an archeal glutamate transporter homologue. Proceedings of the National Academy of Sciences of the United States of America 110, 12486-12491
Schneider N, Cordeiro S, Machtens JP, Fahlke C (2014) Functional properties of the retinal glutamate transporters GLT-1c and EAAT5. The Journal of biological chemistry 289, 1815
Machtens JP, Kortzak D, Lansche C, Leinenweber A, Kilian P, Begemann B, Zachariae U, Ewers D, de Groot BL, Briones R, Fahlke C (2015) Mechanisms of anion conduction by coupled glutamate transporters. Cell 160, 542-53
Ronstedt K, Sternberg D, Detro-Dassen S, Gramkow T, Begemann B, Becher T, Kilian P, Grieschat M, Machtens JP, Schmalzing G, Fischer M, Fahlke C (2015) Impaired surface membrane insertion of homo- and heterodimeric human muscle chloride channels carrying amino-terminal myotonia-causing mutations. Scientific Reports 5, 15382
Fahlke C, Kortzak D, Machtens, JP (2016) Molecular physiology of EAAT anion channels. Pflügers Arch 486(3):491-502
Kutzner C, Köpfer DA, Machtens JP, de Groot BL, Song C, Zachariae U (2016) Insights into the function of ion channels by computational electrophysiology simulations. Biochim. Biophys. Acta 1858:1741-1752
Vickery ON, Machtens JP, Tamburrino G, Seeliger D, Zachariae U (2016) Structural Mechanisms of Voltage Sensing in G Protein-Coupled Receptors. Structure 24:997-1007
Vickery ON, Machtens JP, Zachariae U (2016) Membrane potentials regulating GPCRs: insights from experiments and molecular dynamics simulations. Current Opinion in Pharmacology 30, 44-50
Machtens JP, Briones R, Alleva C, de Groot BL, Fahlke C (2017) Gating Charge Calculations by Computational Electrophysiology Simulations. Biophysical Journal 112(7):1396-1405
Körner J, Meents J, Machtens JP, Lampert A (2018) β1 subunit stabilises sodium channel Nav1.7 against mechanical stress. Journal of Physiology 596(12):2433-2445
Bratanov D, Kovalev K, Machtens JP, Astashkin R, Chizhov I, Soloviov D, Volkov D, Polovinkin V, Zabelskii D, Mager T, Gushchin I, Rokitskaya T, Alekseev A, Shevchenko V, Yutin N, Rosselli R, Baeken C, Borshchevskiy V, Bourenkov G, Popov A, Balandin T, Büldt G, Manstein DJ, Rodriguez-Valera F, Fahlke C, Bamberg E, Koonin E, Gordeliy V (2019) Unique structure and function of viral rhodopsins. Nature Communications 10(1):4939
Kortzak D, Alleva C, Weyand I, Ewers D, Zimmermann MI, Franzen A, Machtens JP*, Fahlke C* (2019) Allosteric gate modulation confers K+ coupling in glutamate transporters. The EMBO Journal 38:e101468 *shared last authorship
Rühlmann AH, Körner J, Bebrivenski N, Detro-Dassen S, Hautvast P, Benasolo CA, Meents J, Machtens JP, Schmalzing G, Lampert A. (2020) Uncoupling sodium channel dimers rescues phenotype of pain-linked Nav1.7 mutation. British Journal of Pharmacology 177(19):4481-96
Alberione MP, Moeller R, Kirui J, Ginkel C, Doepke M, Ströh LJ, Machtens JP, Pietschmann T, Gerold G. (2020) Single-nucleotide variants in human CD81 influence hepatitis C virus infection of hepatoma cells. Medical Microbiology and Immunology 209(4):499-514
Alleva C, Kovalev K, Astashkin R, Berndt MI, Baeken C, Balandin T, Gordeliy V, Fahlke C*, Machtens JP*. (2020) Na+-dependent gate dynamics and electrostatic attraction ensure substrate coupling in glutamate transporters. Science Advances 6(47):eaba9854 *shared last authorship
Kostritskii AY, Alleva C, Cönen S, Machtens JP. (2021) g_elpot: A Tool for Quantifying Biomolecular Electrostatics from Molecular Dynamics Trajectories. Journal of Chemical Theory and Computation 17(5):3157-3167
Kostritskii AY, Machtens JP. (2021) Molecular mechanisms of ion conduction and ion selectivity in TMEM16 lipid scramblases. Nature Communications 12(1):2826
Alleva C, Machtens JP, Kortzak D, Weyand I, Fahlke C. (2021) Molecular Basis of Coupled Transport and Anion Conduction in Excitatory Amino Acid Transporters. Neurochemical Research
Etges A, Hellmig N, Walenda G, Haddad BG, Machtens JP, Morosan T, Rump LC, Scholl UI. (2022) A novel homozygous KLHL3 mutation as a cause of autosomal recessive pseudohypoaldosteronism type II diagnosed late in life. Nephron 146(4):418–428
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. Pharmacology 14:1120360
Kostritskii AY, Machtens JP. (2023) Domain- and state-specific shape of the electric field tunes voltage sensing in voltage-gated sodium channels. Biophysical Journal 122(10):1807–1821
Suslova M, Kortzak D, Machtens JP, Kovermann P, Fahlke C. (2023) Apo state pore opening as functional basis of increased EAAT anion channel activity in episodic ataxia 6. Frontiers Physiology 14:1147216
Fahlke C, Machtens JP, Sandtner W, Schicker K, Sun H (2023) Combining computational and experimental approaches to characterize ion channels and transporters. Front. Physiology 14: 1320336
Kuwabara MF, Haddad BG, Lenz-Schwab D, Hartmann J, Longo P, Huckschlag BM, Fuss A, Questino A, Berger TK, Machtens JP*, Oliver D* (2023) Elevator-like movements of prestin mediate outer hair cell electromotility. Nature Communications 14: 7145 *shared corresponding last authorship