Research Groups

Group Kocer

Ion channels are proteins present in the cell membrane of both animal and plant tissues but are particularly present in the nervous system and heart where they transmit electrical signals. Their main function is to identify, select and guide specific ions and to respond to electrical, chemical and mechanical signals to regulate a variety of processes in a cell.

Our scientists are interested in exploring the mechanism of these membrane proteins and their potential applications to solve societal problems.

Recently, our researchers have expanded their interest to ion channels involved in neurodegenerative diseases. We study the voltage-gated potassium channel Kv4.3 at the single-molecule level, to understand how it works, how its function is modulated by accessory proteins and how its mutants cause neuronal death.

Our scientists have core competencies in the areas of synthetic biology, biochemistry, biophysics, and electrophysiology.

  • People
  • Publications
  • Alumni
  • Ion channels
  • Triggered drug delivery
  • Mechanosensation
  • Functional membranes
  • Armagan Kocer PhD Visit
    Position

    Professor Neurobiology of ion channels

    Research fields

    biochemistry, biophysics, synthetic biology, and electrophysiology

    PhD student
    • C. E. Price, A. Koçer, S. Kol, J. P. van der Berg, A. J.M. Driessen (2011) In vitro synthesis and oligomerization of the mechanosensitive channel of large conductance, MscL, into a functional ion channel. FEBS Letters
    • A. Kocer, Lara Tauk,Philippe Dejardin (2012) Nanopore sensors: from hybrid to abiotic systems.  Biosensors and Bioelectronics
    • M. Urban, Al. Kleefen, N. Mukherjee, B. Windschiegl, P. Seelheim, M. vor der Brüggen, A. Koçer, and R. Tampé. (2014) Highly parallel transport recordings on a membrane-on-nanopore chip at single molecule resolution. Nano Letters
    • A. Koçer, M. Walko, E. Bulten, E. Halza, B. L. Feringa, W. Meijberg.(2006) Rationally Designed Chemical Modulators Convert a Bacterial Channel Protein into a pH-Sensory Valve.  Angew. Chem. Int. Ed
    • A. Koçer.(2007) A Remote Controlled Valve in Liposomes for Triggered Liposomal Release. J Liposome Research
    • A Koçer (2009) Functional Liposomal Membranes for Triggered Release, Methods in Molecular Biology, vol. 605, 243-255. Liposomes (Volkman Weissig (ed) Humana Press
    • Jesus Pacheco-Torres, Nobina Mukherjee, Martin Walko, Pilar López-Larrubia, Paloma Ballesteros, Sebastian Cerdan and A. Kocer (2015) Image Guided Drug Release From pH-sensitive Ion Channel-functionalized Stealth Liposomes into an in vivo Glioblastoma Model.  Nanomedicine: Nanotechnology, Biology, and Medicine
    • D. Calle, D. Yilmaz, S. Cerdan, A. Kocer (2017) Drug delivery from engineered organisms and nanocarriers as monitored by multimodal imaging technologies.  AIMS Bioengineering
    • Koçer, M. Walko, W. Meijberg, B. L. Feringa. (2005) A Light-Actuated Nanovalve Derived from a Channel Protein. Science
    • Koçer, M. Walko, E. Bulten, E. Halza, B. L. Feringa, W. Meijberg.(2006) Rationally Designed Chemical Modulators Convert a Bacterial Channel Protein into a pH-Sensory Valve. Angew. Chem. Int. Ed
    • Koçer, M. Walko, B. L. Feringa.(2007) Synthesis and Utilization of reversible and irreversible light-activatednanovalvesderived from the channel protein MscL. Nature Protocols
    • P. Birkner, B. Poolman, A. Koçer(2012) Hydrophobic gating of Mechanosensitive channel of large conductance evidenced by single-subunit resolution.   Proc Natl Acad Sci USA
    • D. Yilmaz, A. Konijnenberg, H. I. Ingólfsson, A. Dimitrova, S. J. Marrink, Z. Lid, C. Vénien-Bryand, F. Sobott and A. Koçer.(2013) Global structural changes of an ion channel during its gating are followed by ion mobility mass spectrometry. Proc Natl Acad Sci USA
    • J. T. Mika, J. P. Birkner, D. Yilmaz, B. Poolman, A. Koçer (2013) On the role of individual subunits in MscL gating: All for one, one for all? FASEB J
    • Szymanski, D. Yilmaz, A. Kocer, B.L. Feringa.(2013) Bright ion channels and lipid bilayers. Accounts of Chemical Research
    • M.Barthmes, M. D.F. Jose, J. P. Birkner, A. Brüggemann, C. Wahl-Schott, A. Kocer (2014) Studying mechanosensitive ion channels with automated patch clamp. European Biophysics Journal
    • I. Ingólfsson, P. Thakur, K.F. Herold, E. A. Hobart, N. B. Ramsey, X. Periole, D. H. deJong,M. Zwama, D. Yilmaz, K. Hall, T. Maretzky, H. C. Hemmings, C. Blobel, S. J. Marrink, A.Kocer, J. T. Sack, O. S. Andersen(2014) Phytochemicals perturb membranes and promiscuously alter protein function. ACS Chemical Biology
    • N.Mukherjee, M. D. Jose, J. P.Birkner, M. Walko, H. I. Ingólfsson, A. Dimitrova, C. Arnarez, S. J. Marrink, A. Koçer (2014) The activation mode of the mechanosensitive ion channel, MscL, by lysophosphatidylcholine differs from tension-induced gating. FASEB J
    • A. Konijnenberg, J. B. Gonzalez, L. Bannwarth, D. Yilmaz, A. Kocer, C. Venien-Bryan, N. Zitzmann and F. Sobott.(2015) Top-down mass spectrometry of intact membrane protein complexes reveals oligomeric state and sequence information in a single experiment. Protein Science
    • D. Yilmaz, A. I. Dimitrova, M. Walko, A. Kocer. (2015) Study of light-induced MscL gating by EPR spectroscopy. European Biophysics Journal
    • A. Kocer.(2015) Mechanisms of mechanosensing - Mechanosensitive channels, function and re-engineering. Current Opinion In Chemical Biology
    • Dimitrova, Walko, M. Hashemi Shabestari, P. Kumar, M. Huber, and A. Kocer.(2016)In situ, Reversible Gating of a Mechanosensitive Ion Channel through Protein-Lipid Interactions. Frontiers in Physiology
    • N. Melo, C. Arnarez, H. Sikkema, N. Kumar, M. Walko, H. J. C. Berendsen, A.Kocer, S. J. Marrink, H. I. Ingólfsson(2017) High-throughput simulations reveal membrane-mediated effects of alcohols on MscL gating. J. Am. Chem. Soc.
    • Dr Martin Walko (2009), Institute of Chemistry, Faculty of Science, P.J. Safarik University, Slovakia (Assistant Professor)
    • Dr Erik Halza (2011), Syncom BV (Research Scientist)
    • Dr Jan Peter Birkner (2012), University of Groningen (Zernike Institute, Research Manager)
    • Dr Nobina Mukherjee (2014), Oxford University, Department of Chemistry (Postdoctoral Fellow)
    • Dr Duygu Yilmaz (2014), ProQR, Leiden (Research Scientist)
    • Dr Mac Donald Jose (2015), University of Malawi, Zomba, Malawi (Researcher)
  • Neurobiology of ion channels is concerned with understanding the role of ionchannels in the healthy nervous system and elucidating why and how mutated ion channels cause dysfunction. Ion channels are membrane proteins responsible for neuronal excitability, signaling, and ion homeostasis. They are involved in a wide spectrum of essential functions including breathing, hearing, and learning.

    Brancato et al.,

    Our goal is to take advantage of the rapidly accumulating genetic information on ion channel disorders of the nervous system, combining it with my expertise on single channel structure-function relations to understand and control the electrical communication between excitable cells.

    Our bottom-up approach is to determine the single channel properties of the wild-type and mutant ion channels and their interactions with the accessory proteins in a well-controlled, artificial, cell-like experimental system. Then, translating the findings back to the cellular level in cultured neurons. Currently, we are working on voltage-gated potassium channel Kv4.3 and GluA1/GluA2/GluA3 AMPA receptor channels

     

  • In order to reduce the toxicity and increase the efficacy of drugs, there is a need for smart drug delivery systems. Lipid-based systems are one of the promising tools for this purpose. An ideal delivery system should be stable, long-circulating, accumulating at the target site and releasing its drug in a controlled manner.

    In vivo drug delivery to a brain tumor and drug release in response to the acidity of the tumor (MRI image)

    Even though there have been many developments to this end, the dilemma of having a stable vehicle during circulation but converting it into a leaky structure at the target site is still a major challenge. So far, most attempts have focused on destabilizing the vehicle structure in response to a particular stimulus at a target site, but with limited success. Our approach is to generate long-circulating lipid-based nanovehicles with a build-in remote-controlled ion channel. The ion channel functions both as a sensor to detect target-specific cues and as a nanovalve to release the drug. We showed that the system can detect the mildly acidic pH of the tumor microenvironment with 0.2 pH unit precision and release their intraluminal content into C6 glioma tumors selectively, in vivo.

  • We are investigating how ion channels sense mechanical force at the molecular level. Mechanosensitive (MS) ion channels, present in membranes, are the molecules that sense membrane tension in all species ranging from bacteria to man.  In recent years many diseases related to the malfunctioning of MS channels were discovered such as cardiac arrhythmias, polycystic kidney disease, hypertension, glioma, glaucoma, atherosclerosis, and tumorigenesis. In spite of their importance, their working mechanism is still unknown.

    Mechanosensitive channel of large conductance, MscL

    The “simplest” forms of MS channels from bacteria have been the objects of the study of mechanosensation for the past decade. They sense changes in membrane tension invoked by osmotic stress and as a response, they undergo structural rearrangements and generate large transient pores in the membrane. Even when isolated from their native membrane environment and reconstituted into artificial membranes composed of synthetic lipids, they are still capable of mechanosensing and responding to the alteration in membrane tension.

    The long-term objective of my research is to understand the molecular mechanism of mechanosensation by analyzing individual forces acting on the system, those of the membrane acting on the protein and those of the protein acting on the membrane.

  • Toward the realization of sensory devices, there have been significant efforts on the use of synthetic or biological nanopores in single-molecule sensing platforms. The most attractive features of such systems are the ease of detection as the passage of analytes through the pores generates detectable changes in ionic pore current; no requirement of labeling or surface attachment of the analytes, and least their cost.

    Among the pores, gated ion channels stand out for their intrinsic high sensitivity. They are natural excitable nanopores with two states: “closed (off)”, and “open (on)”. They are embedded in lipid bilayer membranes.

    In this project, we engineer new functionalities into ion channels and incorporate them into hybrid devices with the final goal of obtaining very sensitive and stable biosensory devices.

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