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Over onsWaar vindt u onsprof. dr. A. (Armagan) Kocer
University Medical Center Groningen

prof. dr. A. Kocer

Tenure-Track Associate Professor

Neurobiology of ion channels

Neurobiology of ion channels is concerned with understanding the role of ion channels 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.

My 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.

My 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. 

Mechanosensation at the molecular level

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.

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.

Related publications:

  1. N. Melo, C. Arnarez, H. Sikkema, N. Kumar, M. Walko, H. J. C. Berendsen, A.Kocer, S. J. Marrink and H. I. Ingólfsson "High-throughput simulations reveal membrane-mediated effects of alcohols on MscL gating"J. Am. Chem. Soc. 139: 2664-2671 (2017) DOI:10.1021/jacs.6b1109 (pdf)
  2. Dimitrova, Walko, M. Hashemi Shabestari, P. Kumar, M. Huber, and A. Kocer“In situ, Reversible Gating of a Mechanosensitive Ion Channel through Protein-Lipid Interactions"Frontiers in Physiology 7: Article 409 (2016) (pdf)
  3. A. Kocer "Mechanisms of mechanosensing - Mechanosensitive channels, function and re-engineering" Current Opinion In Chemical Biology 29: 120-127 (2015) (pdf)
  4. D. Yilmaz, A. I. Dimitrova, M. Walko, A. Kocer "Study of light-induced MscL gating by EPR spectroscopy" European Biophysics Journal 44: 557-565 (2015) (pdf)
  5. A. Konijnenberg, J. B. Gonzalez, L. Bannwarth, D. Yilmaz, A. Kocer, C. Venien-Bryan, N. Zitzmann and F. Sobott "Top-down mass spectrometry of intact membrane protein complexes reveals oligomeric state and sequence information in a single experiment" Protein Science 24: 1292-1300 (2015) (pdf)
  6. N.Mukherjee, M. D. Jose, J. P.Birkner, M. Walko, H. I. Ingólfsson, A. Dimitrova, C. Arnarez, S. J. Marrink, A. Koçer "The activation mode of the mechanosensitive ion channel, MscL, by lysophosphatidylcholine differs from tension-induced gating" FASEB J 28: 4292-4302 (2014) DOI: 10.1096/fj.14-251579 (pdf)
  7. 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 "Phytochemicals perturb membranes and promiscuously alter protein function" ACS Chemical Biology  9: 1788-1798 (2014) DOI: 10.1021/cb500086e (pdf)
  8. M.Barthmes, M. D.F. Jose, J. P. Birkner, A. Brüggemann, C. Wahl-Schott, A. Kocer "Studying mechanosensitive ion channels with automated patch clamp". European Biophysics Journal 43: 97-104 (2014) (pdf)
  9. Szymanski, D. Yilmaz, A. Kocer, B.L. Feringa "Bright ion channels and lipid bilayers". Accounts of Chemical Research46: 2910-2923 (2013)
  10. J. T. Mika, J. P. Birkner, D. Yilmaz, B. Poolman, A. Koçer "On the role of individual subunits in MscL gating: “All for one, one for all?” FASEB J 27: 882-892 (2013) DOI: 10.1096/fj.12-214361
  11. D. Yilmaz, A. Konijnenberg, H. I. Ingólfsson, A. Dimitrova, S. J. Marrink, Z. Lid, C. Vénien-Bryand, F. Sobott and A. Koçer. “Global structural changes of an ion channel during its gating are followed by ion mobility mass spectrometry”Proc Natl Acad Sci USA111: 17170-17175 (2014) DOI:10.1073/pnas.1413118111 (pdf)
  12. P. Birkner, B. Poolman, A. Koçer "Hydrophobic gating of Mechanosensitive channel of large conductance evidenced by single-subunit resolution"   Proc Natl Acad Sci USA109 (32): 12944-12949 (2012) (pdf)
  13. Koçer, M. Walko, B. L. Feringa. “Synthesis and Utilization of reversible and irreversible light-activatednanovalvesderived from the channel protein MscL” Nature Protocols 2(6): 1426-1437, (2007)
  14. Koçer, M. Walko, E. Bulten, E. Halza, B. L. Feringa, W. Meijberg. ”Rationally Designed Chemical Modulators Convert a Bacterial Channel Protein into a pH-Sensory Valve”Angew. Chem. Int. Ed. 45: 3126-3130, (2006)(pdf)
  15. Koçer, M. Walko, W. Meijberg, B. L. Feringa. “A Light-Actuated Nanovalve Derived from a Channel Protein.”Science 309: 755-759, (2005) (pdf)

Triggered drug delivery 

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. 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. 

Related publications:

  1. D. Calle, D. Yilmaz, S. Cerdan, A. Kocer "Drug delivery from engineered organisms and nanocarriers as monitored by multimodal imaging technologies"  AIMS Bioengineering 4(2): 198- 222 (2017) (pdf)
  2. Jesus Pacheco-Torres, Nobina Mukherjee, Martin Walko, Pilar López-Larrubia, Paloma Ballesteros, Sebastian Cerdan and Armagan Kocer "Image Guided Drug Release From pH-sensitive Ion Channel-functionalized Stealth Liposomes into an in vivo Glioblastoma Model" Nanomedicine: Nanotechnology, Biology, and Medicine 11: 1345-1354 (2015)
  3. A Koçer “ Functional Liposomal Membranes for Triggered Release”, Methods in Molecular Biology, vol. 605, 243-255. Liposomes (Volkman Weissig (ed) Humana Press, ISBN 978-1-60327-359-6, (2009)
  4. A. Koçer. “A Remote Controlled Valve in Liposomes for Triggered Liposomal Release” J Liposome Research 17 (3): 219 – 225, (2007)
  5. A. Koçer, M. Walko, E. Bulten, E. Halza, B. L. Feringa, W. Meijberg. ”Rationally Designed Chemical Modulators Convert a Bacterial Channel Protein into a pH-Sensory Valve” Angew. Chem. Int. Ed. 45: 3126-3130, (2006)

Functional membranes

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.

Related publications:

  1. M. Urban, Al. Kleefen, N. Mukherjee, B. Windschiegl, P. Seelheim, M. vor der Brüggen, A. Koçer, and R. Tampé “Highly parallel transport recordings on a membrane-on-nanopore chip at single molecule resolution” Nano Letters 14: 1674-1680 (2014) (pdf)
  2. A. Kocer, Lara Tauk,Philippe Dejardin “Nanopore sensors: from hybrid to abiotic systems” Biosensors and Bioelectronics 38(1): 1-10 (2012) DOI 10.1016/j.bios.2012.05.013)
  3. C. E. Price, A. Koçer, S. Kol, J. P. van der Berg, A. J.M. Driessen “In vitro synthesis and oligomerization of the mechanosensitive channel of large conductance, MscL, into a functional ion channel” FEBS Letters 585(1):  249-254 (2011)
  4.  I. Kusters, N. Mukherjee, M. R. de Jong, S. Tans, A. Koçer, A.Driessen “Taming Membranes: Functional Immobilization of Biological Membranes in Hydrogels” PLoS ONE 6(5): e20435. (2011) doi:10.1371/journal.pone.0020435 
  5. A.Dudia, A. Koçer, V. Subramaniam, H. Kanger. “Biofunctionalized lipid-polymer hybrid nanocontainers with controlled permeability” Nano Letters 8 (4): 1105-1110, (2008) 
  6.  A. Koçer, M. Walko, B. L. Feringa. “Synthesis and Utilization of reversible and irreversible light-activated nanovalves derived from the channel protein MscL” Nature Protocols 2(6): 1426- 1437, (2007)
  7.  A. Koçer, M. Walko, E. Bulten, E. Halza, B. L. Feringa, W. Meijberg. ”Rationally Designed Chemical Modulators Convert a Bacterial Channel Protein into a pH-Sensory Valve” Angew. Chem. Int. Ed. 45: 3126-3130, (2006)
  8. A. Koçer, M. Walko, W. Meijberg, B. L. Feringa. “A Light-Actuated Nanovalve Derived from a Channel Protein.” Science 309: 755-759, (2005)
Laatst gewijzigd:06 september 2017 12:07