Struktur des OCT1 der Ratte
Transporter für organische Kationen gehören zur großen Proteinfamilie der "Solute Carrier" (SLC) und zeichnen sich durch eine hohe Polyspezifität aus. Zu diesen Transportern gehören u.a. die elektrogenen OCT-Uniporter, die die Aufnahme von kationischen endogenen Metaboliten, sowie vielen exogenen Medikamenten und Toxinen in Zellen z.B. der Niere, der Leber oder im ZNS vermitteln, sowie die elektroneutralen Protonen-Antiporter (OCTNs und MATEs), die für den Auswärtstransport vieler Substrate in diesen Zellen sorgen. In unserem Forschungsschwerpunkt werden Struktur-Funktionsbeziehungen und Interaktion mit anderen regulatorischen Proteinen von Transportern für organische Kationen molekular- und zellbiologisch sowie funktionell charakterisiert.Hierbei stehen folgende Teilaspekte im Vordergrund:
  • Charakterisierung von Transportern für organische Kationen (OCTs, OCTNs, MATEs)
  • Regulation von Transportern für organischer Kationen durch Kinasen
  • Oligomerisierung von organischen Kationentransportern
  • Interaktion von organischen Kationentransportern mit  zytosolischen Proteinen
  • Transporter für organische Kationen und Zytotoxizität (Nephrotoxizität, Ototoxizität, periphere Neurotoxizität)
  • Interaktion von Medikamenten (Zytostatika, Thyrosinkinasen-Inhibitoren, Immunsuppressiva, Antirheumatika, Antibiotika, Antihypertensiva) mit Transportern für organischen Kationen
  • Identifikation von Polymorphismen von organischen Kationentransportern
Für diese Untersuchungen werden folgende experimentelle Modelle eingesetzt:
  • Zelllinienen und Primärkulturen
  • Expressionssysteme
  • Wildtyp- und Knockout-Mausmodelle
  • Humanes OP-Material
Oligomerisierung von hOCT2-Proteinen. Aufnahme am konfokalen Mikroskop von HEK293-Zellen, die mit GFP (green fluorescence protein) markiertem hOCT2 transfiziert wurden. Rot = in vivo Markierung mit Antikörpern gegen die extrazelluläre Schleife des hOCT2; Grün = hOCT2 GFP - assoziierte Fluoreszenz; Gelb = Überlappung

Eigene Publikationen zum Thema

  1. Koepp TN, Tokaj A, Nedvetsky PI, Conchon Costa AC, Snieder B, Schröter R, Ciarimboli G.Properties of transport mediated by the human organic cation transporter 2 studied in a polarized three-dimensional epithelial cell culture model. Int J Mol Sci. 2021; Vol. 22, Issue 17, 9658
  2. Schorn S, Dicke AK, Neugebauer U, Schröter R, Friedrich M, Reuter S, Ciarimboli G. Expression and function of organic cation transporter 2 in pancreas. Front. Cell Dev. Biol. - Cellular Biochemistry2021;9:688885. doi: 10.3389/fcell.2021.688885
  3. Ciarimboli G. Physiology, Biochemistry, and Pharmacology of Transporters for Organic Cations (Editorial). Int J Mol Sci. 2021;22(2):732. doi: 10.3390/ijms22020732
  4. Amrhein J, Drynda S, Schlatt L, Karst U, Lohmann CH, Ciarimboli G, Bertrand J. Tofacitinib and Baricitinib are taken up by different uptake mechanisms determining the efficacy of both drugs in RA. Int J Mol Sci 2020; 21, 6632; doi:10.3390/ijms21186632
  5. Ciarimboli G. Fishing for protective compounds.eLife 2020;9:e61547. doi: https://doi.org/10.7554/eLife.61547
  6. Kantauskaitė M, Hucke A, Reike M, Ahmed Eltayeb S, Xiao C, Barz V, Ciarimboli G. Rapid regulation of human multidrug and extrusion transporters hMATE1 and hMATE2K. Int J Mol Sci 2020Jul 21;21(14):E5157. doi: 10.3390/ijms21145157.
  7. Oswald S, Müller J, Neugebauer U, Schröter R, Herrmann E, Pavenstädt H and Ciarimboli G.Protein Abundance of Clinically Relevant Drug Transporters in The Human Kidneys.Int J Mol Sci 2019, 20, 5303; doi:10.3390/ijms20215303
  8. Frenzel D, Köppen C, Bauer OB, Karst U, Schröter R, Tzvetkov MV, Ciarimboli G.Effects of Single Nucleotide Polymorphism Ala270Ser (rs316019) on the Function and Regulation of hOCT2.Biomolecules. 2019; 7;9(10). pii: E578. doi: 10.3390/biom9100578.
  9. Hucke A, Rinschen MM, Bauer OB, Sperling M, Karst U, Köppen C, Sommer K, Schröter R, Ceresa C, Chiorazzi A, Canta A, Semperboni S, Marmiroli P, Cavaletti G, Schlatt S, Schlatter E, Pavenstädt H, Heitplatz B, Van Marck V, Sparreboom A, Barz V, Knief A, Deuster D, Zehnhoff-Dinnesen AA, Ciarimboli G.An integrative approach to cisplatin chronic toxicities in mice reveals importance of organic cation-transporter-dependent protein networks for renoprotection.Arch Toxicol. 2019;93(10):2835-2848. doi: 10.1007/s00204-019-02557-9.
  10. Snieder B, Brast S, Grabner A, Buchholz S, Schröter R, Spoden GA, Florin L, Salomon J, Albrecht T, Barz V, Sparreboom A, Ciarimboli G.Identification of the Tetraspanin CD9 as an Interaction Partner of Organic Cation Transporters 1 and 2.SLAS Discov. 2019;24(9):904-914. doi: 10.1177/2472555219859837
  11. Harrach S, Barz V, Pap T, Pavenstädt H, Schlatter E, Edemir B, Distler J, Ciarimboli G*, Bertrand J: Notch-signaling activity determines uptake and biological effect of imatinib in systemic sclerosis dermal fibroblasts. J Invest Dermatol. 2018; pii: S0022-202X(18)32642-3. doi: 10.1016/j.jid.2018.08.021.
  12. Hucke A, Park GY, Bauer OB, Beyer G, Köppen C, Zeeh D, Wehe CA, Sperling M, Schröter R, Kantauskaitè M, Hagos Y, Karst U, Lippard SJ, Ciarimboli G: Interaction of the new monofunctional anticancer agent Phenanthriplatin with transporters for organic cations. Front Chem. 2018; 6:180. doi: 10.3389/fchem.2018.00180.
  13. Hu S, Leblanc AF, Gibson AA, Hong KW, Kim JY, Janke LJ, Li L, Vasilyeva A, Finkelstein DB, Sprowl JA, Sweet DH, Schlatter E, Ciarimboli G, Schellens JHM, Baker SD, Pabla N and SparreboomA. Identification of OAT1/OAT3 as contributors to cisplatin toxicity.Clin Transl Sci 2017; 00, 1–9; doi:10.1111/cts.12480.
  14. Harrach S, Edemir B, Schmidt-Lauber C, Pap T, Bertrand J, Ciarimboli G.Importance of the novel organic cation transporter 1 for tyrosine kinase inhibition by saracatinib in rheumatoid arthritis synovial fibroblasts.Sci Rep. 2017;7(1):1258. doi: 10.1038/s41598-017-01438-4.
  15. Schulze U, Brast S, Grabner A, Albiker C, Snieder B, Holle S, Schlatter E, Schröter R, Pavenstädt H, Herrmann E, Lambert C, Spoden GA, Florin L, Saftig P, Ciarimboli G.Tetraspanin CD63 controls basolateral sorting of organic cation transporter 2 in renal proximal tubules.FASEB J. 201731(4):1421-1433. doi: 10.1096/fj.201600901R.
  16. Harrach S, Schmidt-Lauber C, Pap T, Pavenstädt H, Schlatter E, Schmidt E, Berdel WE, Schulze U, Edemir B, Jeromin S, Haferlach T, Ciarimboli G*, Bertrand J*. MATE1 regulates cellular uptake and sensitivity to imatinib in CML patients.Blood Cancer J. 2016; 6:e470. doi: 10.1038/bcj.2016.79.
  17. Ciarimboli G. In reference to immunohistochemical localization of OCT2 in the cochlea of various species.Laryngoscope. 2016; 126(6):E231. doi: 10.1002/lary.25881.
  18. Sprowl J, Ong SS, Gibson AA, Hu S, Du G, Lin W, Li L, Bharill S, Ness RA, Stecula A, Offer SO, Diasio RB,Nies A, Schwab M, Cavaletti G, Schlatter E, Ciarimboli G, Schellens JHM, Isacoff EY, Sali A, Chen T, Baker SD, Sparreboom A, Pabla N. A phosphotyrosine switch regulates organic cation transporters. Nature Communications, 2016, 7:10880 doi: 10.1038/ncomms10880.
  19. Köppen C, Reifschneider O, Castanheira I, Sperling M, Karst U, Ciarimboli G. Quantitative imaging of platinum based on laser ablation inductively coupled plasma-mass spectrometry to investigate toxic side effects of cisplatin. Metallomics, 2015, 7(12):1595-603.
  20. Lanvers-Kaminsky C, Sprowl JA, Malath I, Deuster D, Eveslage M, Schlatter E, Mathijssen RH, Boos J, Jürgens H, Am Zehnhoff-Dinnesen AG, Sparreboom A, Ciarimboli G. Human organic cation transporter 2 variant c.808G>T carriers confers protection effect against cisplatin-induced ototoxicity. Pharmacogenomics, 2015, 16, (4): 323-332
  21. Pabla N, Gibson AA, Buege M, Ong SS, Li L, Hu S, Du G, Sprowl JA, Vasilyeva A, Janke LI, Schlatter E, Chen T, Ciarimboli G, Sparreboom A. Mitigation of acute kidney injury by cell cycle inhibitors that suppress both CDK4/6 and OCT2 functions Proc Natl Acad Sci USA, 2015, 12(16):5231-5236  
  22. Sprowl JA, Lancaster CS, Pabla N, Hermann E, Kosloske AM, Gibson AA, Li L, Zeeh D, Schlatter E, Janke LJ, Ciarimboli G, Sparreboom A. Cisplatin-induced renal injury is independently mediated by OCT2 and p53. Clin Cancer Res. 2014,20(15):4026-35.
  23. Schlatter E, Klassen P, Massmann V, Holle SK, Guckel D, Edemir B, Pavenstädt H, Ciarimboli G: Mouse organic cation transporter 1 determines properties and regulation of basolateral organic cation transport in renal proximal tubules Pflugers Arch 2013, 466(8):1581-9.
  24. Massmann V, Edemir B, Schlatter E, Al-Monajjed R, Harrach S, Klassen P, Holle SK, Sindic A, Dobrivojevic M, Pavenstädt H, Ciarimboli G: The organic cation transporter 3 (OCT3) as molecular target of psychotropic drugs: transport characteristics and acute regulation of cloned murine OCT3. Pflugers Arch 2014, 466(3):517-27. DOI: 10.1007/s00424-013-1335-8
  25. Sprowl JA, Ciarimboli G, Lancaster CS, Giovinazzo H, Gibson AA, Du G, Janke LJ, Cavaletti G, Shields AF, Sparreboom A. Oxaliplatin-induced neurotoxicity is dependent on the organic cation transporter OCT2. Proc Natl Acad Sci USA 2013; 110(27):11199-11204.
  26. Thévenod F, Ciarimboli G, Leistner M, Wolff NA, Lee WK, Schatz I, Keller T, Al-Monajjed R, Gorboulev V, Koepsell H. Substrate- and cell contact-dependent inhibitor affinity of human organic cation transporter 2: studies with two classical organic cation substrates and the novel substrate Cd(2+). Mol Pharm 2013;10(8):3045-3056.
  27. Ciarimboli G, Schröter R, Neugebauer U, Vollenbröker B, Gabriëls G, Brzica H, Sabolić I, Pietig G, Pavenstädt H, Schlatter E, Edemir B. Kidney transplantation down-regulates expression of organic cation transporters, which translocate β-blockers and fluoroquinolones. Mol Pharm 2013; 10(6):2370-2380.
  28. Schmidt-Lauber C, Harrach S, Pap T, Fischer M, Victor M, Heitzmann M, Hansen U, Fobker M, Brand SM, Sindic A, Pavenstädt H, Edemir B, Schlatter E, Bertrand J, Ciarimboli G. Transport mechanisms and their pathology-induced regulation govern tyrosine kinase inhibitor delivery in rheumatoid arthritis. PLoS One 2012; 7(12):e52247.
  29. Ciarimboli G, Lancaster CS, Schlatter E, Franke RM, Sprowl JA, Pavenstädt H, Massmann V, Guckel D, Mathijssen RH, Yang W, Pui CH, Relling MV, Herrmann E, Sparreboom A: Proximal tubular secretion of creatinine by organic cation transporter OCT2 in cancer patients. Clin Cancer Res 2012; 15;18(4):1101-1108.
  30. Brast S, Grabner A, Sucic S, Sitte HH, Hermann E, Pavenstädt H, Schlatter E, Ciarimboli G: The cysteines of the extracellular loop are crucial for trafficking of human organic cation transporter 2 to the plasma membrane and are involved in  oligomerization. FASEB J 2012; 26(3):976-986.
  31. Guckel D, Ciarimboli G, Pavenstädt H, Schlatter E: Regulation of organic cation transport in isolated mouse proximal tubules involves complex changes in protein trafficking and substrate affinity. Cell Physiol Biochem 2012; 30(1):269-281.
  32. Grabner A, Brast S, Sucic S, Bierer S, Hirsch B, Pavenstädt H, Sitte HH, Schlatter E, Ciarimboli G: LAPTM4A interacts with hOCT2 and regulates its endocytotic recruitment. Cell Mol Life Sci 2011; 68(24):4079-4090.
  33. Holle SK, Ciarimboli G, Edemir B, Neugebauer U, Pavenstädt H, Schlatter E: Properties and regulation of organic cation transport in freshly isolated mouse proximal tubules analyzed with a fluorescence reader-based method. Pflugers Arch 2011; 462(2):359-369.
  34. Ciarimboli G, Holle SK, Vollenbröcker B, Hagos Y, Reuter S, Burckhardt G, Bierer S, Herrmann E, Pavenstädt H, Rossi R, Kleta R, Schlatter E: New clues for nephrotoxicity induced by ifosfamide: preferential renal uptake via the human organic cation transporter 2. Mol Pharm 2011; 7;8(1):270-279.
  35. Ehrsson H, Wallin I Ciarimboli G, Schlatter E: Cimetidine as an organic cation transporter antagonist. Am J Pathol 2010; 177(3):1573-1574.
  36. Ciarimboli G, Deuster D, Knief A, Sperling M, Holtkamp M, Edemir B, Pavenstädt H, Lanvers-Kaminsky C, am Zehnhoff-Dinnesen A, Schinkel AH, Jürgens H, Schlatter E: Organic cation transporter 2 mediates cisplatin-induced oto- and nephrotoxicity and is target for protective interventions. Am J Pathol 2010; 176(3), 1169-1180.
  37. Lee WK, Reichold M, Edemir B, Ciarimboli G, Warth R, Koepsell H, Thévenod F: Organic cation transporters OCT1, 2, and 3 mediate high-affinity transport of the mutagenic vital dye ethidium in the kidney proximal tubule. Am J Physiol Renal Physiol 2009; 296(6): F1504-1513.
  38. Wilde S, Schlatter E, Koepsell H, Edemir B, Reuter S, Pavenstädt H, Neugebauer U, Schröter R, Brast S, Ciarimboli G: Calmodulin-associated post-translational regulation of rat organic cation transporter 2 in the kidney is gender dependent. Cell Mol Life Sci 2009; 66(10):1729-1740.
  39. Sturm A, Gorboulev V, Gorbunov D, Keller T, Volk C, Schmitt BM, Schlachtbauer P, Ciarimboli G, Koepsell H. Identification of cysteines in rat organic cation transporters rOCT1 (C322, C451) and rOCT2 (C451) critical for transport activity and substrate affinity. Am J Physiol Renal Physiol 2007; 293(3):F767-79
  40. Biermann J, Lang D, Gorboulev V, Koepsell H, Sindic A, Schröter R, Zvirbliene A, Pavenstädt H, Schlatter E, Ciarimboli G. Characterization of regulatory mechanisms and states of human organic cation transporter 2. Am J Physiol Cell Physiol 2006; 290(6):C1521-31.
  41. Ciarimboli G, Ludwig T, Lang D, Pavenstädt H, Koepsell H, Piechota HJ, Haier J, Jaehde U, Zisowsky J, Schlatter E: Cisplatin nephrotoxicity is critically mediated via the human organic cation transporter 2. Am J Pathol 2005; 167(6):1477-1484.
  42. Ciarimboli G, Koepsell H, Iordanova M, Gorboulev V, Dürner B, Lang D, Edemir B, Schröter R, Van Le T, Schlatter E: Individual PKC- phosphorylation sites in organic cation transporter 1 determine substrate selectivity and transport regulation. J Am Soc Nephrol 2005; 16:1562-1570.
  43. Ciarimboli G, Struwe K, Arndt P, Gorboulev V, Koepsell H, Schlatter E, Hirsch JR: Regulation of the human organic cation transporters hOCT1. J Cell Physiol 2004; 201:420-428.
  44. Cetinkaya I, Ciarimboli G, Yalcinkaya G, Mehrens T, Velic A, Hirsch JR, Gorboulev V, Koepsell H, Schlatter E: The human organic cation transporter hOCT2 is regulated by Ca2+/calmodulin-, cAMP- and phosphatidylinositol-3-dependent kinases. Am J Physiol Renal Physiol 2003; 284(2):F293-302.
  45. Schlatter E, Monnich V, Cetinkaya I, Mehrens T, Ciarimboli G, Hirsch JR, Popp C, Koepsell H: The organic cation transporters rOCT1 and hOCT2 are inhibited by cGMP. J Membr Biol 2002; 189(3):237-244.