Journal of Neuroimmune Pharmacology

, Volume 9, Issue 3, pp 293–301 | Cite as

TREK-King the Blood–Brain-Barrier

  • Stefan Bittner
  • Tobias Ruck
  • Juncal Fernández-Orth
  • Sven G. Meuth


TWIK-related potassium channel-1 (TREK1, KCNK2) is the most extensively studied member of the two-pore domain potassium (K2P) channel family. Recent studies have already demonstrated a key role in the pathophysiology of depression, pain and neurodegenerative damage pointing towards an important role in a broad spectrum of CNS disorders. The mammalian blood–brain barrier (BBB) is a highly specialized structure and an integral part of the neurovascular unit, which controls the transition of cells and molecules into the CNS. While BBB dysregulation is common in neurologic diseases, the molecular mechanisms involved in this process remain largely unknown. Recently, we were able to describe a role of TREK1 in this context. TREK1 was downregulated in murine and human BBB upon inflammation. Blocking of TREK1 increased lymphocyte migration, while activation had the opposite effect. In TREK1-deficient (Trek1 −/− ) mice, brain endothelial cells displayed an inflammatory phenotype and leukocyte trafficking was facilitated, as demonstrated in experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis. Here we summarize these findings and discuss the implications in diseases related to BBB dysfunction.


Multiple Sclerosis Ion channels K2P channels TREK1 Blood–brain barrier Neuroinflammation 



This work was supported by the Deutsche Forschungsgemeinschaft (SFB TR128, TP B6 to S.G.M., FOR1086, TP2 to S.G.M. and ME3283/2-1 to S.G.M.), the Else-Kröner-Fresenius Stiftung (S.B., S.G.M.), the Interdisciplinary Center for Clinical Research (IZKF) Münster (SEED 03/12 to S.B.) and the excellence cluster ‘Cells in motion’ (CIM, to S.G.M., H.W., S.B.).


The authors have no conflicts of interest or financial disclosures to make.


  1. Abdullaev IF, Bisaillon JM, Potier M, Gonzalez JC, Motiani RK, Trebak M (2008) Stim1 and Orai1 mediate CRAC currents and store-operated calcium entry important for endothelial cell proliferation. Circ Res 103(11):1289–1299. doi: 10.1161/01.RES.0000338496.95579.56 PubMedCentralPubMedCrossRefGoogle Scholar
  2. Alloui A, Zimmermann K, Mamet J, Duprat F, Noel J, Chemin J, Guy N, Blondeau N, Voilley N, Rubat-Coudert C, Borsotto M, Romey G, Heurteaux C, Reeh P, Eschalier A, Lazdunski M (2006) TREK-1, a K+ channel involved in polymodal pain perception. EMBO J 25(11):2368–2376. doi: 10.1038/sj.emboj.7601116 PubMedCentralPubMedCrossRefGoogle Scholar
  3. Anthony TL, Brooks HL, Boassa D, Leonov S, Yanochko GM, Regan JW, Yool AJ (2000) Cloned human aquaporin-1 is a cyclic GMP-gated ion channel. Mol Pharmacol 57(3):576–588PubMedGoogle Scholar
  4. Bagriantsev SN, Ang KH, Gallardo-Godoy A, Clark KA, Arkin MR, Renslo AR, Minor DL Jr (2013) A high-throughput functional screen identifies small molecule regulators of temperature- and mechano-sensitive K2P channels. ACS Chem Biol 8(8):1841–1851. doi: 10.1021/cb400289x PubMedCentralPubMedCrossRefGoogle Scholar
  5. Balbuena P, Li W, Rzigalinski BA, Ehrich M (2012) Malathion/oxon and lead acetate increase gene expression and protein levels of transient receptor potential canonical channel subunits TRPC1 and TRPC4 in rat endothelial cells of the blood–brain barrier. Int J Toxicol 31(3):238–249. doi: 10.1177/1091581812442688 PubMedCrossRefGoogle Scholar
  6. Barel O, Shalev SA, Ofir R, Cohen A, Zlotogora J, Shorer Z, Mazor G, Finer G, Khateeb S, Zilberberg N, Birk OS (2008) Maternally inherited Birk Barel mental retardation dysmorphism syndrome caused by a mutation in the genomically imprinted potassium channel KCNK9. Am J Hum Genet 83(2):193–199. doi: 10.1016/j.ajhg.2008.07.010 PubMedCentralPubMedCrossRefGoogle Scholar
  7. Barreiro O, Yanez-Mo M, Serrador JM, Montoya MC, Vicente-Manzanares M, Tejedor R, Furthmayr H, Sanchez-Madrid F (2002) Dynamic interaction of VCAM-1 and ICAM-1 with moesin and ezrin in a novel endothelial docking structure for adherent leukocytes. J Cell Biol 157(7):1233–1245. doi: 10.1083/jcb.200112126 PubMedCentralPubMedCrossRefGoogle Scholar
  8. Berrout J, Jin M, O’Neil RG (2012) Critical role of TRPP2 and TRPC1 channels in stretch-induced injury of blood–brain barrier endothelial cells. Brain Res 1436:1–12. doi: 10.1016/j.brainres.2011.11.044 PubMedCrossRefGoogle Scholar
  9. Bittner S, Meuth SG (2013) Targeting ion channels for the treatment of autoimmune neuroinflammation. Ther Adv Neurol Disord 6(5):322–336. doi: 10.1177/1756285613487782 PubMedCentralPubMedCrossRefGoogle Scholar
  10. Bittner S, Bobak N, Herrmann AM, Gobel K, Meuth P, Hohn KG, Stenner MP, Budde T, Wiendl H, Meuth SG (2010) Upregulation of K2P5.1 potassium channels in multiple sclerosis. Ann Neurol 68(1):58–69. doi: 10.1002/ana.22010 PubMedCrossRefGoogle Scholar
  11. Bittner S, Ruck T, Schuhmann MK, Herrmann AM, Moha ou Maati H, Bobak N, Gobel K, Langhauser F, Stegner D, Ehling P, Borsotto M, Pape HC, Nieswandt B, Kleinschnitz C, Heurteaux C, Galla HJ, Budde T, Wiendl H, Meuth SG (2013) Endothelial TWIK-related potassium channel-1 (TREK1) regulates immune-cell trafficking into the CNS. Nat Med 19(9):1161–1165. doi: 10.1038/nm.3303 PubMedCrossRefGoogle Scholar
  12. Blondeau N, Petrault O, Manta S, Giordanengo V, Gounon P, Bordet R, Lazdunski M, Heurteaux C (2007) Polyunsaturated fatty acids are cerebral vasodilators via the TREK-1 potassium channel. Circ Res 101(2):176–184. doi: 10.1161/CIRCRESAHA.107.154443 PubMedCrossRefGoogle Scholar
  13. Boassa D, Stamer WD, Yool AJ (2006) Ion channel function of aquaporin-1 natively expressed in choroid plexus. J Neurosci 26(30):7811–7819. doi: 10.1523/JNEUROSCI.0525-06.2006 PubMedCrossRefGoogle Scholar
  14. Brown RC, Wu L, Hicks K, O’Neil RG (2008) Regulation of blood–brain barrier permeability by transient receptor potential type C and type v calcium-permeable channels. Microcirculation 15(4):359–371. doi: 10.1080/10739680701762656 PubMedCentralPubMedCrossRefGoogle Scholar
  15. Carman CV, Jun CD, Salas A, Springer TA (2003) Endothelial cells proactively form microvilli-like membrane projections upon intercellular adhesion molecule 1 engagement of leukocyte LFA-1. J Immunol 171(11):6135–6144PubMedCrossRefGoogle Scholar
  16. Celli L, Ryckewaert JJ, Delachanal E, Duperray A (2006) Evidence of a functional role for interaction between ICAM-1 and nonmuscle alpha-actinins in leukocyte diapedesis. J Immunol 177(6):4113–4121PubMedCrossRefGoogle Scholar
  17. Cheng YD, Al-Khoury L, Zivin JA (2004) Neuroprotection for ischemic stroke: two decades of success and failure. NeuroRx 1(1):36–45. doi: 10.1602/neurorx.1.1.36 PubMedCentralPubMedCrossRefGoogle Scholar
  18. Chung YC, Ko HW, Bok E, Park ES, Huh SH, Nam JH, Jin BK (2010) The role of neuroinflammation on the pathogenesis of Parkinson’s disease. BMB Rep 43(4):225–232PubMedCrossRefGoogle Scholar
  19. Clare JJ (2010) Targeting ion channels for drug discovery. Discov Med 9(46):253–260PubMedGoogle Scholar
  20. Correale J, Villa A (2007) The blood–brain-barrier in multiple sclerosis: functional roles and therapeutic targeting. Autoimmunity 40(2):148–160. doi: 10.1080/08916930601183522 PubMedCrossRefGoogle Scholar
  21. Csanady L, Adam-Vizi V (2003) Ca(2+)- and voltage-dependent gating of Ca(2+)- and ATP-sensitive cationic channels in brain capillary endothelium. Biophys J 85(1):313–327. doi: 10.1016/S0006-3495(03)74476-2 PubMedCentralPubMedCrossRefGoogle Scholar
  22. Dejana E, Corada M, Lampugnani MG (1995) Endothelial cell-to-cell junctions. FASEB J 9(10):910–918PubMedGoogle Scholar
  23. Dhib-Jalbut S, Marks S (2010) Interferon-beta mechanisms of action in multiple sclerosis. Neurology 74(Suppl 1):S17–S24. doi: 10.1212/WNL.0b013e3181c97d99 PubMedCrossRefGoogle Scholar
  24. Diotti RA, Nakanishi A, Clementi N, Mancini N, Criscuolo E, Solforosi L, Clementi M (2013) JC polyomavirus (JCV) and monoclonal antibodies: friends or potential foes? Clin Dev Immunol 2013:967581. doi: 10.1155/2013/967581 PubMedCentralPubMedCrossRefGoogle Scholar
  25. Drummond JC, Piyash PM, Kimbro JR (2000) Neuroprotection failure in stroke. Lancet 356(9234):1032–1033. doi: 10.1016/S0140-6736(05)72654-4 PubMedCrossRefGoogle Scholar
  26. Enciu AM, Popescu BO (2013) Is there a causal link between inflammation and dementia? Biomed Res Int 2013:316495. doi: 10.1155/2013/316495 PubMedCentralPubMedCrossRefGoogle Scholar
  27. Engelhardt B (2006) Molecular mechanisms involved in T cell migration across the blood–brain barrier. J Neural Transm 113(4):477–485. doi: 10.1007/s00702-005-0409-y PubMedCrossRefGoogle Scholar
  28. Engelhardt B, Sorokin L (2009) The blood–brain and the blood-cerebrospinal fluid barriers: function and dysfunction. Semin Immunopathol 31(4):497–511. doi: 10.1007/s00281-009-0177-0 PubMedCrossRefGoogle Scholar
  29. Erickson MA, Banks WA (2013) Blood–brain barrier dysfunction as a cause and consequence of Alzheimer’s disease. J Cereb Blood Flow Metab 33(10):1500–1513. doi: 10.1038/jcbfm.2013.135 PubMedCrossRefGoogle Scholar
  30. Etienne-Manneville S, Manneville JB, Adamson P, Wilbourn B, Greenwood J, Couraud PO (2000) ICAM-1-coupled cytoskeletal rearrangements and transendothelial lymphocyte migration involve intracellular calcium signaling in brain endothelial cell lines. J Immunol 165(6):3375–3383PubMedCrossRefGoogle Scholar
  31. Fernandez-Borja M, van Buul JD, Hordijk PL (2010) The regulation of leucocyte transendothelial migration by endothelial signalling events. Cardiovasc Res 86(2):202–210. doi: 10.1093/cvr/cvq003 PubMedCrossRefGoogle Scholar
  32. Fox R (2011) Advances in the management of PML: focus on natalizumab. Cleve Clin J Med 78(Suppl 2):S33–S37. doi: 10.3949/ccjm.78.s2.08 PubMedCrossRefGoogle Scholar
  33. Garcia JG, Verin AD, Herenyiova M, English D (1988) Adherent neutrophils activate endothelial myosin light chain kinase: role in transendothelial migration. J Appl Physiol (1985) 84(5):1817–1821Google Scholar
  34. Garry A, Fromy B, Blondeau N, Henrion D, Brau F, Gounon P, Guy N, Heurteaux C, Lazdunski M, Saumet JL (2007) Altered acetylcholine, bradykinin and cutaneous pressure-induced vasodilation in mice lacking the TREK1 potassium channel: the endothelial link. EMBO Rep 8(4):354–359. doi: 10.1038/sj.embor.7400916 PubMedCentralPubMedCrossRefGoogle Scholar
  35. Goldman DE (1943) Potential, impedance, and rectification in membranes. J Gen Physiol 27(1):37–60PubMedCentralPubMedCrossRefGoogle Scholar
  36. Goldstein SA, Bockenhauer D, O’Kelly I, Zilberberg N (2001) Potassium leak channels and the KCNK family of two-P-domain subunits. Nat Rev Neurosci 2(3):175–184. doi: 10.1038/35058574 PubMedCrossRefGoogle Scholar
  37. Hervieu GJ, Cluderay JE, Gray CW, Green PJ, Ranson JL, Randall AD, Meadows HJ (2001) Distribution and expression of TREK-1, a two-pore-domain potassium channel, in the adult rat CNS. Neuroscience 103(4):899–919PubMedCrossRefGoogle Scholar
  38. Heurteaux C, Laigle C, Blondeau N, Jarretou G, Lazdunski M (2006a) Alpha-linolenic acid and riluzole treatment confer cerebral protection and improve survival after focal brain ischemia. Neuroscience 137(1):241–251. doi: 10.1016/j.neuroscience.2005.08.083 PubMedCrossRefGoogle Scholar
  39. Heurteaux C, Lucas G, Guy N, El Yacoubi M, Thummler S, Peng XD, Noble F, Blondeau N, Widmann C, Borsotto M, Gobbi G, Vaugeois JM, Debonnel G, Lazdunski M (2006b) Deletion of the background potassium channel TREK-1 results in a depression-resistant phenotype. Nat Neurosci 9(9):1134–1141. doi: 10.1038/nn1749 PubMedCrossRefGoogle Scholar
  40. Hicks K, O’Neil RG, Dubinsky WS, Brown RC (2010) TRPC-mediated actin-myosin contraction is critical for BBB disruption following hypoxic stress. Am J Physiol Cell Physiol 298(6):C1583–C1593. doi: 10.1152/ajpcell.00458.2009 PubMedCentralPubMedCrossRefGoogle Scholar
  41. Hille B, Armstrong CM, MacKinnon R (1999) Ion channels: from idea to reality. Nat Med 5(10):1105–1109. doi: 10.1038/13415 PubMedCrossRefGoogle Scholar
  42. Hodgkin AL, Huxley AF (1952) A quantitative description of membrane current and its application to conduction and excitation in nerve. J Physiol 117(4):500–544PubMedCentralPubMedGoogle Scholar
  43. Hodgkin AL, Katz B (1949) The effect of sodium ions on the electrical activity of giant axon of the squid. J Physiol 108(1):37–77PubMedCentralPubMedGoogle Scholar
  44. Honore E (2007) The neuronal background K2P channels: focus on TREK1. Nat Rev Neurosci 8(4):251–261. doi: 10.1038/nrn2117 PubMedCrossRefGoogle Scholar
  45. Hu DE, Easton AS, Fraser PA (2005) TRPV1 activation results in disruption of the blood–brain barrier in the rat. Br J Pharmacol 146(4):576–584. doi: 10.1038/sj.bjp.0706350 PubMedCentralPubMedCrossRefGoogle Scholar
  46. Huppert J, Closhen D, Croxford A, White R, Kulig P, Pietrowski E, Bechmann I, Becher B, Luhmann HJ, Waisman A, Kuhlmann CR (2010) Cellular mechanisms of IL-17-induced blood–brain barrier disruption. FASEB J 24(4):1023–1034. doi: 10.1096/fj.09-141978 PubMedCrossRefGoogle Scholar
  47. Innamaa A, Jackson L, Asher V, van Shalkwyk G, Warren A, Keightley A, Hay D, Bali A, Sowter H, Khan R (2013) Expression and effects of modulation of the K2P potassium channels TREK-1 (KCNK2) and TREK-2 (KCNK10) in the normal human ovary and epithelial ovarian cancer. Clin Transl Oncol 15(11):910–918. doi: 10.1007/s12094-013-1022-4
  48. Kaczorowski GJ, McManus OB, Priest BT, Garcia ML (2008) Ion channels as drug targets: the next GPCRs. J Gen Physiol 131(5):399–405. doi: 10.1085/jgp.200709946 PubMedCentralPubMedCrossRefGoogle Scholar
  49. Kanters E, van Rijssel J, Hensbergen PJ, Hondius D, Mul FP, Deelder AM, Sonnenberg A, van Buul JD, Hordijk PL (2008) Filamin B mediates ICAM-1-driven leukocyte transendothelial migration. J Biol Chem 283(46):31830–31839. doi: 10.1074/jbc.M804888200 PubMedCrossRefGoogle Scholar
  50. Kebir H, Kreymborg K, Ifergan I, Dodelet-Devillers A, Cayrol R, Bernard M, Giuliani F, Arbour N, Becher B, Prat A (2007) Human TH17 lymphocytes promote blood–brain barrier disruption and central nervous system inflammation. Nat Med 13(10):1173–1175. doi: 10.1038/nm1651 PubMedCrossRefGoogle Scholar
  51. Kelleher RJ, Soiza RL (2013) Evidence of endothelial dysfunction in the development of Alzheimer’s disease: Is Alzheimer’s a vascular disorder? Am J Cardiovasc Dis 3(4):197–226PubMedCentralPubMedGoogle Scholar
  52. Kelley LC, Hayes KE, Ammer AG, Martin KH, Weed SA (2011) Revisiting the ERK/Src cortactin switch. Commun Integr Biol 4(2):205–207. doi: 10.4161/cib.4.2.14420 PubMedCentralPubMedCrossRefGoogle Scholar
  53. Ketchum KA, Joiner WJ, Sellers AJ, Kaczmarek LK, Goldstein SA (1995) A new family of outwardly rectifying potassium channel proteins with two pore domains in tandem. Nature 376(6542):690–695. doi: 10.1038/376690a0 PubMedCrossRefGoogle Scholar
  54. Kim E, Hwang EM, Yarishkin O, Yoo JC, Kim D, Park N, Cho M, Lee YS, Sun CH, Yi GS, Yoo J, Kang D, Han J, Hong SG, Park JY (2010) Enhancement of TREK1 channel surface expression by protein-protein interaction with beta-COP. Biochem Biophys Res Commun 395(2):244–250. doi: 10.1016/j.bbrc.2010.03.171 PubMedCrossRefGoogle Scholar
  55. Kim SY, Buckwalter M, Soreq H, Vezzani A, Kaufer D (2012) Blood–brain barrier dysfunction-induced inflammatory signaling in brain pathology and epileptogenesis. Epilepsia 53(Suppl 6):37–44. doi: 10.1111/j.1528-1167.2012.03701.x PubMedCentralPubMedCrossRefGoogle Scholar
  56. Kito H, Yamazaki D, Ohya S, Yamamura H, Asai K, Imaizumi Y (2011) Up-regulation of K(ir)2.1 by ER stress facilitates cell death of brain capillary endothelial cells. Biochem Biophys Res Commun 411(2):293–298. doi: 10.1016/j.bbrc.2011.06.128 PubMedCrossRefGoogle Scholar
  57. Kleinschnitz C, Blecharz K, Kahles T, Schwarz T, Kraft P, Gobel K, Meuth SG, Burek M, Thum T, Stoll G, Forster C (2011) Glucocorticoid insensitivity at the hypoxic blood–brain barrier can be reversed by inhibition of the proteasome. Stroke 42(4):1081–1089. doi: 10.1161/STROKEAHA.110.592238 PubMedCrossRefGoogle Scholar
  58. Larochelle C, Alvarez JI, Prat A (2011) How do immune cells overcome the blood–brain barrier in multiple sclerosis? FEBS Lett 585(23):3770–3780. doi: 10.1016/j.febslet.2011.04.066 PubMedCrossRefGoogle Scholar
  59. Lauritzen I, Chemin J, Honore E, Jodar M, Guy N, Lazdunski M, Jane Patel A (2005) Cross-talk between the mechano-gated K2P channel TREK-1 and the actin cytoskeleton. EMBO Rep 6(7):642–648. doi: 10.1038/sj.embor.7400449 PubMedCentralPubMedCrossRefGoogle Scholar
  60. Li J, Cubbon RM, Wilson LA, Amer MS, McKeown L, Hou B, Majeed Y, Tumova S, Seymour VA, Taylor H, Stacey M, O’Regan D, Foster R, Porter KE, Kearney MT, Beech DJ (2011) Orai1 and CRAC channel dependence of VEGF-activated Ca2+ entry and endothelial tube formation. Circ Res 108(10):1190–1198. doi: 10.1161/CIRCRESAHA.111.243352 PubMedCentralPubMedCrossRefGoogle Scholar
  61. Lo EH, Dalkara T, Moskowitz MA (2003) Mechanisms, challenges and opportunities in stroke. Nat Rev Neurosci 4(5):399–415. doi: 10.1038/nrn1106 PubMedCrossRefGoogle Scholar
  62. Luh C, Kuhlmann CR, Ackermann B, Timaru-Kast R, Luhmann HJ, Behl C, Werner C, Engelhard K, Thal SC (2010) Inhibition of myosin light chain kinase reduces brain edema formation after traumatic brain injury. J Neurochem 112(4):1015–1025. doi: 10.1111/j.1471-4159.2009.06514.x PubMedCrossRefGoogle Scholar
  63. Lyck R, Reiss Y, Gerwin N, Greenwood J, Adamson P, Engelhardt B (2003) T-cell interaction with ICAM-1/ICAM-2 double-deficient brain endothelium in vitro: the cytoplasmic tail of endothelial ICAM-1 is necessary for transendothelial migration of T cells. Blood 102(10):3675–3683. doi: 10.1182/blood-2003-02-0358 PubMedCrossRefGoogle Scholar
  64. Maingret F, Honore E, Lazdunski M, Patel AJ (2002) Molecular basis of the voltage-dependent gating of TREK-1, a mechano-sensitive K(+) channel. Biochem Biophys Res Commun 292(2):339–346. doi: 10.1006/bbrc.2002.6674 PubMedCrossRefGoogle Scholar
  65. Mazella J, Petrault O, Lucas G, Deval E, Beraud-Dufour S, Gandin C, El-Yacoubi M, Widmann C, Guyon A, Chevet E, Taouji S, Conductier G, Corinus A, Coppola T, Gobbi G, Nahon JL, Heurteaux C, Borsotto M (2010) Spadin, a sortilin-derived peptide, targeting rodent TREK-1 channels: a new concept in the antidepressant drug design. PLoS Biol 8(4):e1000355. doi: 10.1371/journal.pbio.1000355 PubMedCentralPubMedCrossRefGoogle Scholar
  66. Medhurst AD, Rennie G, Chapman CG, Meadows H, Duckworth MD, Kelsell RE, Gloger II, Pangalos MN (2001) Distribution analysis of human two pore domain potassium channels in tissues of the central nervous system and periphery. Brain Res Mol Brain Res 86(1–2):101–114PubMedCrossRefGoogle Scholar
  67. Millar ID, Wang S, Brown PD, Barrand MA, Hladky SB (2008) Kv1 and Kir2 potassium channels are expressed in rat brain endothelial cells. Pflugers Arch 456(2):379–391. doi: 10.1007/s00424-007-0377-1 PubMedCrossRefGoogle Scholar
  68. Moha ou Maati H, Peyronnet R, Devader C, Veyssiere J, Labbal F, Gandin C, Mazella J, Heurteaux C, Borsotto M (2011) A human TREK-1/HEK cell line: a highly efficient screening tool for drug development in neurological diseases. PLoS One 6(10):e25602. doi: 10.1371/journal.pone.0025602 PubMedCentralPubMedCrossRefGoogle Scholar
  69. Moha Ou Maati H, Veyssiere J, Labbal F, Coppola T, Gandin C, Widmann C, Mazella J, Heurteaux C, Borsotto M (2012) Spadin as a new antidepressant: absence of TREK-1-related side effects. Neuropharmacology 62(1):278–288. doi: 10.1016/j.neuropharm.2011.07.019 PubMedCrossRefGoogle Scholar
  70. Nagelhus EA, Ottersen OP (2013) Physiological roles of aquaporin-4 in brain. Physiol Rev 93(4):1543–1562. doi: 10.1152/physrev.00011.2013 PubMedCentralPubMedCrossRefGoogle Scholar
  71. Neuwelt EA, Bauer B, Fahlke C, Fricker G, Iadecola C, Janigro D, Leybaert L, Molnar Z, O’Donnell ME, Povlishock JT, Saunders NR, Sharp F, Stanimirovic D, Watts RJ, Drewes LR (2011) Engaging neuroscience to advance translational research in brain barrier biology. Nat Rev Neurosci 12(3):169–182. doi: 10.1038/nrn2995 PubMedCentralPubMedCrossRefGoogle Scholar
  72. Nilius B, Droogmans G (2001) Ion channels and their functional role in vascular endothelium. Physiol Rev 81(4):1415–1459PubMedGoogle Scholar
  73. Overington JP, Al-Lazikani B, Hopkins AL (2006) How many drug targets are there? Nat Rev Drug Discov 5(12):993–996. doi: 10.1038/nrd2199 PubMedCrossRefGoogle Scholar
  74. Papadopoulos MC, Verkman AS (2012) Aquaporin 4 and neuromyelitis optica. Lancet Neurol 11(6):535–544. doi: 10.1016/S1474-4422(12)70133-3 PubMedCentralPubMedCrossRefGoogle Scholar
  75. Patel AJ, Honore E (2001) Properties and modulation of mammalian 2P domain K+ channels. Trends Neurosci 24(6):339–346PubMedCrossRefGoogle Scholar
  76. Patel AJ, Honore E, Maingret F, Lesage F, Fink M, Duprat F, Lazdunski M (1998) A mammalian two pore domain mechano-gated S-like K+ channel. EMBO J 17(15):4283–4290. doi: 10.1093/emboj/17.15.4283 PubMedCentralPubMedCrossRefGoogle Scholar
  77. Rossi JL, Todd T, Bazan NG, Belayev L (2013) Inhibition of Myosin light-chain kinase attenuates cerebral edema after traumatic brain injury in postnatal mice. J Neurotrauma 30(19):1672–1679. doi: 10.1089/neu.2013.2898 PubMedCrossRefGoogle Scholar
  78. Sandoz G, Thummler S, Duprat F, Feliciangeli S, Vinh J, Escoubas P, Guy N, Lazdunski M, Lesage F (2006) AKAP150, a switch to convert mechano-, pH- and arachidonic acid-sensitive TREK K(+) channels into open leak channels. EMBO J 25(24):5864–5872. doi: 10.1038/sj.emboj.7601437 PubMedCentralPubMedCrossRefGoogle Scholar
  79. Sandoz G, Tardy MP, Thummler S, Feliciangeli S, Lazdunski M, Lesage F (2008) Mtap2 is a constituent of the protein network that regulates twik-related K(+) channel expression and trafficking. J Neurosci 28(34):8545–8552. doi: 10.1523/Jneurosci.1962-08.2008 PubMedCrossRefGoogle Scholar
  80. Sorensen PS, Bertolotto A, Edan G, Giovannoni G, Gold R, Havrdova E, Kappos L, Kieseier BC, Montalban X, Olsson T (2012) Risk stratification for progressive multifocal leukoencephalopathy in patients treated with natalizumab. Mult Scler 18(2):143–152. doi: 10.1177/1352458511435105 PubMedCrossRefGoogle Scholar
  81. Steinman L (2005) Blocking adhesion molecules as therapy for multiple sclerosis: natalizumab. Nat Rev Drug Discov 4(6):510–518. doi: 10.1038/nrd1752 PubMedGoogle Scholar
  82. Steinman L (2014) Immunology of Relapse and Remission in Multiple Sclerosis. Annu Rev Immunol. doi: 10.1146/annurev-immunol-032713-120227
  83. Tiruppathi C, Ahmmed GU, Vogel SM, Malik AB (2006) Ca2+ signaling, TRP channels, and endothelial permeability. Microcirculation 13(8):693–708. doi: 10.1080/10739680600930347 PubMedCrossRefGoogle Scholar
  84. Tradtrantip L, Zhang H, Saadoun S, Phuan PW, Lam C, Papadopoulos MC, Bennett JL, Verkman AS (2012) Anti-aquaporin-4 monoclonal antibody blocker therapy for neuromyelitis optica. Ann Neurol 71(3):314–322. doi: 10.1002/ana.22657 PubMedCentralPubMedCrossRefGoogle Scholar
  85. van Buul JD, Kanters E, Hordijk PL (2007) Endothelial signaling by Ig-like cell adhesion molecules. Arterioscler Thromb Vasc Biol 27(9):1870–1876. doi: 10.1161/ATVBAHA.107.145821 PubMedCrossRefGoogle Scholar
  86. Verin AD, Lazar V, Torry RJ, Labarrere CA, Patterson CE, Garcia JG (1998) Expression of a novel high molecular-weight myosin light chain kinase in endothelium. Am J Respir Cell Mol Biol 19(5):758–766. doi: 10.1165/ajrcmb.19.5.3125 PubMedCrossRefGoogle Scholar
  87. Voloshyna I, Besana A, Castillo M, Matos T, Weinstein IB, Mansukhani M, Robinson RB, Cordon-Cardo C, Feinmark SJ (2008) TREK-1 is a novel molecular target in prostate cancer. Cancer Res 68(4):1197–1203. doi: 10.1158/0008-5472.Can-07-5163 PubMedCrossRefGoogle Scholar
  88. Williams S, Bateman A, O’Kelly I (2013) Altered expression of two-pore domain potassium (K2P) channels in cancer. PLoS One 8(10):e74589. doi: 10.1371/journal.pone.0074589 PubMedCentralPubMedCrossRefGoogle Scholar
  89. Yamazaki D, Aoyama M, Ohya S, Muraki K, Asai K, Imaizumi Y (2006) Novel functions of small conductance Ca2+−activated K+ channel in enhanced cell proliferation by ATP in brain endothelial cells. J Biol Chem 281(50):38430–38439. doi: 10.1074/jbc.M603917200 PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Stefan Bittner
    • 1
    • 2
  • Tobias Ruck
    • 1
  • Juncal Fernández-Orth
    • 1
  • Sven G. Meuth
    • 1
    • 3
  1. 1.Department of NeurologyUniversity of MünsterMünsterGermany
  2. 2.Interdisciplinary Center for Clinical Research (IZKF)MünsterGermany
  3. 3.Institute of Physiology I – NeuropathophysiologyUniversity of MünsterMünsterGermany

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