Publikationsserver der Universitätsbibliothek Marburg
Titel:Die Cav- und KCa/SK- Ionenkanalfamilien in Locus Coeruleus Neuronen der Maus - Funktionelle Charakterisierung und Implikationen für die Parkinson-Erkrankung
Autor:Matschke, Lina
Weitere Beteiligte: Decher, Niels (Prof. Dr.)
Veröffentlicht:2016
URI:https://archiv.ub.uni-marburg.de/diss/z2016/0458
DOI: https://doi.org/10.17192/z2016.0458
URN: urn:nbn:de:hebis:04-z2016-04585
DDC: Naturwissenschaften
Titel (trans.):The Cav- und KCa/SK- ion channel families in Locus Coeruleus neurons of the mouse - Functional characterization and implications for Parkinson’s disease
Publikationsdatum:2017-02-03
Lizenz:https://creativecommons.org/licenses/by-nc-sa/4.0

Dokument

Schlagwörter:
Locus Coeruleus, Patch Clamp, Calciumkanal, calciumaktivierter Kaliumkanal, calcium activated potassium channel, Locus coeruleus, Parkinson-Krankheit, calcium channel, Parkinson´s disease, Kaliumkanal

Zusammenfassung:
Der Locus Coeruleus (LC) ist ein noradrenerger Kern des Hirnstammes, der an der Regulation vielfältiger, physiologischer Prozesse beteiligt ist. Störungen des LC-Noradrenalin Systems sind in der Pathogenese verschiedener psychiatrischer und neurodegenerativer Erkrankungen beteiligt und sind ein frühes Kennzeichen der Parkinson-Krankheit (PD). Während die Degeneration von Neuronen der Substantia Nigra pars compacta (SNpc) den motorischen Leitsymptomen der PD unterliegt, wird der ausgeprägte Verlust noradrenerger Neurone des LC für einen Großteil der nichtmotorischen Dysfunktionen dieser Erkrankung verantwortlich gemacht. Die Ursachen für die selektive Vulnerabilität der LC Neurone in der Pathogenese der PD sind bislang jedoch weitestgehend unklar. Um eine tonische Noradrenalin-Ausschüttung zu gewährleisten, verfügen LC Neurone über einen intrinsischen Schrittmachermechanismus, welcher direkt an intrazelluläre Überlebenssignalwege gekoppelt ist. So führt aktivitätsabhängiger, durch L-Typ Ca2+ Kanäle vermittelter Ca2+ Influx, zu oxidativem Stress in LC Neuronen und anderen von der PD Pathogenese betroffenen Kerngebieten. Des Weiteren wird eine neuroprotektive Rolle Ca2+ aktivierter Kaliumkanäle postuliert, welche den Schrittmachermechanismus dopaminerger SNpc Neurone modulieren. Die Identifikation von Ionenkanälen, die der elektrischen Aktivität unterliegen, kann somit zu einem besseren Verständnis der selektiven Vulnerabilität coerulärer Neurone führen. Innerhalb dieser Arbeit wurden daher mittels RT-PCR Expressionsanalysen und Patch-Clamp Messungen in akuten Hirnstammschnitten die molekulare Komposition und Funktion verschiedener Ionenkanalfamilien in LC Neuronen der Maus charakterisiert. Zunächst erstellte ich ein Profil bezüglich der elektrophysiologischen Charakteristika und der Expression kaliumselektiver Ionenkanäle coerulärer Neurone. Diese Analysen zeigten, dass der elektrophysiologische Phänotyp der LC Neurone durch regelmäßige, breite Aktionspotenziale mit einer ausgeprägten Nachhyperpolarisation, die um ein depolarisiertes Membranpotenzial fluktuieren, gekennzeichnet ist. Mittels der Expressionsanalyse konnte ich die molekulare Komposition spannungsabhängiger Kaliumkanäle aufklären, die wahrscheinlich den A-Typ K+ Strom und den persistierenden K+ Strom der LC Neurone vermitteln. Als A-Typ Kaliumkanäle wurden unter anderem Kv4.3 sowie Kv1 in Kombination mit Kvβ1 detektiert, welche durch das oxidative Potenzial der Zelle reguliert werden und deshalb unter pathologischen Bedingungen mit gestörter Funktion der Mitochondrien von Bedeutung sein könnten. Des Weiteren detektierte ich Amplifikate der GIRK Kanal Unterheinheiten GIRK-1 und GIRK-4 sowie verschiedene K2P Kanal-Untereinheiten, welche an der Aufrechterhaltung des Ruhemembranpotenzials zentraler Neurone beteiligt sind. Zur funktionellen Charakterisierung spannungsabhängiger Ca2+ Kanäle führte ich RT-PCR Expressionsanalysen sowie Patch-Clamp Messungen in Kombination mit L- und T-Typ Ca2+ Kanal Blockern durch. Diese Experimente zeigten, dass sowohl Ca2+ Kanäle der Unterfamilien Cav1 als auch Cav3 in LC Neuronen exprimiert sind und eine ausgeprägte „low voltage“ aktivierte Ca2+ Leitfähigkeit vermitteln. Die Analyse der Aktionspotenzial-Folgen ergab, dass weder die Inhibition von L- noch von T-Typ Ca2+ Kanälen allein die Feurrate oder die Aktionspotenzial-Parameter der LC Neurone verändert. Die kombinierte Applikation der Kanal-Blocker führte jedoch zu einer signifikanten Reduktion der Nachhyperpolarisation und daraus resultierend zu einer Beschleunigung der Feuerrate. Diese Ergebnisse beschreiben erstmals die funktionelle Expression von T-Typ Ca2+ Kanälen in LC Neuronen und demonstrieren ihre Rolle bei der Modulation des Schrittmachermechanismus im Zusammenspiel mit L-Typ Ca2+ Kanälen. T-Typ Ca2+ Kanäle sollten demnach neben den „low-voltage“ aktivierten L-Typ Ca2+ Kanälen als Kandidaten in Betracht gezogen werden, die aktivitätsabhängigen oxidativen Stress im Kontext pathologischer Bedingungen vermitteln könnten. Im Rahmen der funktionellen Charakterisierung Ca2+ aktivierter Kaliumkanäle detektierte ich die Expression der SK Kanal Familienmitglieder SK1, SK2 und SK3 in LC Neuronen. Mittels Patch-Clamp Messungen in Kombination mit dem selektiven SK Kanal Blocker Apamin und dem positiven SK Kanal Modulator NS309 konnte ich demonstrieren, dass SK Kanäle maßgeblich für die während der Nachhyperpolarisation fließenden K+ Auswärtsströme verantwortlich sind. Während Aufnahmen der Aktionspotenzialabfolgen bewirkte die Inhibition der SK Kanäle eine Reduktion der Nachhyperpolarisation und eine beschleunigte Feuerrate, während ihre Aktivierung zu einer Vergrößerung der Nachhyperpolarisation und einer verlangsamten Frequenz führte. SK Kanäle können demnach als wichtige Regulatoren der Schrittmacherfrequenz von LC Neuronen angesehen werden. Mittels Calcium Imaging Experimenten im in vitro Glutamat- und Rotenon-Toxizitätsmodell konnte ich darüber hinaus zeigen, dass die pharmakologische SK Kanal Aktivierung die Dysregulation der Ca2+ Homöostase unter toxischen Bedingungen verhindert. Mittels Patch-Clamp Messungen konnte ich erstmals demonstrieren, dass die akute Rotenon-Exposition eine Depolarisation und eine Steigerung der Aktionspotenzial-Frequenz in LC Neuronen induziert, welche durch die SK Kanal Aktivierung unterbunden werden konnte. Stereologische Analysen zeigten schließlich, dass die SK Kanal Aktivierung mit NS309 signifikant der Degeneration von LC Neuronen im in vitro Rotenon- Toxizitätsmodell entgegenwirkt. Die Aktivierung von SK Kanälen wird demnach als ein vielversprechender Ansatzpunkt zur Neuroprotektion des LC während früher Stadien der PD Pathogenese postuliert.

Bibliographie / References

  1. Selikhova, M., Williams, D. R., Kempster, P. A., Holton, J. L., Revesz, T. & Lees, A. J. 2009. A clinicopathological study of subtypes in Parkinson's disease. Brain, 132, 2947-57.
  2. Lee, T. S., Kaku, T., Takebayashi, S., Uchino, T., Miyamoto, S., Hadama, T., Perez-Reyes, E. & Ono, K. 2006. Actions of mibefradil, efonidipine and nifedipine block of recombinant T- and L-type Ca channels with distinct inhibitory mechanisms. Pharmacology, 78, 11-20.
  3. Strøbaek, D., Teuber, L., Jørgensen, T. D., Ahring, P. K., Kjaer, K., Hansen, R. S., Olesen, S. P., Christophersen, P. & Skaaning-Jensen, B. 2004. Activation of human IK and SK Ca2+ -activated K+ channels by NS309 (6,7-dichloro-1H-indole-2,3-dione 3-oxime). Biochim Biophys Acta, 1665, 1-5.
  4. Rajkowski, J., Majczynski, H., Clayton, E. & Aston-Jones, G. 2004. Activation of monkey locus coeruleus neurons varies with difficulty and performance in a target detection task. J Neurophysiol, 92, 361-71.
  5. Freestone, P. S., Chung, K. K., Guatteo, E., Mercuri, N. B., Nicholson, L. F. & Lipski, J. 2009. Acute action of rotenone on nigral dopaminergic neurons--involvement of reactive oxygen species and disruption of Ca2+ homeostasis. Eur J Neurosci, 30, 1849-59.
  6. Heginbotham, L., Abramson, T. & MacKinnon, R. 1992. A functional connection between the pores of distantly related ion channels as revealed by mutant K+ channels. Science, 258, 1152-5.
  7. Lamy, C., Goodchild, S. J., Weatherall, K. L., Jane, D. E., Liégeois, J. F., Seutin, V. & Marrion, N. V. 2010. Allosteric block of KCa2 channels by apamin. J Biol Chem, 285, 27067-77.
  8. Koschak, A., Reimer, D., Huber, I., Grabner, M., Glossmann, H., Engel, J. & Striessnig, J. 2001. alpha 1D (Cav1.3) subunits can form l-type Ca2+ channels activating at negative voltages. J Biol Chem, 276, 22100-6.
  9. Storm, J. F. 1989. An after-hyperpolarization of medium duration in rat hippocampal pyramidal cells. J Physiol, 409, 171-90.
  10. Jones, B. E., Halaris, A. E., McIlhany, M. & Moore, R. Y. 1977. Ascending projections of the locus coeruleus in the rat. I. Axonal transport in central noradrenaline neurons. Brain Res, 127, 1- 21.
  11. Niepel, G., Bibani, R. H., Vilisaar, J., Langley, R. W., Bradshaw, C. M., Szabadi, E. & Constantinescu, C. S. 2013. Association of a deficit of arousal with fatigue in multiple sclerosis: effect of modafinil. Neuropharmacology, 64, 380-8.
  12. Kurata, H. T. & Fedida, D. 2006. A structural interpretation of voltage-gated potassium channel inactivation. Prog Biophys Mol Biol, 92, 185-208.
  13. Klugbauer, N., Marais, E., Lacinová, L. & Hofmann, F. 1999. A T-type calcium channel from mouse brain. Pflugers Arch, 437, 710-5.
  14. Hetzenauer, A., Sinnegger-Brauns, M. J., Striessnig, J. & Singewald, N. 2006. Brain activation pattern induced by stimulation of L-type Ca2+-channels: contribution of CaV1.3 and CaV1.2 isoforms. Neuroscience, 139, 1005-15.
  15. Sah, P. 1996. Ca2+-activated K+ currents in neurones: types, physiological roles and modulation. Trends Neurosci, 19, 150-4.
  16. Murai, Y., Ishibashi, H., Koyama, S. & Akaike, N. 1997. Ca2+-activated K+ currents in rat locus coeruleus neurons induced by experimental ischemia, anoxia, and hypoglycemia. J Neurophysiol, 78, 2674-81.
  17. Sah, P. & McLachlan, E. M. 1991. Ca2+-activated K+ currents underlying the afterhyperpolarization in guinea pig vagal neurons: a role for Ca2+-activated Ca2+ release. Neuron, 7, 257-64.
  18. Osmanović, S. S. & Shefner, S. A. 1993. Calcium-activated hyperpolarizations in rat locus coeruleus neurons in vitro. J Physiol, 469, 89-109.
  19. Goldberg, J. A., Guzman, J. N., Estep, C. M., Ilijic, E., Kondapalli, J., Sanchez-Padilla, J. & Surmeier, D. J. 2012. Calcium entry induces mitochondrial oxidant stress in vagal neurons at risk in Parkinson's disease. Nat Neurosci, 15, 1414-21.
  20. Lipton, S. A. & Nicotera, P. 1998. Calcium, free radicals and excitotoxins in neuronal apoptosis. Cell Calcium, 23, 165-71.
  21. O'Neil, J. N., Mouton, P. R., Tizabi, Y., Ottinger, M. A., Lei, D. L., Ingram, D. K. & Manaye, K. F. 2007. Catecholaminergic neuronal loss in locus coeruleus of aged female dtg APP/PS1 mice. J Chem Neuroanat, 34, 102-7.
  22. Kish, S. J., Shannak, K. S., Rajput, A. H., Gilbert, J. J. & Hornykiewicz, O. 1984. Cerebellar norepinephrine in patients with Parkinson's disease and control subjects. Arch Neurol, 41, 612-4.
  23. Sah, P. & Faber, E. S. 2002. Channels underlying neuronal calcium-activated potassium currents. Prog Neurobiol, 66, 345-53.
  24. Inanobe, A., Yoshimoto, Y., Horio, Y., Morishige, K. I., Hibino, H., Matsumoto, S., Tokunaga, Y., Maeda, T., Hata, Y., Takai, Y. & Kurachi, Y. 1999. Characterization of G-protein-gated K+ channels composed of Kir3.2 subunits in dopaminergic neurons of the substantia nigra. J Neurosci, 19, 1006-17.
  25. Höglinger, G. U., Féger, J., Prigent, A., Michel, P. P., Parain, K., Champy, P., Ruberg, M., Oertel, W. H. & Hirsch, E. C. 2003. Chronic systemic complex I inhibition induces a hypokinetic multisystem degeneration in rats. J Neurochem, 84, 491-502.
  26. Ruppersberg, J. P., Frank, R., Pongs, O. & Stocker, M. 1991. Cloned neuronal IKA channels reopen during recovery from inactivation. Nature, 353, 657-60.
  27. Lee, J. H., Daud, A. N., Cribbs, L. L., Lacerda, A. E., Pereverzev, A., Klöckner, U., Schneider, T. & PerezReyes, E. 1999. Cloning and expression of a novel member of the low voltage-activated Ttype calcium channel family. J Neurosci, 19, 1912-21.
  28. Papazian, D. M., Schwarz, T. L., Tempel, B. L., Jan, Y. N. & Jan, L. Y. 1987. Cloning of genomic and complementary DNA from Shaker, a putative potassium channel gene from Drosophila. Science, 237, 749-53.
  29. Sanguinetti, M. C., Curran, M. E., Zou, A., Shen, J., Spector, P. S., Atkinson, D. L. & Keating, M. T. 1996. Coassembly of KVLQT1 and minK (IsK) proteins to form cardiac IKs potassium channel. Nature, 384, 80-3.
  30. Sharma, Y., Xu, T., Graf, W. M., Fobbs, A., Sherwood, C. C., Hof, P. R., Allman, J. M. & Manaye, K. F. 2010. Comparative anatomy of the locus coeruleus in humans and nonhuman primates. J Comp Neurol, 518, 963-71.
  31. Sailer, C. A., Kaufmann, W. A., Marksteiner, J. & Knaus, H. G. 2004. Comparative immunohistochemical distribution of three small-conductance Ca2+-activated potassium channel subunits, SK1, SK2, and SK3 in mouse brain. Mol Cell Neurosci, 26, 458-69.
  32. Wang, Z., Kiehn, J., Yang, Q., Brown, A. M. & Wible, B. A. 1996. Comparison of binding and block produced by alternatively spliced Kvbeta1 subunits. J Biol Chem, 271, 28311-7.
  33. Klöckner, U., Lee, J. H., Cribbs, L. L., Daud, A., Hescheler, J., Pereverzev, A., Perez-Reyes, E. & Schneider, T. 1999. Comparison of the Ca2+ currents induced by expression of three cloned alpha1 subunits, alpha1G, alpha1H and alpha1I, of low-voltage-activated T-type Ca2 + channels. Eur J Neurosci, 11, 4171-8.
  34. Hockerman, G. H., Peterson, B. Z., Sharp, E., Tanada, T. N., Scheuer, T. & Catterall, W. A. 1997. Construction of a high-affinity receptor site for dihydropyridine agonists and antagonists by single amino acid substitutions in a non-L-type Ca2+ channel. Proc Natl Acad Sci U S A, 94, 14906-11.
  35. Yi, B. A., Minor, D. L., Lin, Y. F., Jan, Y. N. & Jan, L. Y. 2001. Controlling potassium channel activities: Interplay between the membrane and intracellular factors. Proc Natl Acad Sci U S A, 98, 11016-23.
  36. Fakler, B. & Adelman, J. P. 2008. Control of K(Ca) channels by calcium nano/microdomains. Neuron, 59, 873-81.
  37. Valentino, R. J. & Van Bockstaele, E. 2008. Convergent regulation of locus coeruleus activity as an adaptive response to stress. Eur J Pharmacol, 583, 194-203.
  38. Irwin, D. J., Brettschneider, J., McMillan, C. T., Cooper, F., Olm, C., Arnold, S. E., Van Deerlin, V. M., Seeley, W. W., Miller, B. L., Lee, E. B., Lee, V. M., Grossman, M. & Trojanowski, J. Q. 2015. Deep Clinical and Neuropathological Phenotyping of Pick's Disease. Ann Neurol.
  39. Destexhe, A., Neubig, M., Ulrich, D. & Huguenard, J. 1998. Dendritic low-threshold calcium currents in thalamic relay cells. J Neurosci, 18, 3574-88.
  40. Schmitz, C. & Hof, P. R. 2005. Design-based stereology in neuroscience. Neuroscience, 130, 813-31.
  41. Shipe, W. D., Barrow, J. C., Yang, Z. Q., Lindsley, C. W., Yang, F. V., Schlegel, K. A., Shu, Y., Rittle, K. E., Bock, M. G., Hartman, G. D., Tang, C., Ballard, J. E., Kuo, Y., Adarayan, E. D., Prueksaritanont, T., Zrada, M. M., et al. 2008. Design, synthesis, and evaluation of a novel 4-aminomethyl-4- fluoropiperidine as a T-type Ca2+ channel antagonist. J Med Chem, 51, 3692-5.
  42. Stocker, M. & Pedarzani, P. 2000. Differential distribution of three Ca2+-activated K+ channel subunits, SK1, SK2, and SK3, in the adult rat central nervous system. Mol Cell Neurosci, 15, 476-93.
  43. Wolfart, J., Neuhoff, H., Franz, O. & Roeper, J. 2001. Differential expression of the small-conductance, calcium-activated potassium channel SK3 is critical for pacemaker control in dopaminergic midbrain neurons. J Neurosci, 21, 3443-56.
  44. Epstein, B. J., Vogel, K. & Palmer, B. F. 2007. Dihydropyridine calcium channel antagonists in the management of hypertension. Drugs, 67, 1309-27.
  45. German, D. C., Manaye, K. F., White, C. L., Woodward, D. J., McIntire, D. D., Smith, W. K., Kalaria, R. N. & Mann, D. M. 1992. Disease-specific patterns of locus coeruleus cell loss. Ann Neurol, 32, 667-76.
  46. Nagai, T., Satoh, K., Imamoto, K. & Maeda, T. 1981. Divergent projections of catecholamine neurons of the locus coeruleus as revealed by fluorescent retrograde double labeling technique. Neurosci Lett, 23, 117-23.
  47. Jahnsen, H. & Llinás, R. 1984. Electrophysiological properties of guinea-pig thalamic neurones: an in vitro study. J Physiol, 349, 205-26.
  48. Llinás, R. & Yarom, Y. 1981. Electrophysiology of mammalian inferior olivary neurones in vitro. Different types of voltage-dependent ionic conductances. J Physiol, 315, 549-67.
  49. Elbaz, A. & Tranchant, C. 2007. Epidemiologic studies of environmental exposures in Parkinson's disease. J Neurol Sci, 262, 37-44.
  50. West, M. J., Ostergaard, K., Andreassen, O. A. & Finsen, B. 1996. Estimation of the number of somatostatin neurons in the striatum: an in situ hybridization study using the optical fractionator method. J Comp Neurol, 370, 11-22.
  51. Flucher, B. E. & Franzini-Armstrong, C. 1996. Formation of junctions involved in excitation-contraction coupling in skeletal and cardiac muscle. Proc Natl Acad Sci U S A, 93, 8101-6.
  52. Scholze, A., Plant, T. D., Dolphin, A. C. & Nurnberg, B. 2001. Functional expression and characterization of a voltage-gated CaV1.3 (alpha1D) calcium channel subunit from an insulin-secreting cell line. Mol Endocrinol, 15, 1211-21.
  53. Szabadi, E. 2013. Functional neuroanatomy of the central noradrenergic system. J Psychopharmacol, 27, 659-93.
  54. Osmanović, S. S., Shefner, S. A. & Brodie, M. S. 1990. Functional significance of the apamin-sensitive conductance in rat locus coeruleus neurons. Brain Res, 530, 283-9.
  55. Ennis, M. & Aston-Jones, G. 1989. GABA-mediated inhibition of locus coeruleus from the dorsomedial rostral medulla. J Neurosci, 9, 2973-81.
  56. Johnson, S. M., Haxhiu, M. A. & Richerson, G. B. 2008. GFP-expressing locus ceruleus neurons from Prp57 transgenic mice exhibit CO2/H+ responses in primary cell culture. J Appl Physiol (1985), 105, 1301-11.
  57. van den Pol, A. N., Ghosh, P. K., Liu, R. J., Li, Y., Aghajanian, G. K. & Gao, X. B. 2002. Hypocretin (orexin) enhances neuron activity and cell synchrony in developing mouse GFP-expressing locus coeruleus. J Physiol, 541, 169-85.
  58. Nieber, K., Sevcik, J. & Illes, P. 1995. Hypoxic changes in rat locus coeruleus neurons in vitro. J Physiol, 486 ( Pt 1), 33-46.
  59. Kalasz, H., Watanabe, T., Yabana, H., Itagaki, K., Naito, K., Nakayama, H., Schwartz, A. & Vaghy, P. L. 1993. Identification of 1,4-dihydropyridine binding domains within the primary structure of the alpha 1 subunit of the skeletal muscle L-type calcium channel. FEBS Lett, 331, 177-81.
  60. Foote, S. L., Aston-Jones, G. & Bloom, F. E. 1980. Impulse activity of locus coeruleus neurons in awake rats and monkeys is a function of sensory stimulation and arousal. Proc Natl Acad Sci U S A, 77, 3033-7.
  61. Rettig, J., Heinemann, S. H., Wunder, F., Lorra, C., Parcej, D. N., Dolly, J. O. & Pongs, O. 1994. Inactivation properties of voltage-gated K+ channels altered by presence of beta-subunit. Nature, 369, 289-94.
  62. Patel, A. J., Honoré, E., Lesage, F., Fink, M., Romey, G. & Lazdunski, M. 1999. Inhalational anesthetics activate two-pore-domain background K+ channels. Nat Neurosci, 2, 422-6.
  63. Leuranguer, V., Mangoni, M. E., Nargeot, J. & Richard, S. 2001. Inhibition of T-type and L-type calcium channels by mibefradil: physiologic and pharmacologic bases of cardiovascular effects. J Cardiovasc Pharmacol, 37, 649-61.
  64. Strøbaek, D., Hougaard, C., Johansen, T. H., Sørensen, U. S., Nielsen, E., Nielsen, K. S., Taylor, R. D., Pedarzani, P. & Christophersen, P. 2006. Inhibitory gating modulation of small conductance Ca2+-activated K+ channels by the synthetic compound I-N-(benzimidazol-2-yl)-1,2,3,4- tetrahydro-1-naphtylamine (NS8593) reduces afterhyperpolarizing current in hippocampal CA1 neurons. Mol Pharmacol, 70, 1771-82.
  65. Gutman, G. A., Chandy, K. G., Grissmer, S., Lazdunski, M., McKinnon, D., Pardo, L. A., Robertson, G. A., Rudy, B., Sanguinetti, M. C., Stühmer, W. & Wang, X. 2005. International Union of Pharmacology. LIII. Nomenclature and molecular relationships of voltage-gated potassium channels. Pharmacol Rev, 57, 473-508.
  66. Wei, A. D., Gutman, G. A., Aldrich, R., Chandy, K. G., Grissmer, S. & Wulff, H. 2005. International Union of Pharmacology. LII. Nomenclature and molecular relationships of calcium-activated potassium channels. Pharmacol Rev, 57, 463-72.
  67. Hille, B. 2001. Ion Channels of Excitable Membranes, USA, Sinauer Associates.
  68. Kuiper, E. F., Nelemans, A., Luiten, P., Nijholt, I., Dolga, A. & Eisel, U. 2012. KCa2 and KCa3 channels in learning and memory processes, and neurodegeneration. Front Pharmacol, 3, 107.
  69. Dolga, A. M., Terpolilli, N., Kepura, F., Nijholt, I. M., Knaus, H. G., D'Orsi, B., Prehn, J. H., Eisel, U. L., Plant, T., Plesnila, N. & Culmsee, C. 2011. KCa2 channels activation prevents [Ca2+]i deregulation and reduces neuronal death following glutamate toxicity and cerebral ischemia. Cell Death Dis, 2, e147.
  70. Gompf, H. S., Mathai, C., Fuller, P. M., Wood, D. A., Pedersen, N. P., Saper, C. B. & Lu, J. 2010. Locus ceruleus and anterior cingulate cortex sustain wakefulness in a novel environment. J Neurosci, 30, 14543-51.
  71. Heneka, M. T., Ramanathan, M., Jacobs, A. H., Dumitrescu-Ozimek, L., Bilkei-Gorzo, A., Debeir, T., Sastre, M., Galldiks, N., Zimmer, A., Hoehn, M., Heiss, W. D., Klockgether, T. & Staufenbiel, M. 2006. Locus ceruleus degeneration promotes Alzheimer pathogenesis in amyloid precursor protein 23 transgenic mice. J Neurosci, 26, 1343-54.
  72. Takahashi, K., Kayama, Y., Lin, J. S. & Sakai, K. 2010. Locus coeruleus neuronal activity during the sleepwaking cycle in mice. Neuroscience, 169, 1115-26.
  73. Lipscombe, D., Helton, T. D. & Xu, W. 2004. L-type calcium channels: the low down. J Neurophysiol, 92, 2633-41.
  74. Stocker, M., Hirzel, K., D'hoedt, D. & Pedarzani, P. 2004. Matching molecules to function: neuronal Ca2+-activated K+ channels and afterhyperpolarizations. Toxicon, 43, 933-49.
  75. Xia, X. M., Fakler, B., Rivard, A., Wayman, G., Johnson-Pais, T., Keen, J. E., Ishii, T., Hirschberg, B., Bond, C. T., Lutsenko, S., Maylie, J. & Adelman, J. P. 1998. Mechanism of calcium gating in smallconductance calcium-activated potassium channels. Nature, 395, 503-7.
  76. Williams, J. T., North, R. A., Shefner, S. A., Nishi, S. & Egan, T. M. 1984. Membrane properties of rat locus coeruleus neurones. Neuroscience, 13, 137-56.
  77. Martin, R. L., Lee, J. H., Cribbs, L. L., Perez-Reyes, E. & Hanck, D. A. 2000. Mibefradil block of cloned Ttype calcium channels. J Pharmacol Exp Ther, 295, 302-8.
  78. Gomora, J. C., Enyeart, J. A. & Enyeart, J. J. 1999. Mibefradil potently blocks ATP-activated K+ channels in adrenal cells. Mol Pharmacol, 56, 1192-7.
  79. Liu, J. H., Bijlenga, P., Occhiodoro, T., Fischer-Lougheed, J., Bader, C. R. & Bernheim, L. 1999. Mibefradil (Ro 40-5967) inhibits several Ca2+ and K+ currents in human fusion-competent myoblasts. Br J Pharmacol, 126, 245-50.
  80. Xiong, N., Long, X., Xiong, J., Jia, M., Chen, C., Huang, J., Ghoorah, D., Kong, X., Lin, Z. & Wang, T. 2012. Mitochondrial complex I inhibitor rotenone-induced toxicity and its potential mechanisms in Parkinson's disease models. Crit Rev Toxicol, 42, 613-32.
  81. Sanchez-Padilla, J., Guzman, J. N., Ilijic, E., Kondapalli, J., Galtieri, D. J., Yang, B., Schieber, S., Oertel, W., Wokosin, D., Schumacker, P. T. & Surmeier, D. J. 2014. Mitochondrial oxidant stress in locus coeruleus is regulated by activity and nitric oxide synthase. Nat Neurosci, 17, 832-40.
  82. Dolga, A. M., Netter, M. F., Perocchi, F., Doti, N., Meissner, L., Tobaben, S., Grohm, J., Zischka, H., Plesnila, N., Decher, N. & Culmsee, C. 2013. Mitochondrial small conductance SK2 channels prevent glutamate-induced oxytosis and mitochondrial dysfunction. J Biol Chem, 288, 10792- 804.
  83. Nerbonne, J. M. 2000. Molecular basis of functional voltage-gated K+ channel diversity in the mammalian myocardium. J Physiol, 525 Pt 2, 285-98.
  84. Perez-Reyes, E. 1998. Molecular characterization of a novel family of low voltage-activated, T-type, calcium channels. J Bioenerg Biomembr, 30, 313-8.
  85. Pedarzani, P., Kulik, A., Muller, M., Ballanyi, K. & Stocker, M. 2000. Molecular determinants of Ca2+- dependent K+ channel function in rat dorsal vagal neurones. J Physiol, 527 Pt 2, 283-90.
  86. Perez-Reyes, E., Wei, X. Y., Castellano, A. & Birnbaumer, L. 1990. Molecular diversity of L-type calcium channels. Evidence for alternative splicing of the transcripts of three non-allelic genes. J Biol Chem, 265, 20430-6.
  87. Perez-Reyes, E., Van Deusen, A. L. & Vitko, I. 2009. Molecular pharmacology of human Cav3.2 T-type Ca2+ channels: block by antihypertensives, antiarrhythmics, and their analogs. J Pharmacol Exp Ther, 328, 621-7.
  88. Perez-Reyes, E. 2003. Molecular physiology of low-voltage-activated t-type calcium channels. Physiol Rev, 83, 117-61.
  90. Filosa, J. A. & Putnam, R. W. 2003a. Multiple targets of chemosensitive signaling in locus coeruleus neurons: role of K+ and Ca2+ channels. Am J Physiol Cell Physiol, 284, C145-55.
  91. Subramaniam, M., Althof, D., Gispert, S., Schwenk, J., Auburger, G., Kulik, A., Fakler, B. & Roeper, J. 2014. Mutant α-synuclein enhances firing frequencies in dopamine substantia nigra neurons by oxidative impairment of A-type potassium channels. J Neurosci, 34, 13586-99.
  92. Parvizi, J. & Damasio, A. R. 2003. Neuroanatomical correlates of brainstem coma. Brain, 126, 1524-36.
  93. Xu, W. & Lipscombe, D. 2001. Neuronal CaV1.3alpha(1) L-type channels activate at relatively hyperpolarized membrane potentials and are incompletely inhibited by dihydropyridines. J Neurosci, 21, 5944-51.
  94. Waterhouse, B. D., Devilbiss, D., Fleischer, D., Sessler, F. M. & Simpson, K. L. 1998. New perspectives on the functional organization and postsynaptic influences of the locus ceruleus efferent projection system. Adv Pharmacol, 42, 749-54.
  95. Roeper, J., Sewing, S., Zhang, Y., Sommer, T., Wanner, S. G. & Pongs, O. 1998. NIP domain prevents Ntype inactivation in voltage-gated potassium channels. Nature, 391, 390-3.
  96. Ertel, E. A., Campbell, K. P., Harpold, M. M., Hofmann, F., Mori, Y., Perez-Reyes, E., Schwartz, A., Snutch, T. P., Tanabe, T., Birnbaumer, L., Tsien, R. W. & Catterall, W. A. 2000. Nomenclature of voltage-gated calcium channels. Neuron, 25, 533-5.
  97. O'Sullivan, S. S., Williams, D. R., Gallagher, D. A., Massey, L. A., Silveira-Moriyama, L. & Lees, A. J. 2008. Nonmotor symptoms as presenting complaints in Parkinson's disease: a clinicopathological study. Mov Disord, 23, 101-6.
  98. Shannak, K., Rajput, A., Rozdilsky, B., Kish, S., Gilbert, J. & Hornykiewicz, O. 1994. Noradrenaline, dopamine and serotonin levels and metabolism in the human hypothalamus: observations in Parkinson's disease and normal subjects. Brain Res, 639, 33-41.
  99. Grenhoff, J., Nisell, M., Ferré, S., Aston-Jones, G. & Svensson, T. H. 1993. Noradrenergic modulation of midbrain dopamine cell firing elicited by stimulation of the locus coeruleus in the rat. J Neural Transm Gen Sect, 93, 11-25.
  100. Espay, A. J., LeWitt, P. A. & Kaufmann, H. 2014. Norepinephrine deficiency in Parkinson's disease: the case for noradrenergic enhancement. Mov Disord, 29, 1710-9.
  101. Fornai, F., Bassi, L., Torracca, M. T., Scalori, V. & Corsini, G. U. 1995. Norepinephrine loss exacerbates methamphetamine-induced striatal dopamine depletion in mice. Eur J Pharmacol, 283, 99- 102.
  102. Rommelfanger, K. S. & Weinshenker, D. 2007. Norepinephrine: The redheaded stepchild of Parkinson's disease. Biochem Pharmacol, 74, 177-90.
  103. Foote, S. L., Bloom, F. E. & Aston-Jones, G. 1983. Nucleus locus ceruleus: new evidence of anatomical and physiological specificity. Physiol Rev, 63, 844-914.
  104. Tanner, C. M., Ross, G. W., Jewell, S. A., Hauser, R. A., Jankovic, J., Factor, S. A., Bressman, S., Deligtisch, A., Marras, C., Lyons, K. E., Bhudhikanok, G. S., Roucoux, D. F., Meng, C., Abbott, R. D. & Langston, J. W. 2009. Occupation and risk of parkinsonism: a multicenter case-control study. Arch Neurol, 66, 1106-13.
  105. Janitzky, K., Lippert, M. T., Engelhorn, A., Tegtmeier, J., Goldschmidt, J., Heinze, H. J. & Ohl, F. W. 2015. Optogenetic silencing of locus coeruleus activity in mice impairs cognitive flexibility in an attentional set-shifting task. Front Behav Neurosci, 9, 286.
  106. Murai, Y. & Akaike, T. 2005. Orexins cause depolarization via nonselective cationic and K+ channels in isolated locus coeruleus neurons. Neurosci Res, 51, 55-65.
  107. Schwarz, L. A. & Luo, L. 2015. Organization of the Locus Coeruleus-Norepinephrine System. Curr Biol, 25, R1051-6.
  108. Giasson, B. I., Duda, J. E., Murray, I. V., Chen, Q., Souza, J. M., Hurtig, H. I., Ischiropoulos, H., Trojanowski, J. Q. & Lee, V. M. 2000. Oxidative damage linked to neurodegeneration by selective alpha-synuclein nitration in synucleinopathy lesions. Science, 290, 985-9.
  109. Sakmann, B. & Neher, E. 1984. Patch clamp techniques for studying ionic channels in excitable membranes. Annu Rev Physiol, 46, 455-72.
  110. Oertel, W. H. & Kupsch, A. 1993. Pathogenesis and animal studies of Parkinson's disease. Curr Opin Neurol Neurosurg, 6, 323-32.
  111. Mann, D. M. & Yates, P. O. 1983. Pathological basis for neurotransmitter changes in Parkinson's disease. Neuropathol Appl Neurobiol, 9, 3-19.
  112. Kyrozis, A. & Reichling, D. B. 1995. Perforated-patch recording with gramicidin avoids artifactual changes in intracellular chloride concentration. J Neurosci Methods, 57, 27-35.
  113. Kamel, F., Tanner, C., Umbach, D., Hoppin, J., Alavanja, M., Blair, A., Comyns, K., Goldman, S., Korell, M., Langston, J., Ross, G. & Sandler, D. 2007. Pesticide exposure and self-reported Parkinson's disease in the agricultural health study. Am J Epidemiol, 165, 364-74.
  114. Perchenet, L., Bénardeau, A. & Ertel, E. A. 2000. Pharmacological properties of CaV3.2, a low voltageactivated Ca2+ channel cloned from human heart. Naunyn Schmiedebergs Arch Pharmacol, 361, 590-9.
  115. Pedarzani, P. & Storm, J. F. 1993. PKA mediates the effects of monoamine transmitters on the K+ current underlying the slow spike frequency adaptation in hippocampal neurons. Neuron, 11, 1023-35.
  116. Petrovitch, H., Ross, G. W., Abbott, R. D., Sanderson, W. T., Sharp, D. S., Tanner, C. M., Masaki, K. H., Blanchette, P. L., Popper, J. S., Foley, D., Launer, L. & White, L. R. 2002. Plantation work and risk of Parkinson disease in a population-based longitudinal study. Arch Neurol, 59, 1787-92.
  117. Imber, A. N. & Putnam, R. W. 2012. Postnatal development and activation of L-type Ca2+ currents in locus ceruleus neurons: implications for a role for Ca2+ in central chemosensitivity. J Appl Physiol (1985), 112, 1715-26.
  118. Greif, K. F., Erlander, M. G., Tillakaratne, N. J. & Tobin, A. J. 1991. Postnatal expression of glutamate decarboxylases in developing rat cerebellum. Neurochem Res, 16, 235-42.
  119. Jodo, E., Chiang, C. & Aston-Jones, G. 1998. Potent excitatory influence of prefrontal cortex activity on noradrenergic locus coeruleus neurons. Neuroscience, 83, 63-79.
  120. Smith, J. C., Ellenberger, H. H., Ballanyi, K., Richter, D. W. & Feldman, J. L. 1991. Pre-Bötzinger complex: a brainstem region that may generate respiratory rhythm in mammals. Science, 254, 726-9.
  121. Huang, Z., Lujan, R., Kadurin, I., Uebele, V. N., Renger, J. J., Dolphin, A. C. & Shah, M. M. 2011. Presynaptic HCN1 channels regulate Cav3.2 activity and neurotransmission at select cortical synapses. Nat Neurosci, 14, 478-86.
  122. Pavese, N., Rivero-Bosch, M., Lewis, S. J., Whone, A. L. & Brooks, D. J. 2011. Progression of monoaminergic dysfunction in Parkinson's disease: a longitudinal 18F-dopa PET study. Neuroimage, 56, 1463-8.
  123. Lancaster, B. & Nicoll, R. A. 1987. Properties of two calcium-activated hyperpolarizations in rat hippocampal neurones. J Physiol, 389, 187-203.
  124. Dolga, A. M. & Culmsee, C. 2012. Protective Roles for Potassium SK/K(Ca)2 Channels in Microglia and Neurons. Front Pharmacol, 3, 196.
  125. Kilbourn, M. R., Sherman, P. & Abbott, L. C. 1998. Reduced MPTP neurotoxicity in striatum of the mutant mouse tottering. Synapse, 30, 205-10.
  126. Tsien, R. W., Lipscombe, D., Madison, D., Bley, K. & Fox, A. 1995. Reflections on Ca2+-channel diversity, 1988-1994. Trends Neurosci, 18, 52-4.
  127. Oyamada, Y., Ballantyne, D., Mückenhoff, K. & Scheid, P. 1998. Respiration-modulated membrane potential and chemosensitivity of locus coeruleus neurones in the in vitro brainstem-spinal cord of the neonatal rat. J Physiol, 513 ( Pt 2), 381-98.
  128. Guzman, J. N., Sánchez-Padilla, J., Chan, C. S. & Surmeier, D. J. 2009. Robust pacemaking in substantia nigra dopaminergic neurons. J Neurosci, 29, 11011-9.
  129. Striessnig, J., Koschak, A., Sinnegger-Brauns, M. J., Hetzenauer, A., Nguyen, N. K., Busquet, P., Pelster, G. & Singewald, N. 2006. Role of voltage-gated L-type Ca2+ channel isoforms for brain function. Biochem Soc Trans, 34, 903-9.
  130. Marrion, N. V. & Tavalin, S. J. 1998. Selective activation of Ca2+-activated K+ channels by co-localized Ca2+ channels in hippocampal neurons. Nature, 395, 900-5.
  131. Wolfart, J. & Roeper, J. 2002. Selective coupling of T-type calcium channels to SK potassium channels prevents intrinsic bursting in dopaminergic midbrain neurons. J Neurosci, 22, 3404-13.
  132. Hougaard, C., Eriksen, B. L., Jørgensen, S., Johansen, T. H., Dyhring, T., Madsen, L. S., Strøbaek, D. & Christophersen, P. 2007. Selective positive modulation of the SK3 and SK2 subtypes of small conductance Ca2+-activated K+ channels. Br J Pharmacol, 151, 655-65.
  133. Kawano, T., Zhao, P., Nakajima, S. & Nakajima, Y. 2004. Single-cell RT-PCR analysis of GIRK channels expressed in rat locus coeruleus and nucleus basalis neurons. Neurosci Lett, 358, 63-7.
  134. Faber, E. S., Delaney, A. J. & Sah, P. 2005. SK channels regulate excitatory synaptic transmission and plasticity in the lateral amygdala. Nat Neurosci, 8, 635-41.
  135. Köhler, M., Hirschberg, B., Bond, C. T., Kinzie, J. M., Marrion, N. V., Maylie, J. & Adelman, J. P. 1996. Small-conductance, calcium-activated potassium channels from mammalian brain. Science, 273, 1709-14.
  136. Snyders, D. J. 1999. Structure and function of cardiac potassium channels. Cardiovasc Res, 42, 377-90.
  137. Dolga, A. M., de Andrade, A., Meissner, L., Knaus, H. G., Höllerhage, M., Christophersen, P., Zischka, H., Plesnila, N., Höglinger, G. U. & Culmsee, C. 2014. Subcellular expression and neuroprotective effects of SK channels in human dopaminergic neurons. Cell Death Dis, 5, e999.
  138. Magee, J. C., Christofi, G., Miyakawa, H., Christie, B., Lasser-Ross, N. & Johnston, D. 1995. Subthreshold synaptic activation of voltage-gated Ca2+ channels mediates a localized Ca2+ influx into the dendrites of hippocampal pyramidal neurons. J Neurophysiol, 74, 1335-42.
  139. Ishimatsu, M. & Williams, J. T. 1996. Synchronous activity in locus coeruleus results from dendritic interactions in pericoerulear regions. J Neurosci, 16, 5196-204.
  140. Puschmann, A., Bhidayasiri, R. & Weiner, W. J. 2012. Synucleinopathies from bench to bedside. Parkinsonism Relat Disord, 18 Suppl 1, S24-7.
  141. Huang, X. & Jan, L. Y. 2014. Targeting potassium channels in cancer. J Cell Biol, 206, 151-62.
  142. Schneider, T., Regulla, S. & Hofmann, F. 1991. The devapamil-binding site of the purified skeletal muscle receptor for organic-calcium channel blockers is modulated by micromolar and millimolar concentrations of Ca2+. Eur J Biochem, 200, 245-53.
  143. Jones, B. E. & Yang, T. Z. 1985. The efferent projections from the reticular formation and the locus coeruleus studied by anterograde and retrograde axonal transport in the rat. J Comp Neurol, 242, 56-92.
  144. Sara, S. J. 2009. The locus coeruleus and noradrenergic modulation of cognition. Nat Rev Neurosci, 10, 211-23.
  145. Lambert, R. C., Bessaïh, T., Crunelli, V. & Leresche, N. 2014. The many faces of T-type calcium channels. Pflugers Arch, 466, 415-23.
  146. Surmeier, D. J., Guzman, J. N., Sanchez-Padilla, J. & Goldberg, J. A. 2011. The origins of oxidant stress in Parkinson's disease and therapeutic strategies. Antioxid Redox Signal, 14, 1289-301.
  147. Langston, J. W. 2006. The Parkinson's complex: parkinsonism is just the tip of the iceberg. Ann Neurol, 59, 591-6.
  148. Fuller, P. M., Saper, C. B. & Lu, J. 2007. The pontine REM switch: past and present. J Physiol, 584, 735- 41.
  149. Harik, S. I. & McGunigal, T. 1984. The protective influence of the locus ceruleus on the blood-brain barrier. Ann Neurol, 15, 568-74.
  150. Shao, L. R., Halvorsrud, R., Borg-Graham, L. & Storm, J. F. 1999. The role of BK-type Ca2+-dependent K+ channels in spike broadening during repetitive firing in rat hippocampal pyramidal cells. J Physiol, 521 Pt 1, 135-46.
  151. Usher, M., Cohen, J. D., Servan-Schreiber, D., Rajkowski, J. & Aston-Jones, G. 1999. The role of locus coeruleus in the regulation of cognitive performance. Science, 283, 549-54.
  152. Gesi, M., Soldani, P., Giorgi, F. S., Santinami, A., Bonaccorsi, I. & Fornai, F. 2000. The role of the locus coeruleus in the development of Parkinson's disease. Neurosci Biobehav Rev, 24, 655-68.
  153. Sirois, J. E., Lei, Q., Talley, E. M., Lynch, C. & Bayliss, D. A. 2000. The TASK-1 two-pore domain K+ channel is a molecular substrate for neuronal effects of inhalation anesthetics. J Neurosci, 20, 6347- 54.
  154. Kokubun, S., Porzig, H., Prod'hom, B. & Reuter, H. 1986. The voltage-dependent effect of 1,4- dihydropyridine enantiomers on Ca channels in cardiac cells. Jpn Heart J, 27 Suppl 1, 57-63.
  155. Lory, P. & Chemin, J. 2007. Towards the discovery of novel T-type calcium channel blockers. Expert Opin Ther Targets, 11, 717-22.
  156. Ito, H., Klugbauer, N. & Hofmann, F. 1997. Transfer of the high affinity dihydropyridine sensitivity from L-type To non-L-type calcium channel. Mol Pharmacol, 52, 735-40.
  157. Tringham, E., Powell, K. L., Cain, S. M., Kuplast, K., Mezeyova, J., Weerapura, M., Eduljee, C., Jiang, X., Smith, P., Morrison, J. L., Jones, N. C., Braine, E., Rind, G., Fee-Maki, M., Parker, D., Pajouhesh, H., et al. 2012. T-type calcium channel blockers that attenuate thalamic burst firing and suppress absence seizures. Sci Transl Med, 4, 121ra19.
  158. Liss, B., Franz, O., Sewing, S., Bruns, R., Neuhoff, H. & Roeper, J. 2001. Tuning pacemaker frequency of individual dopaminergic neurons by Kv4.3L and KChip3.1 transcription. EMBO J, 20, 5715-24.
  159. Hoshi, T., Zagotta, W. N. & Aldrich, R. W. 1991. Two types of inactivation in Shaker K+ channels: effects of alterations in the carboxy-terminal region.) Neuron. United States.
  160. Forsythe, I. D., Linsdell, P. & Stanfield, P. R. 1992. Unitary A-currents of rat locus coeruleus neurones grown in cell culture: rectification caused by internal Mg2+ and Na+. J Physiol, 451, 553-83.
  161. Gray, A. T., Zhao, B. B., Kindler, C. H., Winegar, B. D., Mazurek, M. J., Xu, J., Chavez, R. A., Forsayeth, J. R. & Yost, C. S. 2000. Volatile anesthetics activate the human tandem pore domain baseline K+ channel KCNK5. Anesthesiology, 92, 1722-30.
  162. Hagiwara, S., Ozawa, S. & Sand, O. 1975. Voltage clamp analysis of two inward current mechanisms in the egg cell membrane of a starfish. J Gen Physiol, 65, 617-44.
  163. Lacinová, L. 2005. Voltage-dependent calcium channels. Gen Physiol Biophys, 24 Suppl 1, 1-78.
  164. Murata, M. 2010. Zonisamide: a new drug for Parkinson's disease. Drugs Today (Barc), 46, 251-8.

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