Distribution in Rat Brain of Binding Sites of Kaliotoxin, a Blocker of Kv1.1 and Kv1.3 α-Subunits1

  1. Christiane Mourre1,
  2. Marina N. Chernova3,
  3. Marie-France Martin-Eauclaire4,
  4. Richard Bessone2,
  5. Guy Jacquet2,
  6. Maurice Gola2,
  7. Seth. L. Alper3 and
  8. Marcel Crest2
  1. 1Laboratoire de Neurobiologie Intégrative et Adaptative, Centre National de la Recherche Scientifique-Université de Provence, Marseille, France (C.M.); 2Laboratoire de Neurobiologie, Centre National de la Recherche Scientifique, Marseille, France (R.B., G.J., M.G., M.C.); 3Molecular Medicine and Renal Units, Beth Israel Deaconess Medical Center, Departments of Medicine and Cell Biology, Harvard Medical School, Boston, Massachusetts (M.M.C., S.L.A.); and4Laboratoire d'Ingénierie des Protéines, Centre National de la Recherche Scientifique-Université de la Méditerranée, Marseille, France (M.-F.M.-E.)

    Abstract

    The distribution of the binding sites for kaliotoxin (KTX), a blocker of voltage-dependent K+ channels, was studied with quantitative autoradiography in adult rat brain and during postnatal brain maturation. Iodinated KTX bound specifically to tissue sections with a high affinity (Kd = 82 pM) and a maximal binding capacity of 13.4 fmol/mg protein. The distribution of KTX binding sites within the central nervous system was heterogeneous. The highest densities were found in the neocortex, hypothalamus, dentate gyrus, bed nucleus of the stria terminalis, and parabrachial nuclei. The lowest level was observed in the white matter. From postnatal day 5 onward, KTX binding sites were detectable only in the hindbrain. The density of KTX binding sites in whole brain drastically increased after postnatal day 15 to achieve adult levels at postnatal day 60 in the whole brain. Bath application of KTX to Xenopus laevis oocytes blocked recombinant Kv1.3 and Kv1.1 channels potently and Kv1.2 channels less potently, with respectiveKd values of 0.1, 1.5, and 25 nM. KTX affinities for each of these channels expressed in mammalian cells were about 10-fold lower. A comparison of the distribution of KTX binding sites with that of Kv1 channel polypeptides, together with the pharmacology of KTX block, suggests that the principal targets for KTX in rat brain are K+ channels containing Kv1.1 and Kv1.3 α-subunits.

    Footnotes

    • Send reprint requests to: Dr. C. Mourre, Laboratoire de Neurobiologie Intégrative et Adaptative, UMR 6562, CNRS-Université de Provence, Escadrille Normandie-Niemen, Case 351, 13397, Marseille, Cedex 20, France. E-mail:mourre{at}newsup.univ-mrs.fr

    • ↵1 This work was supported by the Centre National de la Recherche Scientifique and by the Association Française contre les Myopathies (Grant 5030). M.N. and S.L.A. were supported by NIH Grants HL15157 (Boston Sickle Cell Center) and DK34854 (Harvard Digestive Diseases Center). S.L.A. is an Established Investigator of the American Heart Association.

    • Abbreviations:
      Kv
      voltage-gated potassium
      CTX
      charybdotoxin
      DTX
      dendrotoxin
      KTX
      kaliotoxin
      MCD
      mast cell-degranulating
      IKCa
      intermediate conductance Ca2+-activated K+
      MgTX
      margatoxin
      BK
      high conductance Ca2+-activated K+
      • Received April 20, 1999.
      • Accepted July 27, 1999.
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    1. JPET December 1, 1999 vol. 291 no. 3 943-952
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