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Vol. 291, Issue 3, 943-952, December 1999

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

Christiane Mourre, Marina N. Chernova, Marie-France Martin-Eauclaire, Richard Bessone, Guy Jacquet, Maurice Gola, Seth. L. Alper and Marcel Crest

Laboratoire de Neurobiologie Intégrative et Adaptative, Centre National de la Recherche Scientifique-Université de Provence, Marseille, France (C.M.); Laboratoire de Neurobiologie, Centre National de la Recherche Scientifique, Marseille, France (R.B., G.J., M.G., M.C.); Molecular 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.); and Laboratoire d'Ingénierie des Protéines, Centre National de la Recherche Scientifique-Université de la Méditerranée, Marseille, France (M.-F.M.-E.)

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 respective Kd 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 alpha -subunits.

0022-3565/99/2913-0943$03.00/0
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
Copyright © 1999 by The American Society for Pharmacology and Experimental Therapeutics


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