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Original Article

Anuroctoxin, a New Scorpion Toxin of the -KTx 6 Subfamily, Is Highly Selective for Kv1.3 over IKCa1 Ion Channels of Human T Lymphocytes

Miklós Bagdáany, Cesar V. F. Batista, Norma A. Valdez-Cruz, Sándor Somodi, Ricardo C. Rodriguez de la Vega, Alexei F. Licea, Zoltáan Varga, Rezs Gáspár, Lourival D. Possani, and György Panyi

Department of Biophysics and Cell Biology, University of Debrecen, Medical and Health Science Center, Debrecen, Hungary (M.B., S.S., Z.V., R.G., G.P); Department of Molecular Medicine and Bioprocesses, Institute of Biotechnology, National Autonomous University of Mexico, Avenida Universidad, Cuernavaca, Mexico (C.V.F.B., N.A.V.-C., R.C.R.-V., L.D.P.); and Laboratory of Molecular Immunology and Biotoxins, Centro de Investigación Científica y de Educación de Ensenada, Ensenada, Mexico (A.F.L.)

Abstract

The physiological function of T lymphocytes can be modulated selectively by peptide toxins acting on Kv1.3 K⁺ channels. Because Kv1.3-specific peptide toxins are considered to have a significant therapeutic potential in the treatment of autoimmune diseases, the discovery of new toxins is highly motivated. Through chromatographic procedures and electrophysiological assays, using patch-clamp methodology, the isolation of a novel peptide named anuroctoxin was accomplished using the venom of the Mexican scorpion Anuroctonus phaiodactylus. It has 35 amino acid residues with a molecular weight of 4082.8, tightly bound by four disulfide bridges whose complete covalent structure was determined. It has a pyroglutamic acid at the N-terminal region and an amidated C-terminal residue. Sequence comparison and phylogenetic clustering analysis classifies anuroctoxin into subfamily 6 of the -KTx scorpion toxins (systematic name, -KTx 6.12). Patch-clamp experiments show that anuroctoxin is a high-affinity blocker of Kv1.3 channels of human T lymphocytes with a K_d of 0.73 nM, and it does not block the Ca²⁺-activated IKCa1 K⁺ channels. These two channels play different but important roles in T-lymphocyte activation. Furthermore, the toxin practically does not inhibit Shaker IR, mKv1.1, and rKv2.1 channels, whereas the affinity of anuroctoxin for hKv1.2 is almost an order of magnitude smaller than for Kv1.3. The pharmacological profile and the selectivity of this new toxin for Kv1.3 over IKCa1 may provide an important tool for the modulation of the immune system, especially in cases in which selective inhibition of Kv1.3 is required.

Address correspondence to: Dr. György Panyi, Department of Biophysics and Cell Biology, University of Debrecen, Medical and Health Science Center, 98 Nagyerdei krt., Debrecen, Hungary 4012. E-mail: panyi{at}jaguar.dote.hu

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