Anuroctoxin, a new scorpion toxin of the alpha-KTx 6 subfamily, is highly selective for Kv1.3 over IKCa1 ion channels of human T lymphocytes.
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 alpha-KTx scorpion toxins (systematic name, alpha-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 Ca(2+)-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.
Bagdány
Miklós
M
Department of Biophysics and Cell Biology, University of Debrecen, Medical and Health Science Center, 98 Nagyerdei krt., Debrecen, Hungary 4012.
Batista
Cesar V F
CV
Valdez-Cruz
Norma A
NA
Somodi
Sándor
S
Rodriguez de la Vega
Ricardo C
RC
Licea
Alexei F
AF
Varga
Zoltán
Z
Gáspár
Rezso
R
Possani
Lourival D
LD
Panyi
György
G
D000818:Animals; D006801:Humans; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; D051664:Kv1.3 Potassium Channel; D008958:Models, Molecular; D010802:Phylogeny; D026902:Potassium Channel Blockers / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D024681:Potassium Channels, Calcium-Activated / Q000037:antagonists & inhibitors*; D024642:Potassium Channels, Voltage-Gated / Q000037:antagonists & inhibitors*; D012604:Scorpion Venoms / Q000032:analysis*; D016415:Sequence Alignment; D013601:T-Lymphocytes / Q000187:drug effects*; D014118:Toxins, Biological / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology
D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; C496973:KCNA3 protein, human; C496923:KCNN4 protein, human; D051664:Kv1.3 Potassium Channel; D026902:Potassium Channel Blockers; D024681:Potassium Channels, Calcium-Activated; D024642:Potassium Channels, Voltage-Gated; D012604:Scorpion Venoms; D014118:Toxins, Biological