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Three new toxins from the scorpion Pandinus imperator selectively block certain voltage-gated K+ channels. 1996

R S Rogowski, and J H Collins, and T J O'Neill, and T A Gustafson, and T R Werkman, and M A Rogawski, and T C Tenenholz, and D J Weber, and M P Blaustein
Department of Physiology, School of Medicine, University of Maryland, Baltimore 21201, USA.

Three 35-amino acid peptide K+ channel toxins (pandinotoxins) were purified from the venom of the scorpion Pandinus imperaton the toxins are designated pandinotoxin (PiTX)-K alpha, PiTX-K beta, and PiTX-K gamma. In an 86Rb tracer flux assay on rat brain synaptosomes, all three toxins selectively blocked the component of the K(+)-stimulated 86Rb efflux that corresponds to a voltage-gated, rapidly inactivating (A-type) K+ current (IC50 = 6, 42, and 100 nM, respectively). These toxins blocked neither the noninactivating component of the K(+)-stimulated 86Rb efflux (corresponding to a delayed rectifier) nor the Ca(2+)-dependent component of the 86Rb efflux (i.e., a Ca(2+)-activated K+ current) in these terminals. PiTX-K alpha, which was expressed by recombinant methods, also blocked the Kv1.2 channel expressed in fibroblasts (IC50 = 32 pM). PiTX-K alpha and PiTX-K beta have identical amino acid sequences except for the seventh amino acid: a proline in PiTX-K alpha, and a glutamic acid in PiTX-K beta. They have substantial sequence homology, especially at the carboxyl termini, with another scorpion toxin, charybdotoxin (ChTX), which blocks both the Ca(2+)-activated and the rapidly inactivating. K(+)-stimulated 86Rb efflux components in synaptosomes and the Kv 1.2 channel PiTX-K gamma, however, has much less sequence homology. Conserved in all four toxins are three identically positioned disulfide bridges; an asparagine at position 30; and positive charges at positions 27, 31, and 34 (based on ChTX numbering). PiTX-K gamma is novel in that it has a fourth pair of cysteines. The PiTX structures were computer simulated, using ChTX as a model. We speculate that the three-dimensional structures of all three PiTXs resemble that of ChTX: a beta-sheet at the carboxyl terminus, containing three cysteines, is linked to the central alpha-helix by two disulfide bridges (C17-C35 and C13-C33) and to an extended amino-terminal fragment by the third disulfide bridge (C7-C28). Further analysis of the three-dimensional structures reveals differences that may help to explain the selectivity and affinity differences of these toxins.

UI MeSH Term Description Entries
D008958 Models, Molecular Models used experimentally or theoretically to study molecular shape, electronic properties, or interactions; includes analogous molecules, computer-generated graphics, and mechanical structures. Molecular Models,Model, Molecular,Molecular Model
D008969 Molecular Sequence Data Descriptions of specific amino acid, carbohydrate, or nucleotide sequences which have appeared in the published literature and/or are deposited in and maintained by databanks such as GENBANK, European Molecular Biology Laboratory (EMBL), National Biomedical Research Foundation (NBRF), or other sequence repositories. Sequence Data, Molecular,Molecular Sequencing Data,Data, Molecular Sequence,Data, Molecular Sequencing,Sequencing Data, Molecular
D004594 Electrophysiology The study of the generation and behavior of electrical charges in living organisms particularly the nervous system and the effects of electricity on living organisms.
D000595 Amino Acid Sequence The order of amino acids as they occur in a polypeptide chain. This is referred to as the primary structure of proteins. It is of fundamental importance in determining PROTEIN CONFORMATION. Protein Structure, Primary,Amino Acid Sequences,Sequence, Amino Acid,Sequences, Amino Acid,Primary Protein Structure,Primary Protein Structures,Protein Structures, Primary,Structure, Primary Protein,Structures, Primary Protein
D001483 Base Sequence The sequence of PURINES and PYRIMIDINES in nucleic acids and polynucleotides. It is also called nucleotide sequence. DNA Sequence,Nucleotide Sequence,RNA Sequence,DNA Sequences,Base Sequences,Nucleotide Sequences,RNA Sequences,Sequence, Base,Sequence, DNA,Sequence, Nucleotide,Sequence, RNA,Sequences, Base,Sequences, DNA,Sequences, Nucleotide,Sequences, RNA
D012413 Rubidium An element that is an alkali metal. It has an atomic symbol Rb, atomic number 37, and atomic weight 85.47. It is used as a chemical reagent and in the manufacture of photoelectric cells.
D012414 Rubidium Radioisotopes Unstable isotopes of rubidium that decay or disintegrate emitting radiation. Rb atoms with atomic weights 79-84, and 86-95 are radioactive rubidium isotopes. Radioisotopes, Rubidium
D012604 Scorpion Venoms Venoms from animals of the order Scorpionida of the class Arachnida. They contain neuro- and hemotoxins, enzymes, and various other factors that may release acetylcholine and catecholamines from nerve endings. Of the several protein toxins that have been characterized, most are immunogenic. Scorpion Toxin,Scorpion Toxins,Scorpion Venom Peptide,Tityus serrulatus Venom,Scorpion Venom,alpha-Scorpion Toxin,beta-Scorpion Toxin,gamma-Scorpion Toxin,Peptide, Scorpion Venom,Toxin, Scorpion,Toxin, alpha-Scorpion,Toxin, beta-Scorpion,Venom Peptide, Scorpion,Venom, Scorpion,Venom, Tityus serrulatus,alpha Scorpion Toxin,beta Scorpion Toxin,gamma Scorpion Toxin
D013329 Structure-Activity Relationship The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups. Relationship, Structure-Activity,Relationships, Structure-Activity,Structure Activity Relationship,Structure-Activity Relationships
D013574 Synaptosomes Pinched-off nerve endings and their contents of vesicles and cytoplasm together with the attached subsynaptic area of the membrane of the post-synaptic cell. They are largely artificial structures produced by fractionation after selective centrifugation of nervous tissue homogenates. Synaptosome

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