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Species Diversity and Peptide Toxins Blocking Selectivity of Ether-à-go-go-Related Gene Subfamily K⁺ Channels in the Central Nervous System

Dipartimento di Biotecnologie e Bioscienze, Università di Milano-Bicocca, Milano, Italy (R.R.-C., E.W.); Shemyakin-Ovchinnikov Intitute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia (Y.V.K., E.V.G.); Institut de Pharmacologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique-Unité Mixte Recherche, Valbonne, France (S.D., M.L.); Department of Molecular Medicine and Bioprocesses, Institute of Biotechnology, National Autonomous University of Mexico, Cuernavaca, Mexico (G.G., L.D.P.); and Dipartimento di Patologia e Oncologia Sperimentali, Università di Firenze, Firenze, Italy (L.G., A.A.)

The ether-à-go-go-related gene (erg) K⁺ channels are known to be crucial for life in Caenorhabditis elegans (mating), Drosophila melanogaster (seizure), and humans (LQT syndrome). The erg genes known to date (erg1, erg2, and erg3) are highly expressed in various areas of the rat and mouse central nervous system (CNS), and ERG channel blockers alter firing accommodation. To assign physiological roles to each isoform, it is necessary to design pharmacological strategies to distinguish individual currents. To this purpose, we have investigated the blocking properties of specific peptide inhibitors of hERG1 channels on the human and rat isoforms. In particular, we have tested ErgTx1 (from the scorpion Centruroides noxious), BeKm-1 (from the scorpion Buthus eupeus), and APETx1 (from the sea anemone Anthopleura elegantissima). Because these peptides had different species-specific effects on the six different channels, we have also carried out a biophysical characterization of hERG2 and hERG3 channels that turned out to be different from the rat homologs. It emerged that APETx1 is exquisitely selective for ERG1 and does not compete with the other two toxins. BeKm-1 discriminates well among the three rat members. ErgTx1 is unable to block hERG2, but blocks rERG2 and has the lowest K_D for hERG3. BeKm-1 and ErgTx1 compete for hERG3 but not for rERG2 blockade. Our findings should be helpful for structure-function studies and for novel CNS ERG-specific drug design.

Address correspondence to: Prof. Enzo Wanke, Dipartimento di Biotecnologie e Bioscienze Università di Milano-Bicocca, Piazza della Scienza 2, 20126 Milano, Italy. E-mail: enzo.wanke{at}unimib.it

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