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Received for publication October 11, 2005.
Revised January 31, 2006.
Accepted for publication February 23, 2006.
The ether-a-go-go-related gene (erg) K+ channels are known to be crucial for life in C.elegans (mating), Drosophila (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 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). Since 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 homologues. It emerged that APETx1 is exquisitely selective for ERG1 and does not competes with the other two toxins. BeKm-1 well discriminates the three rat members. ErgTx1 is unable to block hERG2, but blocks rERG2 and has the lowest KD 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.
Key words:
Ion channel regulation, Potassium, Neuropeptides, peptidases
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