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

Abstract

The ether-à -go-go-related gene (erg) K ϩ 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.The ether-à -go-go family of voltage-dependent K ϩ channels consists of the eag, elk (eag-like), and erg (eag-related gene)

IFIH1-GCA-KCNH7 locus: influence on multiple sclerosis risk

“…Nonetheless, in our hands the polymorphism within the KCNH7/ERG3 gene seems to act as a better genetic maker and an evidence in support of the impact of potassium homeostasis in these diseases has also been reported. Voltage-dependent K þ channels are the main determinants in controlling cellular excitability within the central nervous system; specifically, the erg genes are highly expressed in various areas of the rat and mouse central nervous system 22 and erg3 transcripts have also been identified in rat islets and INS-1 b cells. 23 Therefore, implication on autoimmune diseases of an altered function of this gene encoding a potassium channel can not be discarded.…”

Homeostatic Control of Sensory Output in Basal Vomeronasal Neurons: Activity-Dependent Expression ofEther-à-Go-Go-Related Gene Potassium Channels

“…Subunit-specific mERG1 currents were isolated using the recombinant peptide rBeKm-1 at a concentration (100 nM; Alomone Labs) that completely blocks mERG1 without affecting mERG3 (Restano-Cassulini et al, 2006).…”

“…Therefore, we aimed to dissect the role of this specific subunit in generation of vomeronasal ERG currents using a pharmacological approach. In contrast to the less selective agents E-4031 and ErgTx-1, the recombinant peptide rBeKm-1 completely blocks ERG1 at nanomolar concentrations without affecting other channels including ERG3 (Korolkova et al, 2001;Restano-Cassulini et al, 2006). We, thus, repeated various experiments shown in Figures 3 and 4 using rBeKm-1 (100 nM) to study activation, recovery from inactivation, and deactivation of isolated ERG1-mediated currents (Fig.…”

Identification of a Posttranslational Mechanism for the Regulation of hERG1 K+ Channel Expression and hERG1 Current Density in Tumor Cells

“…ERG currents were always elicited under conditions of relatively high extracellular K ϩ concentrations (20 mM) in order to measure currents under optimal signal-to-noise conditions. The currents were recorded at room temperature by using the MultiClamp 700A (Axon Instruments) as previously described (35). Pipette resistances were about 1.5 to 2.2 M⍀.…”