Potassium channels are the most diverse group of the ion channel family [, ]. They are important in shaping the action potential, and in neuronal excitability and plasticity []. The potassium channel family is composed of several functionally distinct isoforms, which can be broadly separated into 2 groups []: the practically non-inactivating 'delayed' group and therapidly inactivating 'transient' group.These are all highly similar proteins, with only small amino acid changes causing the diversity of the voltage-dependent gating mechanism, channel conductance and toxin binding properties. Each type of K+channel is activated by different signals and conditions depending on their type of regulation: some open in response to depolarisation of the plasma membrane; others in response to hyperpolarisation or an increase in intracellular calcium concentration; some can be regulated by binding of a transmitter, together with intracellular kinases; while others are regulated by GTP-binding proteins or other second messengers []. In eukaryotic cells, K+channels are involved in neural signalling and generation of the cardiac rhythm, act as effectors in signal transduction pathways involving G protein-coupled receptors (GPCRs) and may have a role in target cell lysis by cytotoxic T-lymphocytes []. In prokaryotic cells, they play a role in the maintenance of ionic homeostasis [].All K+channels discovered so far possess a core of alpha subunits, each comprising either one or two copies of a highly conserved pore loop domain (P-domain). The P-domain contains the sequence (T/SxxTxGxG), which has been termed the K+selectivity sequence. In families that contain one P-domain, four subunits assemble to form a selective pathway for K+across the membrane. However, it remains unclear how the 2 P-domain subunits assemble to form a selective pore. The functional diversity of these families can arise through homo- or hetero-associations of alpha subunits or association with auxiliary cytoplasmic beta subunits. K+channel subunits containing one pore domain can be assigned into one of two superfamilies: those that possess six transmembrane (TM) domains and those that possess only two TM domains. The six TM domain superfamily can be further subdivided into conserved gene families: the voltage-gated (Kv) channels; the KCNQ channels (originally known as KvLQT channels); the EAG-like K+channels; and three types of calcium (Ca)-activated K+channels (BK, IK and SK) []. The 2TM domain family comprises inward-rectifying K+channels. In addition, there are K+channel alpha-subunits that possess two P-domains. These are usually highly regulated K+selective leak channels.The first EAG K+ channel was identified in Drosophila melanogaster (Fruit fly), following a screen for mutations giving rise to behavioural abnormalities. Disruption of the Eag gene caused an ether-induced, leg-shaking behaviour. Subsequent studies have revealed a conserved multi-gene family of EAG-like K+ channels, which are present in human and many other species. Based on the varying functional properties of the channels, the family has been divided into 3 subfamilies: EAG, ELK and ERG. Interestingly, Caenorhabditis elegans appears to lack the ELK type [].The human ether-a-go-go-related gene (HERG), cloned from hippocampus, shares 49% amino acid identity with EAG. It is also found in the heart, where it helps to control K+ efflux []. Mutations in HERG result in the disruption of the repolarising current and the disease LQT2 syndrome, an inheriteddisorder of cardiac repolarisation that predisposes affected individuals tolife-threatening arrhythmias [].
Potassium voltage-gated channel subfamily H member 6 (KCNH6), also known as ether-a-go-go-related gene (ERG, ERG2), has a key role in the control of cardiac action potential repolarisation [, ]. It is a pore-forming (alpha) subunit of voltage-gated potassium channel. In human, mutations in ERG can cause congenital long QT syndrome, a disorder of cardiac repolarisation [].
The Ergtoxin (ErgTx) family is a class of peptides from scorpion venom that specifically block ERG (ether-a-go-go-related gene) K+ channels of the nerve, heart and endocrine cells [, , ]. Peptides of the ErgTx family have from 42 to 47 amino acid residues cross-linked by four disulphide bridges. The four disulphide bridges have been assigned as C1-C4, C2-C6, C3-C7 and C5-C8 (see the schematic representation below) []. ErgTxs consist of a triple-stranded β-sheet and an α-helix, as is typical of K+ channel scorpion toxins. There is a large hydrophobic patch on the surface of the toxin, surrounding a central lysine residue located near the β-hairpin loop between the second and third strands of the β-sheet. It has been postulated that this hydrophobic patch is likely to form part of the binding surface of the toxin []. Peptides of the ErgTx family possess a Knottin scaffold (see https://www.dsimb.inserm.fr/KNOTTIN/). Some proteins known to belong to the ErgTx family are listed below: ErgTx1, ErgTx2 and ErgTx3 from Centruroides elegans (Bark scorpion). ErgTx1, ErgTx2, ErgTx3 and ErgTx4 from Centruroides exilicauda (Bark scorpion). ErgTx1, ErgTx2 and ErgTx3 from Centruroides gracilis (Slenderbrown scorpion) (Florida bark scorpion). ErgTx1, ErgTx2, ErgTx3 and ErgTx4 from Centruroides limpidus limpidus (Mexican scorpion). ErgTx1, ErgTx2, ErgTx3, ErgTx4, ErgTx5 and gamma-KTx 4.12 from Centruroides sculpturatus (Bark scorpion). ErgTx, ErgTx2, ErgTx3, ErgTx4 and ErgTx5 from Centruroides noxius (Mexican scorpion).
Potassium channels are the most diverse group of the ion channel family [, ]. They are important in shaping the action potential, and in neuronal excitability and plasticity []. The potassium channel family is composed of several functionally distinct isoforms, which can be broadly separated into 2 groups []: the practically non-inactivating 'delayed' group and the rapidly inactivating 'transient' group.These are all highly similar proteins, with only small amino acid changes causing the diversity of the voltage-dependent gating mechanism, channel conductance and toxin binding properties. Each type of K+channel is activated by different signals and conditions depending on their type of regulation: some open in response to depolarisation of the plasma membrane; others in response to hyperpolarisation or an increase in intracellular calcium concentration; some can be regulated by binding of a transmitter, together with intracellular kinases; while others are regulated by GTP-binding proteins or other second messengers []. In eukaryotic cells, K+channels are involved in neural signalling and generation of the cardiac rhythm, act as effectors in signal transduction pathways involving G protein-coupled receptors (GPCRs) and may have a role in target cell lysis by cytotoxic T-lymphocytes []. In prokaryotic cells, they play a role in the maintenance of ionic homeostasis [].All K+channels discovered so far possess a core of alpha subunits, each comprising either one or two copies of a highly conserved pore loop domain (P-domain). The P-domain contains the sequence (T/SxxTxGxG), which has been termed the K+selectivity sequence. In families that contain one P-domain, four subunits assemble to form a selective pathway for K+across the membrane. However, it remains unclear how the 2 P-domain subunits assemble to form a selective pore. The functional diversity of these families can arise through homo- or hetero-associations of alpha subunits or association with auxiliary cytoplasmic beta subunits. K+channel subunits containing one pore domain can be assigned into one of two superfamilies: those that possess six transmembrane (TM) domains and those that possess only two TM domains. The six TM domain superfamily can be further subdivided into conserved gene families: the voltage-gated (Kv) channels; the KCNQ channels (originally known as KvLQT channels); the EAG-like K+channels; and three types of calcium (Ca)-activated K+channels (BK, IK and SK) []. The 2TM domain family comprises inward-rectifying K+channels. In addition, there are K+channel alpha-subunits that possess two P-domains. These are usually highly regulated K+selective leak channels.The first EAG K+ channel was identified in Drosophila melanogaster (Fruit fly), following a screen for mutations giving rise to behavioural abnormalities. Disruption of the Eag gene caused an ether-induced, leg-shaking behaviour. Subsequent studies have revealed a conserved multi-gene family of EAG-like K+ channels, which are present in human and many other species. Based on the varying functional properties of the channels, the family has been divided into 3 subfamilies: EAG, ELK and ERG. Interestingly, Caenorhabditis elegans appears to lack the ELK type [].Little is known about the properties of channels of the ELK subfamily. However, when expressed in frog oocytes, they show properties between thoseof the EAG and ERG subtypes. Included in this family are Bec1 and Bec2,brain-specific genes found in the human telencephalon regions. It is thoughtthat they are involved in cellular excitability of restricted neurons in thehuman central nervous system. Phylogenetic analysis reveals that these genesconstitute a subfamily with Elk within the Eag family []. Recently, afurther Elk subfamily member has been identified in the mouse (Melk). On thebasis of sequence similarity, this indicates a distinct subclass within this family [].
