Ether-à-go-go K+ channels: effective modulators of neuronal excitability

Abstract

Mammalian ether-à-go-go (EAG) channels are voltage-gated K⁺ channels. They are encoded by the KCNH gene family and divided into three subfamilies, eag (Kv10), erg (eag-related gene; Kv11) and elk (eag-like; Kv12). All EAG channel subtypes are expressed in the brain where they effectively modulate neuronal excitability. This Topical Review describes the biophysical properties of each of the EAG channel subtypes, their function in neurons and the neurological diseases induced by EAG channel mutations. In contrast to the function of erg currents in the heart, where they contribute to repolarization of the cardiac action potential, erg currents in neurons are involved in the maintenance of the resting potential, setting of action potential threshold and frequency accommodation. They can even support high frequency firing by preventing a depolarization-induced Na⁺ channel block. EAG channels are modulated differentially, e.g. eag channels by intracellular Ca²⁺ , erg channels by extracellular K⁺ and GPCRs, and elk channels by changes in pH. So far, only currents mediated by erg channels have been recorded in neurons with the help of selective blockers. Neuronal eag and elk currents have not been isolated due to the lack of suitable channel blockers. However, findings in KO mice indicate a physiological role of eag1 currents in synaptic transmission and an involvement of elk2 currents in cognitive performance. Human eag1 and eag2 gain-of-function mutations underlie syndromes associated with epileptic seizures.

Keywords: Ether-à-go-go K+ channel; HERG; Potassium channel; neuronal excitability.

Figure 1. EAG K⁺ channels: family members, characteristic currents and voltage dependence of channel activation

A, phylogenetic tree of the EAG superfamily members according to the IUPHAR Compendium of Voltage‐Gated Ion Channels (Gutman et al. 2003). elk3^* corresponds to elk1 in Engeland et al. (1998). B, schematic drawings of characteristic erg, eag and elk currents elicited with a constant depolarizing pulse preceded by different prepulse potentials (pulse diagram in the middle panel). C, schematic activation curves of the eight EAG channel members according to data obtained by tail current analysis.

Figure 2. EAG channel modulation, characteristic window conductances and schematic subunit structures

A, physiologically important parameters, strongly affecting the activation curves of EAG channel members. Colours refer to the EAG subfamily where the effect is described in the text (eag, red; erg, blue; elk, green). In slowly activating EAG channel subtypes, increases in test pulse duration (time) and temperature (T, °C) shift the isochronal activation curves to the left until steady‐state conditions are achieved. GPCR, activation of G protein‐coupled receptors. B, differences in window conductance of the inactivating EAG channels erg1, erg3 and elk2. Steady‐state open probability was calculated by multiplying normalized activation and inactivation curves. C, scheme of the membrane topology and characteristic cytoplasmic domains of two opposing EAG channel subunits. Yellow encircled negative charges in S2 and S3 are specific to EAG channels. EAG, conserved N‐terminal structure consisting of the PAS (Per‐Arnt‐Sim) domain and the distal PAS cap. cNBHD, cyclic nucleotide binding homology domain in the C‐terminus; the C‐linker connects the cNBHD to the transmembrane segment S6. EAG‐specific features are described in the text.

Figure 3. Diverse functions of erg channels in different neurons: inhibition, support and modulation of electrical activity

A–C, schematic drawings of typical effects of erg channel blockers on neuronal excitability observed in the indicated neurons and in other types of neurons listed in Table 1. Physiological roles of erg channels are deduced from the effects of specific erg channel blockers (see Table 1). Aa, blocker‐induced depolarization of the membrane potential and increase in firing frequency. b, activation of a G protein‐coupled receptor (GPCR, e.g. mGluR1) results in a reduction of the neuronal erg current by shifting the voltage dependence of channel activation to more depolarized potentials and by reducing the maximal current amplitude. In the range of neuronal resting potentials, the erg conductance becomes vanishingly low, explaining the almost identical effects of a potent erg channel blocker and the GPCR ligand. The inset on the right shows schematic drawings of typical erg inward tail currents (elicited by the indicated pulse protocol) used to construct the erg channel activation curves. B, blocker‐induced reduction of frequency accommodation. C, blocker‐induced inhibition of high frequency firing due to accumulated Na⁺ channel inactivation. VSN, vomeronasal sensory neuron.