The Eag Family of K⁺ Channels in Drosophila and Mammals

Abstract

Mutations of eag, first identified in Drosophila on the basis of their leg-shaking phenotype, cause repetitive firing and enhanced transmitter release in motor neurons. The encoded EAG polypeptide is related both to voltage-gated K+ channels and to cyclic nucleotide-gated cation channels. Homology screens identified a family of eag-related channel polypeptides, highly conserved from nematodes to humans, comprising three subfamilies: EAG, ELK, and ERG. When expressed in frog oocytes, EAG channels behave as voltage-dependent, outwardly rectifying K(+)-selective channels. Mutations of the human eag-related gene (HERG) result in a form of cardiac arrhythmia that can lead to ventricular fibrillation and sudden death. Electrophysiological and pharmacological studies have provided evidence that HERG channels specify one component of the delayed rectifier, IKr, that contributes to the repolarization phase of cardiac action potentials. An important role for HERG channels in neuronal excitability is also suggested by the expression of these channels in brain tissue. Moreover, mutations of ERG-type channels in the Drosophila sei mutant cause temperature-induced convulsive seizures associated with aberrant bursting activity in the flight motor pathway. The in vivo function of ELK channels has not yet been established, but when these channels are expressed in frog oocytes, they display properties intermediate between those of EAG- and ERG-type channels. Coexpression of the K(+)-channel beta subunit encoded by Hk with EAG in oocytes dramatically increases current amplitude and also affects the gating and modulation of these currents. Biochemical evidence indicates a direct physical interaction between EAG and HK proteins. Overall, these studies highlight the diverse properties of the eag family of K+ channels, which are likely to subserve diverse functions in vivo.

Structural Basis for the cAMP-dependent Gating in the Human HCN4 Channel

“…This crystal structure contained the C-linker and CNBD, with either cAMP or cGMP bound to the binding pocket. Each CNBD has a very similar fold as other cNMP-binding proteins, containing eight ␤-strands (1)(2)(3)(4)(5)(6)(7)(8) flanked by four ␣-helixes (A-C and P). The negatively charged cyclic-phosphate group in cNMP interacts with a highly conserved positively charged arginine residue (Arg 591 ), which has been shown to be critical for cNMP binding in both CNG and HCN channels (11)(12)(13).…”

“…They bind directly to and regulate not only protein kinases like PKA but also transmembrane ion channels. In the superfamily of voltage-gated potassium channels, CNG, HCN, and EAG channels all contain a sequence fragment homologous to other cNMP-binding proteins downstream from the last transmembrane domain (S6) on the intracellular side (2)(3)(4)(5). Indeed, both cAMP and cGMP directly bind to and open CNG and HCN channels.…”

Regulation of CNGA1 Channel Gating by Interactions with the Membrane

“…subfamily H (KCNH) channels (1,8). They are composed of four subunits forming around the central ion-conducting pore (Fig.…”

Voltage-gated potassium channel EAG2 controls mitotic entry and tumor growth in medulloblastoma via regulating cell volume dynamics

“…The voltage-gated potassium channel ether-à -go-go (eag), first identified in Drosophila melanogaster based on the legshaking mutant phenotype (Kaplan and Trout 1969;Warmke et al 1991), has mammalian homologs that fall into three subfamilies-EAG (EAG1 and EAG2), EAGlike (ELK1, ELK2, and ELK3), and EAG-related (ERG1, ERG2, and ERG3)-which are voltage-gated potassium channels with distinct electrophysiological properties (Ganetzky et al 1999). EAG1 (KCNH1, Kv10.1) has been studied for its potential role in cancer (Pardo et al 1999(Pardo et al , 2005Weber et al 2006).…”