A family of potassium channel genes related to eag in Drosophila and mammals.

Abstract

We have identified a conserved family of genes related to Drosophila eag, which encodes a distinct type of voltage-activated K channel. Three related genes were recovered in screens of cDNA libraries from Drosophila, mouse, and human tissues. One gene is the mouse counterpart of eag; the other two represent additional subfamilles. The human gene maps to chromosome 7. Family members share at least 47% amino acid identity in their hydrophobic cores and all contain a segment homologous to a cyclic nucleotide-bindig domain. Sequence comparisons indicate that members of this family are most closely related to vertebrate cyclic nudleotidegated cation channels and plant inward-rectifying K+ channels. The existence of another family of K+ channel structural genes further extends the known diversity of Ki channels and has important implications for the structure, function, and evolution of the superfamily of voltage-sensitive ion channels.Voltage-activated ion channels are members of evolutionarily conserved multigene families (1, 2). For example, the Shaker (Sh) family of K+ channels comprises four related genes in Drosophila, each of which has one or more mammalian homologs (3). Together these genes define at least four subfamilies of voltage-activated K+ channels within the Sh family. Most of our present understanding of the structure and function of K+ channels is based on studies of the polypeptides encoded by these genes (4).Analysis ofother K+ channels that are not members ofthe Sh family will expand our understanding of these channels. Genes encoding additional types of K+ channels can be identified in Drosophila via molecular analysis of mutations affecting membrane excitability (5). Mutations of eag, identified by their leg-shaking phenotype, cause repetitive firing and enhanced transmitter release in motor neurons, suggesting a possible defect in K+ channels (6,7). Molecular studies revealed that eag encodes a polypeptide structurally related both to K+ channels in the Sh family and to cyclic nucleotide-gated cation channels (8-10). Expression in Xenopus oocytes confirms that the eag polypeptide assembles into channels conducting a voltageactivated K+-selective outward current (11,12

hERG1 channels are overexpressed in glioblastoma multiforme and modulate VEGF secretion in glioblastoma cell lines

“…IRK is a strong inward rectifier and thus is easier to detect at a membrane potential (V m ) more negative than E k . On the other hand, hERG (hereafter referred to as hERG1) and hELK2 channels are voltagedependent outward rectifiers, structurally related to the Shaker family of K þ channels (Warmke and Ganetzky, 1994). However, they are easier to detect when current is flowing inward as well, since large 'tail currents' can be revealed on repolarisation after conditioning at V m X0 mV.…”

Functional consequences of methionine oxidation of hERG potassium channels

“…The HEK 293 cells stably transfected with wild-type (WT) hERG1 cDNA (U04270) [29], have been described previously [30]. Cells were maintained at 37°C in Minimal Eagle Medium (MEM) supplemented with 10% fetal bovine serum, 1% penicillin-streptomycin, 2 mM Lglutamine, 0.1 mM nonessential amino acids, 1 mM sodium pyruvate, and 0.2 mg/ml geneticin (Invitrogen, Carlsbad, CA, USA) and passaged weekly to avoid >80% confluence.…”

Localization of the ergtoxin-1 receptors on the voltage sensing domain of hERG K+ channel by AFM recognition imaging

“…hERG K + channels mediate the rapidly activating delayed rectifier K + current (I Kr ) [2] that plays a key role in repolarization of the ventricular action potential [3,4]. hERG channels [5,6] are largely involved in myocardial repolarization [2,7,8] and associated with both the inherited and the acquired (druginduced) long QT syndromes (LQT2) that may be responsible of fatal cardiac arrhythmias. The inherited mutations in hERG are adverse drug effects that suppress I Kr function.…”

“…In analogy to the Kv family of K + channels, hERG comprises a tetramer, with each subunit containing six transmembrane helices ( Fig. 1) [5]. hERG K + channels are unusually promiscuous drug target through internal pore blockade [2,12] and are especially sensitive to external cations acting as a gating modifiers [13][14][15][16][17].…”