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kcnh mutation

Peter Bronk, Elena A Kuklin, Srinivas Gorur-Shandilya, Chang Liu, Timothy D Wiggin, Martha L Reed, Eve Marder, Leslie C Griffith
Drosophila ether-à-go-go (eag) is the founding member of a large family of voltage-gated K+ channels, the KCNH family, which includes Kv10, 11 and 12, (Ganetzky et al. 1999). Concurrent binding of calcium/calmodulin (Ca2+ /CaM) to N- and C-terminal sites inhibits mammalian EAG1 channels at sub-micromolar Ca2+ concentrations (Schonherr et al. 2000), likely by causing pore constriction (Whicher and MacKinnon 2016). Although the Drosophila EAG channel was believed to be Ca2+ -insensitive (Schonherr et al. 2000), both the N- and C-terminal sites are conserved...
January 24, 2018: Journal of Neurophysiology
Christiane K Bauer, Jürgen R Schwarz
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...
March 1, 2018: Journal of Physiology
Yaxian Zhao, Marcel P Goldschen-Ohm, João H Morais-Cabral, Baron Chanda, Gail A Robertson
Channels in the ether-à-go-go or KCNH family of potassium channels are characterized by a conserved, C-terminal domain with homology to cyclic nucleotide-binding homology domains (CNBhDs). Instead of cyclic nucleotides, two amino acid residues, Y699 and L701, occupy the binding pocket, forming an "intrinsic ligand." The role of the CNBhD in KCNH channel gating is still unclear, however, and a detailed characterization of the intrinsic ligand is lacking. In this study, we show that mutating both Y699 and L701 to alanine, serine, aspartate, or glycine impairs human EAG1 channel function...
February 2017: Journal of General Physiology
Yan Li, Hui Qi Ng, Qingxin Li, CongBao Kang
The human ether-à-go-go related gene (hERG) channel is crucial for the cardiac action potential by contributing to the fast delayed-rectifier potassium current. Mutations in the hERG channel result in type 2 long QT syndrome (LQT2). The hERG channel contains a cyclic nucleotide-binding homology domain (CNBHD) and this domain is required for the channel gating though molecular interactions with the eag domain. Here we present solution structure of the CNBHD of the hERG channel. The structural study reveals that the CNBHD adopts a similar fold to other KCNH channels...
March 30, 2016: Scientific Reports
Ting-Feng Lin, Guey-Mei Jow, Hsin-Yu Fang, Ssu-Ju Fu, Hao-Han Wu, Mei-Miao Chiu, Chung-Jiuan Jeng
Eag (Kv10) and Erg (Kv11) belong to two distinct subfamilies of the ether-à-go-go K+ channel family (KCNH). While Erg channels are characterized by an inward-rectifying current-voltage relationship that results from a C-type inactivation, mammalian Eag channels display little or no voltage-dependent inactivation. Although the amino (N)-terminal region such as the eag domain is not required for the C-type inactivation of Erg channels, an N-terminal deletion in mouse Eag1 has been shown to produce a voltage-dependent inactivation...
2014: PloS One
Chai Ann Ng, Ying Ke, Matthew D Perry, Peter S Tan, Adam P Hill, Jamie I Vandenberg
Kv11.1 potassium channels are important for regulation of the normal rhythm of the heartbeat. Reduced activity of Kv11.1 channels causes long QT syndrome type 2, a disorder that increases the risk of cardiac arrhythmias and sudden cardiac arrest. Kv11.1 channels are members of the KCNH subfamily of voltage-gated K(+) channels. However, they also share many similarities with the cyclic nucleotide gated ion channel family, including having a cyclic nucleotide-binding homology (cNBH) domain. Kv11.1 channels, however, are not directly regulated by cyclic nucleotides...
2013: PloS One
Yoni Haitin, Anne E Carlson, William N Zagotta
The KCNH voltage-dependent potassium channels (ether-à-go-go, EAG; EAG-related gene, ERG; EAG-like channels, ELK) are important regulators of cellular excitability and have key roles in diseases such as cardiac long QT syndrome type 2 (LQT2), epilepsy, schizophrenia and cancer. The intracellular domains of KCNH channels are structurally distinct from other voltage-gated channels. The amino-terminal region contains an eag domain, which is composed of a Per-Arnt-Sim (PAS) domain and a PAS-cap domain, whereas the carboxy-terminal region contains a cyclic nucleotide-binding homology domain (CNBHD), which is connected to the pore through a C-linker domain...
September 19, 2013: Nature
Tinatin I Brelidze, Elena C Gianulis, Frank DiMaio, Matthew C Trudeau, William N Zagotta
The human ether-à-go-go-related gene (hERG) encodes a K(+) channel crucial for repolarization of the cardiac action potential. EAG-related gene (ERG) channels contain a C-terminal cyclic nucleotide-binding homology domain coupled to the pore of the channel by a C-linker. Here, we report the structure of the C-linker/cyclic nucleotide-binding homology domain of a mosquito ERG channel at 2.5-Å resolution. The structure reveals that the region expected to form the cyclic nucleotide-binding pocket is negatively charged and is occupied by a short β-strand, referred to as the intrinsic ligand, explaining the lack of direct regulation of ERG channels by cyclic nucleotides...
July 9, 2013: Proceedings of the National Academy of Sciences of the United States of America
Ricardo Adaixo, Carol A Harley, Artur F Castro-Rodrigues, João H Morais-Cabral
KCNH channels form an important family of voltage gated potassium channels. These channels include a N-terminal Per-Arnt-Sim (PAS) domain with unknown function. In other proteins PAS domains are implicated in cellular responses to environmental queues through small molecule binding or involvement in signaling cascades. To better understand their role we characterized the structural properties of several channel PAS domains. We determined high resolution structures of PAS domains from the mouse EAG (mEAG), drosophila ELK (dELK) and human ERG (hERG) channels and also of the hERG domain without the first nine amino acids...
2013: PloS One
Anne E Carlson, Tinatin I Brelidze, William N Zagotta
The voltage-gated, K(+)-selective ether á go-go 1 (EAG1) channel is expressed throughout the brain where it is thought to regulate neuronal excitability. Besides its normal physiological role in the brain, EAG1 is abnormally expressed in several cancer cell types and promotes tumor progression. Like all other channels in the KCNH family, EAG1 channels have a large intracellular carboxy-terminal region that shares structural similarity with cyclic nucleotide-binding homology domains (CNBHDs). EAG1 channels, however, are not regulated by the direct binding of cyclic nucleotides and have no known endogenous ligands...
March 2013: Journal of General Physiology
Tinatin I Brelidze, Anne E Carlson, Banumathi Sankaran, William N Zagotta
The KCNH family of ion channels, comprising ether-à-go-go (EAG), EAG-related gene (ERG), and EAG-like (ELK) K(+)-channel subfamilies, is crucial for repolarization of the cardiac action potential, regulation of neuronal excitability and proliferation of tumour cells. The carboxy-terminal region of KCNH channels contains a cyclic-nucleotide-binding homology domain (CNBHD) and C-linker that couples the CNBHD to the pore. The C-linker/CNBHD is essential for proper function and trafficking of ion channels in the KCNH family...
January 26, 2012: Nature
Anna-Mari Hekkala, Matti Viitasalo, Heikki Väänänen, Heikki Swan, Lauri Toivonen
AIMS: The identification of affected family members with long QT syndrome (LQTS) is often difficult due to their normal-or only marginally lengthened-QT interval duration. We examined whether physical exercise test could increase the ability to detect the mutation carrier status in phenotypically normal LQTS family members. METHODS AND RESULTS: Sixty-six subjects were included: 15 were carriers of KCNQ1 (LQT1); 15 of KCNH(2) (LQT2); and 9 of SCN5A (LQT3) gene mutations with no, or borderline, QT lengthening; and 27 were healthy controls...
September 2010: Europace: European Pacing, Arrhythmias, and Cardiac Electrophysiology
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