In contrast to other members of the Eag family voltage-gated, outwardly rectifying potassium channels, human eag -related gene ( HERG ) has now been shown encode an inwardly channel. The properties channels are consistent with gating Eag-related and rectifying, S4-containing but addition inactivation mechanism that attenuates efflux during depolarization. Because mutations in cause a form long-QT syndrome, these channel function may be critical maintenance normal cardiac rhythmicity.

Abstract HERG , the human ether-a-go-go –related gene, encodes a K + -selective channel with properties similar to rapidly activating component of delayed rectifier current ( I Kr ). Mutations cause autosomal-dominant long-QT syndrome (LQTS), presumably by disrupting normal function . The produced is not identical however, and mechanism which mutations LQTS remains uncertain. To better define role Erg in heart, we cloned Merg1 from mouse genomic cardiac cDNA libraries. has 16 exons maps...

Background —The congenital long-QT syndrome (LQTS) is an inherited disorder characterized by a prolonged cardiac action potential and QT interval that leads to arrhythmia. Mutations in the human ether-a-go-go–related gene ( HERG ), which encodes rapidly activating component of delayed rectifier current (I Kr cause chromosome 7–linked LQTS (LQT2). Studies mutant channels heterologous systems indicate mechanisms mediating LQT2 are varied include subunits form with altered kinetic properties or...

Abnormalities in repolarization of the cardiac ventricular action potential can lead to life-threatening arrhythmias associated with long QT syndrome. The process depends upon gating properties potassium channels encoded by human ether-à-go-go-related gene (HERG), especially those governing rate recovery from inactivation and deactivation. Previous studies have demonstrated that deletion NH2 terminus increases deactivation rate, but mechanism which regulates wild-type has not been...

Human ether-á-go-go–related gene (hERG) potassium channels have voltage-dependent closing (deactivation) kinetics that are unusually slow. A Per-Arnt-Sim (PAS) domain in the cytoplasmic N-terminal region of hERG regulates slow deactivation by making a direct interaction with another part channel. The mechanism for is unclear, however, because other regions channel participate regulation not known. To identify functional determinants deactivation, we generated deletions C-terminal regions. We...

Significance The 1a subunit of the human ether-à-go-go–related gene (hERG) potassium channel is a critical component cardiac repolarization and cornerstone safety screens for new drug development. A second subunit, 1b, coassembles with modifies gating block sensitivity. Adoption 1a/1b heteromers as model native hERG current, I Kr , has been hampered by absence direct evidence that 1b contributes to repolarization. This study provides first functional evidence, our knowledge, channels rather...

Human ether á go-go related gene (hERG) potassium channels play a central role in cardiac repolarization where channel closing (deactivation) regulates current density during action potentials. Consequently, mutations hERG that perturb deactivation are linked to long QT syndrome (LQTS), catastrophic arrhythmia. Interactions between an N-terminal domain and the pore-forming “core” of were proposed regulate deactivation, however, despite its importance mechanistic basis for is unclear. Here,...

Human ether-á-go-go (eag)-related gene (hERG) potassium channels play a critical role in cardiac repolarization and are characterized by unusually slow closing (deactivation) kinetics. The N-terminal “eag” domain C-terminal C-linker/cyclic nucleotide–binding homology (CNBHD) required for regulation of deactivation. region between the S4 S5 transmembrane domains (S4–S5 linker) is also implicated this process, but mechanism deactivation unclear. Here, using an eag domain–deleted channel (hERG...

The gating behaviour and pharmacological sensitivity of HERG are remarkably different from the corresponding properties M‐eag, a structurally similar member Eag family potassium channels. In contrast to HERG, M‐eag exhibits no apparent inactivation little rectification, is insensitive class III antiarrhythmic drug E‐4031. We generated chimeric channels sequences made point mutations identify region necessary for rapid in HERG. This includes P half S6 putative transmembrane domain, including...

Congenital long QT syndrome 2 (LQT2) is caused by loss-of-function mutations in the human ether-á-go-go-related gene (hERG) voltage-gated potassium (K(+)) channel. hERG channels have slow deactivation kinetics that are regulated an N-terminal Per-Arnt-Sim (PAS) domain. Only a small percentage of containing PAS domain LQT2 (hERG PAS-LQT2) been characterized mammalian cells, so functional effect these unclear. We investigated 11 PAS-LQT2 HEK293 cells and report diversity defects. Most formed...

The human ether-à-go-go–related gene (hERG) encodes a K + channel crucial for repolarization of the cardiac action potential. EAG-related (ERG) channels contain C-terminal cyclic nucleotide-binding homology domain coupled to pore by C-linker. Here, we report structure C-linker/cyclic mosquito ERG at 2.5-Å resolution. reveals that region expected form pocket is negatively charged and occupied short β-strand, referred as intrinsic ligand, explaining lack direct regulation nucleotides. In hERG...

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ABSTRACT: Mutations of eag , first identified in Drosophila on the basis their leg‐shaking phenotype, cause repetitive firing and enhanced transmitter release motor neurons. The encoded EAG polypeptide is related both to voltage‐gated K + channels cyclic nucleotide‐gated cation channels. Homology screens a family ‐related channel polypeptides, highly conserved from nematodes humans, comprising three subfamilies: EAG, ELK, ERG. When expressed frog oocytes, behave as voltage‐dependent,...

Human ether-á-go-go (eag)-related gene (hERG) potassium channel kinetics are characterized by rapid inactivation upon depolarization, along with recovery from and very slow closing (deactivation) repolarization. These factors combine to create a resurgent hERG current, where the current amplitude is paradoxically larger repolarization than depolarization. Previous data showed that N-terminal eag domain regulated deactivation making direct interaction C-terminal region of channel. A primary...

Human ether-à-go-go–related gene (hERG, KCNH2) voltage-activated potassium channels are critical for cardiac excitability. hERG have characteristic slow closing (deactivation), which is auto-regulated by a direct interaction between the N-terminal Per-Arnt-Sim (PAS) domain and C-terminal cyclic nucleotide binding homology (CNBHD). not activated of extrinsic ligands, but rather bind an “intrinsic ligand” that composed residues 860–862 within CNBHD mimics nucleotide. The intrinsic ligand...

Rod cyclic nucleotide-gated (CNG) channels are heterotetramers comprised of both CNGA1 and CNGB1 subunits. Calcium/calmodulin (Ca 2+ /CaM) binds to a site in the N-terminal region subunits inhibits opening conformational change CNGA1/CNGB1 channels. Here, we show that polypeptides derived from an form specific interaction with C-terminal is distal nucleotide-binding domain. Deletion Ca /CaM-binding eliminated /CaM modulation channel intersubunit interaction. Furthermore, was disrupted by...

Human ether-á-go-go–related gene (hERG) potassium channels are critical for cardiac action potential repolarization. Cardiac hERG comprise two primary isoforms: hERG1a, which has a regulatory N-terminal Per-Arnt-Sim (PAS) domain, and hERG1b, does not. Isolated, PAS-containing hERG1a regions (NTRs) directly regulate NTR-deleted channels; however, it is unclear whether hERG1b isoforms contain sufficient machinery to support regulation by NTRs. To test this, we constructed series of PAS...

The human ERG (hERG) K+ channel has a crucial function in cardiac repolarization, and mutations or block can give rise to long QT syndrome catastrophic ventricular arrhythmias. cytosolic assembly formed by the Per-Arnt-Sim (PAS) cyclic nucleotide binding homology (CNBh) domains is defining structural feature of hERG related KCNH channels. However, molecular role these two gating remains unclear. We have previously shown that single-chain variable fragment (scFv) antibodies modulate PAS...

Cyclic nucleotide-gated (CNG) ion channels mediate cellular responses to sensory stimuli. In vertebrate photoreceptors, CNG respond the light-induced decrease in cGMP by closing an ion-conducting pore that is permeable cations, including Ca2+ ions. Rod are directly inhibited Ca2+-calmodulin (Ca2+/CaM), but physiological role of this modulation unknown. Native rod comprise three CNGA1 subunits and one CNGB1 subunit. The single subunit confers several key properties on heteromeric channels,...