Статті в журналах: "HERG gating"

1

Zhou, QinLian, and Glenna C. L. Bett. "Modeling HERG Gating Transitions." Biophysical Journal 100, no. 3 (February 2011): 426a. http://dx.doi.org/10.1016/j.bpj.2010.12.2521.

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2

Bett, Glenna C. L., Qinlian Zhou, and Randall L. Rasmusson. "Models of HERG Gating." Biophysical Journal 101, no. 3 (August 2011): 631–42. http://dx.doi.org/10.1016/j.bpj.2011.06.050.

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3

Smith, Paula L., and Gary Yellen. "Fast and Slow Voltage Sensor Movements in HERG Potassium Channels." Journal of General Physiology 119, no. 3 (February 22, 2002): 275–93. http://dx.doi.org/10.1085/jgp.20028534.

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HERG encodes an inwardly-rectifying potassium channel that plays an important role in repolarization of the cardiac action potential. Inward rectification of HERG channels results from rapid and voltage-dependent inactivation gating, combined with very slow activation gating. We asked whether the voltage sensor is implicated in the unusual properties of HERG gating: does the voltage sensor move slowly to account for slow activation and deactivation, or could the voltage sensor move rapidly to account for the rapid kinetics and intrinsic voltage dependence of inactivation? To probe voltage sensor movement, we used a fluorescence technique to examine conformational changes near the positively charged S4 region. Fluorescent probes attached to three different residues on the NH2-terminal end of the S4 region (E518C, E519C, and L520C) reported both fast and slow voltage-dependent changes in fluorescence. The slow changes in fluorescence correlated strongly with activation gating, suggesting that the slow activation gating of HERG results from slow voltage sensor movement. The fast changes in fluorescence showed voltage dependence and kinetics similar to inactivation gating, though these fluorescence signals were not affected by external tetraethylammonium blockade or mutations that alter inactivation. A working model with two types of voltage sensor movement is proposed as a framework for understanding HERG channel gating and the fluorescence signals.

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4

Hardman, Rachael M., Phillip J. Stansfeld, Sarah Dalibalta, Michael J. Sutcliffe, and John S. Mitcheson. "Activation Gating of hERG Potassium Channels." Journal of Biological Chemistry 282, no. 44 (September 6, 2007): 31972–81. http://dx.doi.org/10.1074/jbc.m705835200.

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5

Zhou, Qinlian, and Glenna C. L. Bett. "Regulation of the voltage-insensitive step of HERG activation by extracellular pH." American Journal of Physiology-Heart and Circulatory Physiology 298, no. 6 (June 2010): H1710—H1718. http://dx.doi.org/10.1152/ajpheart.01246.2009.

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Human ether-à-go-go-related gene (HERG, Kv11.1, KCNH2) voltage-gated K+ channels dominate cardiac action potential repolarization. In addition, HERG channels play a role in neuronal and smooth cell excitability as well as cancer pathology. Extracellular pH (pHo) is modified during myocardial ischemia, inflammation, and respiratory alkalosis, so understanding the response of HERG channels to changes in pH is of clinical significance. The relationship between pHo and HERG channel gating appears complex. Acidification has previously been reported to speed, slow, or have no effect on activation. We therefore undertook comprehensive analysis of the effect of pHo on HERG channel activation. HERG channels have unique and complex activation gating characteristics with both voltage-sensitive and voltage-insensitive steps in the activation pathway. Acidosis decreased the activation rate, suppressed peak current, and altered the sigmoidicity of gating near threshold potentials. At positive voltages, where the voltage-insensitive transition is rate limiting, pHo modified the voltage-insensitive step with a pKa similar to that of histidine. Hill coefficient analysis was incompatible with a coefficient of 1 but was well described by a Hill coefficient of 4. We derived a pHo-sensitive term for a five-state Markov model of HERG channel gating. This model demonstrates the mechanism of pHo sensitivity in HERG channel activation. Our experimental data and mathematical model demonstrate that the pHo sensitivity of HERG channel activation is dominated by the pHo sensitivity of the voltage-insensitive step, in a fashion that is compatible with the presence of at least one proton-binding site on each subunit of the channel tetramer.

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6

Zhang, Mei, Jie Liu, and Gea-Ny Tseng. "Gating Charges in the Activation and Inactivation Processes of the hERG Channel." Journal of General Physiology 124, no. 6 (November 15, 2004): 703–18. http://dx.doi.org/10.1085/jgp.200409119.

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The hERG channel has a relatively slow activation process but an extremely fast and voltage-sensitive inactivation process. Direct measurement of hERG's gating current (Piper, D.R., A. Varghese, M.C. Sanguinetti, and M. Tristani-Firouzi. 2003. PNAS. 100:10534–10539) reveals two kinetic components of gating charge transfer that may originate from two channel domains. This study is designed to address three questions: (1) which of the six positive charges in hERG's major voltage sensor, S4, are responsible for gating charge transfer during activation, (2) whether a negative charge in the cytoplasmic half of S2 (D466) also contributes to gating charge transfer, and (3) whether S4 serves as the sole voltage sensor for hERG inactivation. We individually mutate S4's positive charges and D466 to cysteine, and examine (a) effects of mutations on the number of equivalent gating charges transferred during activation (za) and inactivation (zi), and (b) sidedness and state dependence of accessibility of introduced cysteine side chains to a membrane-impermeable thiol-modifying reagent (MTSET). Neutralizing the outer three positive charges in S4 and D466 in S2 reduces za, and cysteine side chains introduced into these positions experience state-dependent changes in MTSET accessibility. On the other hand, neutralizing the inner three positive charges in S4 does not affect za. None of the charge mutations affect zi. We propose that the scheme of gating charge transfer during hERG's activation process is similar to that described for the Shaker channel, although hERG has less gating charge in its S4 than in Shaker. Furthermore, channel domain other than S4 contributes to gating charge involved in hERG's inactivation process.

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7

Hill, Adam P., Anthony Varghese, Socrates Dokos, Stefan Mann, and Jamie I. Vandenberg. "Developing In Silico Descriptions Of Herg Channel Gating." Biophysical Journal 96, no. 3 (February 2009): 191a. http://dx.doi.org/10.1016/j.bpj.2008.12.897.

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8

Robertson, Gail A. "hERG Subunit-Specific Contributions to Gating and Disease." Biophysical Journal 102, no. 3 (January 2012): 212a. http://dx.doi.org/10.1016/j.bpj.2011.11.1157.

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9

Dou, Ying, Zeineb Es-Salah-Lamoureux, Ping Yu Xiong, and David Fedida. "Understanding hERG Channels Gating using Voltage-Clamp Fluorimetry." Biophysical Journal 102, no. 3 (January 2012): 329a—330a. http://dx.doi.org/10.1016/j.bpj.2011.11.1806.

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10

Kopfer, David A., Ulrike Hahn, Iris Ohmert, Gert Vriend, Olaf Pongs, Bert L. de Groot, and Ulrich Zachariae. "Molecular Determinants in K+ Channel hERG Inactivation Gating." Biophysical Journal 102, no. 3 (January 2012): 529a—530a. http://dx.doi.org/10.1016/j.bpj.2011.11.2894.

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11

Wang, Hui-Zhen, Hong Shi, Shu-Jie Liao, and Zhiguo Wang. "Inactivation gating determines nicotine blockade of human HERG channels." American Journal of Physiology-Heart and Circulatory Physiology 277, no. 3 (September 1, 1999): H1081—H1088. http://dx.doi.org/10.1152/ajpheart.1999.277.3.h1081.

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We have previously found that nicotine blocked multiple K+ currents, including the rapid component of delayed rectifier K+ currents ( I Kr), by interacting directly with the channels. To shed some light on the mechanisms of interaction between nicotine and channels, we performed detailed analysis on the human ether-à-go-go-related gene (HERG) channels, which are believed to be equivalent to the native I Kr when expressed in Xenopus oocytes. Nicotine suppressed the HERG channels in a concentration-dependent manner with greater potency with voltage protocols, which favor channel inactivation. Nicotine caused dramatic shifts of the voltage-dependent inactivation curve to more negative potentials and accelerated the inactivation process. Conversely, maneuvers that weakened the channel inactivation gating considerably relieved the blockade. Elevating the extracellular K+ concentration from 5 to 20 mM increased the nicotine concentration (by ∼100-fold) needed to achieve the same degree of inhibition. Moreover, nicotine lost its ability to block the HERG channels when a single mutation was introduced to a residue located after transmembrane domain 6 (S631A) to remove the rapid channel inactivation. Our data suggest that the inactivation gating determines nicotine blockade of the HERG channels.

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12

Shi, Yu Patrick, Samrat Thouta, Yen May Cheng, and Tom W. Claydon. "Extracellular protons accelerate hERG channel deactivation by destabilizing voltage sensor relaxation." Journal of General Physiology 151, no. 2 (December 7, 2018): 231–46. http://dx.doi.org/10.1085/jgp.201812137.

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hERG channels underlie the delayed-rectifier K+ channel current (IKr), which is crucial for membrane repolarization and therefore termination of the cardiac action potential. hERG channels display unusually slow deactivation gating, which contributes to a resurgent current upon repolarization and may protect against post-depolarization–induced arrhythmias. hERG channels also exhibit robust mode shift behavior, which reflects the energetic separation of activation and deactivation pathways due to voltage sensor relaxation into a stable activated state. The mechanism of relaxation is unknown and likely contributes to slow hERG channel deactivation. Here, we use extracellular acidification to probe the structural determinants of voltage sensor relaxation and its influence on the deactivation gating pathway. Using gating current recordings and voltage clamp fluorimetry measurements of voltage sensor domain dynamics, we show that voltage sensor relaxation is destabilized at pH 6.5, causing an ∼20-mV shift in the voltage dependence of deactivation. We show that the pH dependence of the resultant loss of mode shift behavior is similar to that of the deactivation kinetics acceleration, suggesting that voltage sensor relaxation correlates with slower pore gate closure. Neutralization of D509 in S3 also destabilizes the relaxed state of the voltage sensor, mimicking the effect of protons, suggesting that acidic residues on S3, which act as countercharges to S4 basic residues, are involved in stabilizing the relaxed state and slowing deactivation kinetics. Our findings identify the mechanistic determinants of voltage sensor relaxation and define the long-sought mechanism by which protons accelerate hERG deactivation.

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13

Ganapathi, Sindura B., Todd E. Fox, Mark Kester, and Keith S. Elmslie. "Ceramide modulates HERG potassium channel gating by translocation into lipid rafts." American Journal of Physiology-Cell Physiology 299, no. 1 (July 2010): C74—C86. http://dx.doi.org/10.1152/ajpcell.00462.2009.

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Human ether-à-go-go-related gene (HERG) potassium channels play an important role in cardiac action potential repolarization, and HERG dysfunction can cause cardiac arrhythmias. However, recent evidence suggests a role for HERG in the proliferation and progression of multiple types of cancers, making it an attractive target for cancer therapy. Ceramide is an important second messenger of the sphingolipid family, which due to its proapoptotic properties has shown promising results in animal models as an anticancer agent . Yet the acute effects of ceramide on HERG potassium channels are not known. In the present study we examined the effects of cell-permeable C6-ceramide on HERG potassium channels stably expressed in HEK-293 cells. C6-ceramide (10 μM) reversibly inhibited HERG channel current (IHERG) by 36 ± 5%. Kinetically, ceramide induced a significant hyperpolarizing shift in the current-voltage relationship (Δ V1/2 = −8 ± 0.5 mV) and increased the deactivation rate (43 ± 3% for τfast and 51 ± 3% for τslow). Mechanistically, ceramide recruited HERG channels within caveolin-enriched lipid rafts. Cholesterol depletion and repletion experiments and mathematical modeling studies confirmed that inhibition and gating effects are mediated by separate mechanisms. The ceramide-induced hyperpolarizing gating shift (raft mediated) could offset the impact of inhibition (raft independent) during cardiac action potential repolarization, so together they may nullify any negative impact on cardiac rhythm. Our results provide new insights into the effects of C6-ceramide on HERG channels and suggest that C6-ceramide can be a promising therapeutic for cancers that overexpress HERG.

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14

de la Peña, Pilar, Angeles Machín, Jorge Fernández-Trillo, Pedro Domínguez, and Francisco Barros. "Mapping of interactions between the N- and C-termini and the channel core in HERG K+ channels." Biochemical Journal 451, no. 3 (April 12, 2013): 463–74. http://dx.doi.org/10.1042/bj20121717.

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The characteristic gating properties of the HERG [human eag (ether-a-go-go)-related gene] potassium channel determine its contribution to cardiac repolarization and in setting the electrical behaviour of a variety of cells. In the present study we analysed, using a site-directed cysteine and disulfide chemistry approach, whether the eag/PAS (Per/Arnt/Sim) and proximal domains at the HERG N-terminus exert a role in controlling the access of the N-terminal flexible tail to its binding site in the channel core for interaction with the gating machinery. Whereas the eag/PAS domain is necessary for disulfide bridging, plus the cysteine residues introduced at positions 3 and 542 of the HERG sequence, the presence of the proximal domain seems to be dispensable. The state-dependent formation of a disulfide bridge between Cys3 and an endogenous cysteine residue at position 723 in the C-terminal C-linker suggests that the N-terminal tail of HERG can also get into close proximity with the C-linker structures located at the bottom of helix S6. Therefore the intrinsic flexibility of the N-tail and its proximity to both the S4–S5 loop and the C-linker may dynamically contribute to the modulation of HERG channel gating.

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15

Cortes, D. Marien, and Luis G. Cuello. "A KcsA-hERG Chimera Provides Structural Insights into the Unusual hERG Inactivation Gating Mechanism." Biophysical Journal 104, no. 2 (January 2013): 122a. http://dx.doi.org/10.1016/j.bpj.2012.11.704.

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16

Gang, Hongying, and Shetuan Zhang. "Na+ Permeation and Block of hERG Potassium Channels." Journal of General Physiology 128, no. 1 (June 12, 2006): 55–71. http://dx.doi.org/10.1085/jgp.200609500.

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The inactivation gating of hERG channels is important for the channel function and drug–channel interaction. Whereas hERG channels are highly selective for K+, we have found that inactivated hERG channels allow Na+ to permeate in the absence of K+. This provides a new way to directly monitor and investigate hERG inactivation. By using whole cell patch clamp method with an internal solution containing 135 mM Na+ and an external solution containing 135 mM NMG+, we recorded a robust Na+ current through hERG channels expressed in HEK 293 cells. Kinetic analyses of the hERG Na+ and K+ currents indicate that the channel experiences at least two states during the inactivation process, an initial fast, less stable state followed by a slow, more stable state. The Na+ current reflects Na+ ions permeating through the fast inactivated state but not through the slow inactivated state or open state. Thus the hERG Na+ current displayed a slow inactivation as the channels travel from the less stable, fast inactivated state into the more stable, slow inactivated state. Removal of fast inactivation by the S631A mutation abolished the Na+ current. Moreover, acceleration of fast inactivation by mutations T623A, F627Y, and S641A did not affect the hERG Na+ current, but greatly diminished the hERG K+ current. We also found that external Na+ potently blocked the hERG outward Na+ current with an IC50 of 3.5 mM. Mutations in the channel pore and S6 regions, such as S624A, F627Y, and S641A, abolished the inhibitory effects of external Na+ on the hERG Na+ current. Na+ permeation and blockade of hERG channels provide novel ways to extend our understanding of the hERG gating mechanisms.

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17

Wang, Jixin, Joseph J. Salata, and Paul B. Bennett. "Saxitoxin Is a Gating Modifier of hERG K+ Channels." Journal of General Physiology 121, no. 6 (May 27, 2003): 583–98. http://dx.doi.org/10.1085/jgp.200308812.

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Potassium (K+) channels mediate numerous electrical events in excitable cells, including cellular membrane potential repolarization. The hERG K+ channel plays an important role in myocardial repolarization, and inhibition of these K+ channels is associated with long QT syndromes that can cause fatal cardiac arrhythmias. In this study, we identify saxitoxin (STX) as a hERG channel modifier and investigate the mechanism using heterologous expression of the recombinant channel in HEK293 cells. In the presence of STX, channels opened slower during strong depolarizations, and they closed much faster upon repolarization, suggesting that toxin-bound channels can still open but are modified, and that STX does not simply block the ion conduction pore. STX decreased hERG K+ currents by stabilizing closed channel states visualized as shifts in the voltage dependence of channel opening to more depolarized membrane potentials. The concentration dependence for steady-state modification as well as the kinetics of onset and recovery indicate that multiple STX molecules bind to the channel. Rapid application of STX revealed an apparent “agonist-like” effect in which K+ currents were transiently increased. The mechanism of this effect was found to be an effect on the channel voltage-inactivation relationship. Because the kinetics of inactivation are rapid relative to activation for this channel, the increase in K+ current appeared quickly and could be subverted by a decrease in K+ currents due to the shift in the voltage-activation relationship at some membrane potentials. The results are consistent with a simple model in which STX binds to the hERG K+ channel at multiple sites and alters the energetics of channel gating by shifting both the voltage-inactivation and voltage-activation processes. The results suggest a novel extracellular mechanism for pharmacological manipulation of this channel through allosteric coupling to channel gating.

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18

Goodchild, Samuel J., Logan C. Macdonald, and David Fedida. "Sequence of Gating Charge Movement and Pore Gating in hERG Activation and Deactivation Pathways." Biophysical Journal 108, no. 6 (March 2015): 1435–47. http://dx.doi.org/10.1016/j.bpj.2015.02.014.

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19

Cheng, Yen May, Christina M. Hull, Christine M. Niven, Ji Qi, Charlene R. Allard, and Tom W. Claydon. "Functional interactions of voltage sensor charges with an S2 hydrophobic plug in hERG channels." Journal of General Physiology 142, no. 3 (August 26, 2013): 289–303. http://dx.doi.org/10.1085/jgp.201310992.

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Human ether-à-go-go–related gene (hERG, Kv11.1) potassium channels have unusually slow activation and deactivation kinetics. It has been suggested that, in fast-activating Shaker channels, a highly conserved Phe residue (F290) in the S2 segment forms a putative gating charge transfer center that interacts with S4 gating charges, i.e., R362 (R1) and K374 (K5), and catalyzes their movement across the focused electric field. F290 is conserved in hERG (F463), but the relevant residues in the hERG S4 are reversed, i.e., K525 (K1) and R537 (R5), and there is an extra positive charge adjacent to R537 (i.e., K538). We have examined whether hERG channels possess a transfer center similar to that described in Shaker and if these S4 charge differences contribute to slow gating in hERG channels. Of five hERG F463 hydrophobic substitutions tested, F463W and F463Y shifted the conductance–voltage (G-V) relationship to more depolarized potentials and dramatically slowed channel activation. With the S4 residue reversals (i.e., K525, R537) taken into account, the closed state stabilization by F463W is consistent with a role for F463 that is similar to that described for F290 in Shaker. As predicted from results with Shaker, the hERG K525R mutation destabilized the closed state. However, hERG R537K did not stabilize the open state as predicted. Instead, we found the neighboring K538 residue to be critical for open state stabilization, as K538R dramatically slowed and right-shifted the voltage dependence of activation. Finally, double mutant cycle analysis on the G-V curves of F463W/K525R and F463W/K538R double mutations suggests that F463 forms functional interactions with K525 and K538 in the S4 segment. Collectively, these data suggest a role for F463 in mediating closed–open equilibria, similar to that proposed for F290 in Shaker channels.

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20

Pennefather, Peter S., Wei Zhou, and Thomas E. DeCoursey. "Idiosyncratic Gating of HERG-like K+ Channels in Microglia." Journal of General Physiology 111, no. 6 (June 1, 1998): 795–805. http://dx.doi.org/10.1085/jgp.111.6.795.

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A simple kinetic model is presented to explain the gating of a HERG-like voltage-gated K+ conductance described in the accompanying paper (Zhou, W., F.S. Cayabyab, P.S. Pennefather, L.C. Schlichter, and T.E. DeCoursey. 1998. J. Gen. Physiol. 111:781–794). The model proposes two kinetically distinct closing pathways, a rapid one favored by depolarization (deactivation) and a slow one favored by hyperpolarization (inactivation). The overlap of these two processes leads to a window current between −50 and +20 mV with a peak at −36 mV of ∼12% maximal conductance. The near absence of depolarization-activated outward current in microglia, compared with HERG channels expressed in oocytes or cardiac myocytes, can be explained if activation is shifted negatively in microglia. As seen with experimental data, availability predicted by the model was more steeply voltage dependent, and the midpoint more positive when determined by making the holding potential progressively more positive at intervals of 20 s (starting at −120 mV), rather than progressively more negative (starting at 40 mV). In the model, this hysteresis was generated by postulating slow and ultra-slow components of inactivation. The ultra-slow component takes minutes to equilibrate at −40 mV but is steeply voltage dependent, leading to protocol-dependent modulation of the HERG-like current. The data suggest that “deactivation” and “inactivation” are coupled through the open state. This is particularly evident in isotonic Cs+, where a delayed and transient outward current develops on depolarization with a decay time constant more voltage dependent and slower than the deactivation process observed at the same potential after a brief hyperpolarization.

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21

Melgari, Dario, Kieran E. Brack, Yihong Zhang, Aziza El Harchi, John S. Mitcheson, Christopher E. Dempsey, G. André Ng, and Jules C. Hancox. "hERG potassium channel inhibition by ivabradine requires channel gating." Journal of Molecular and Cellular Cardiology 87 (October 2015): 126–28. http://dx.doi.org/10.1016/j.yjmcc.2015.08.002.

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22

Perry, Matthew D., Chai-Ann Ng, Stefan A. Mann, Arash Sadrieh, Mohammad Imtiaz, Adam P. Hill, and Jamie I. Vandenberg. "Getting to the heart of hERG K+channel gating." Journal of Physiology 593, no. 12 (June 15, 2015): 2575–85. http://dx.doi.org/10.1113/jp270095.

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23

Fontana, Lucrezia, Massimo D'Amico, Olivia Crociani, Tiziana Biagiotti, Michela Solazzo, Barbara Rosati, Annarosa Arcangeli, Enzo Wanke, and Massimo Olivotto. "Long-Term Modulation of HERG Channel Gating in Hypoxia." Biochemical and Biophysical Research Communications 286, no. 5 (September 2001): 857–62. http://dx.doi.org/10.1006/bbrc.2001.5464.

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24

Wang, Zhuren, Ying Dou, Samuel J. Goodchild, Zeineb Es-Salah-Lamoureux, and David Fedida. "Components of gating charge movement and S4 voltage-sensor exposure during activation of hERG channels." Journal of General Physiology 141, no. 4 (March 11, 2013): 431–43. http://dx.doi.org/10.1085/jgp.201210942.

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The human ether-á-go-go–related gene (hERG) K+ channel encodes the pore-forming α subunit of the rapid delayed rectifier current, IKr, and has unique activation gating kinetics, in that the α subunit of the channel activates and deactivates very slowly, which focuses the role of IKr current to a critical period during action potential repolarization in the heart. Despite its physiological importance, fundamental mechanistic properties of hERG channel activation gating remain unclear, including how voltage-sensor movement rate limits pore opening. Here, we study this directly by recording voltage-sensor domain currents in mammalian cells for the first time and measuring the rates of voltage-sensor modification by [2-(trimethylammonium)ethyl] methanethiosulfonate chloride (MTSET). Gating currents recorded from hERG channels expressed in mammalian tsA201 cells using low resistance pipettes show two charge systems, defined as Q1 and Q2, with V1/2’s of −55.7 (equivalent charge, z = 1.60) and −54.2 mV (z = 1.30), respectively, with the Q2 charge system carrying approximately two thirds of the overall gating charge. The time constants for charge movement at 0 mV were 2.5 and 36.2 ms for Q1 and Q2, decreasing to 4.3 ms for Q2 at +60 mV, an order of magnitude faster than the time constants of ionic current appearance at these potentials. The voltage and time dependence of Q2 movement closely correlated with the rate of MTSET modification of I521C in the outermost region of the S4 segment, which had a V1/2 of −64 mV and time constants of 36 ± 8.5 ms and 11.6 ± 6.3 ms at 0 and +60 mV, respectively. Modeling of Q1 and Q2 charge systems showed that a minimal scheme of three transitions is sufficient to account for the experimental findings. These data point to activation steps further downstream of voltage-sensor movement that provide the major delays to pore opening in hERG channels.

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25

Gustina, Ahleah S., and Matthew C. Trudeau. "The eag domain regulates hERG channel inactivation gating via a direct interaction." Journal of General Physiology 141, no. 2 (January 14, 2013): 229–41. http://dx.doi.org/10.1085/jgp.201210870.

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Human ether-á-go-go (eag)-related gene (hERG) potassium channel kinetics are characterized by rapid inactivation upon depolarization, along with rapid recovery from inactivation and very slow closing (deactivation) upon repolarization. These factors combine to create a resurgent hERG current, where the current amplitude is paradoxically larger with repolarization than with depolarization. Previous data showed that the hERG N-terminal eag domain regulated deactivation kinetics by making a direct interaction with the C-terminal region of the channel. A primary mechanism for fast inactivation depends on residues in the channel pore; however, inactivation was also shown to be slower after deletion of a large N-terminal region. The mechanism for N-terminal region regulation of inactivation is unclear. Here, we investigated the contributions of the large N-terminal domains (amino acids 1–354), including the eag domain (amino acids 1–135), to hERG channel inactivation kinetics and steady-state inactivation properties. We found that N-deleted channels lacking just the eag domain (Δ2–135) or both the eag domain and the adjacent proximal domain (Δ2–354) had less rectifying current–voltage (I-V) relationships, slower inactivation, faster recovery from inactivation, and lessened steady-state inactivation. We coexpressed genetically encoded N-terminal fragments for the eag domain (N1–135) or the eag domain plus the proximal domain (N1–354) with N-deleted hERG Δ2–135 or hERG Δ2–354 channels and found that the resulting channels had more rectifying I-V relationships, faster inactivation, slower recovery from inactivation, and increased steady-state inactivation, similar to those properties measured for wild-type (WT) hERG. We also found that the eag domain–containing fragments regulated the time to peak and the voltage at the peak of a resurgent current elicited with a ramp voltage protocol. The eag domain–containing fragments effectively converted N-deleted channels into WT-like channels. Neither the addition of the proximal domain to the eag domain in N1–354 fragments nor the presence of the proximal domain in hERG Δ2–135 channels measurably affected inactivation properties; in contrast, the proximal region regulated steady-state activation in hERG Δ2–135 channels. The results show that N-terminal region-dependent regulation of channel inactivation and resurgent current properties are caused by a direct interaction of the eag domain with the rest of the hERG channel.

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26

Kiehn, Johann, Antonio E. Lacerda, and Arthur M. Brown. "Pathways of HERG inactivation." American Journal of Physiology-Heart and Circulatory Physiology 277, no. 1 (July 1, 1999): H199—H210. http://dx.doi.org/10.1152/ajpheart.1999.277.1.h199.

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The rapid, repolarizing K+ current in cardiomyocytes ( I Kr) has unique inwardly rectifying properties that contribute importantly to the downstroke of the cardiac action potential. The human ether-à-go-go-related gene ( HERG) expresses a macroscopic current virtually identical to I Kr, but a description of the single-channel properties that cause rectification is lacking. For this reason we measured single-channel and macropatch currents heterologously expressed by HERG in Xenopus oocytes. Our experiments had two main findings. First, the single-channel current-voltage relation showed inward rectification, and conductance was 9.7 pS at −100 mV and 3.9 pS at 100 mV when measured in symmetrical 100 mM K+ solutions. Second, single channels frequently showed no openings during depolarization but nevertheless revealed bursts of openings during repolarization. This type of gating may explain the inward rectification of HERG currents. To test this hypothesis, we used a three-closed state kinetics model and obtained rate constants from fits to macropatch data. Results from the model are consistent with rapid inactivation from closed states as a significant source of HERG rectification.

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27

Goodchild, Samuel J., and David Fedida. "Gating charge movement precedes ionic current activation in hERG channels." Channels 8, no. 1 (October 14, 2013): 84–89. http://dx.doi.org/10.4161/chan.26775.

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28

May Cheng, Yen, Christina M. Hull, Christine M. Niven, Charlene R. Allard, and Tom W. Claydon. "Molecular Determinants of Voltage-Dependent Gating in hERG Potassium Channels." Biophysical Journal 102, no. 3 (January 2012): 329a. http://dx.doi.org/10.1016/j.bpj.2011.11.1805.

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29

Sanchez-Chapula, Jose A., and Michael C. Sanguinetti. "Altered gating of HERG potassium channels by cobalt and lanthanum." Pflügers Archiv - European Journal of Physiology 440, no. 2 (March 2, 2000): 264–74. http://dx.doi.org/10.1007/s004240000263.

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30

Sanchez-Chapula, Jose A., and Michael C. Sanguinetti. "Altered gating of HERG potassium channels by cobalt and lanthanum." Pflügers Archiv 440, no. 2 (2000): 264. http://dx.doi.org/10.1007/s004240051048.

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31

Wynia-Smith, Sarah L., Anne Lynn Gillian-Daniel, Kenneth A. Satyshur, and Gail A. Robertson. "hERG Gating Microdomains Defined by S6 Mutagenesis and Molecular Modeling." Journal of General Physiology 132, no. 5 (October 27, 2008): 507–20. http://dx.doi.org/10.1085/jgp.200810083.

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Human ether-à-go-go–related gene (hERG) channels mediate cardiac repolarization and bind drugs that can cause acquired long QT syndrome and life-threatening arrhythmias. Drugs bind in the vestibule formed by the S6 transmembrane domain, which also contains the activation gate that traps drugs in the vestibule and contributes to their efficacy of block. Although drug-binding residues have been identified, we know little about the roles of specific S6 residues in gating. We introduced cysteine mutations into the hERG channel S6 domain and measured mutational effects on the steady-state distribution and kinetics of transitions between the closed and open states. Energy-minimized molecular models based on the crystal structures of rKv1.2 (open state) and MlotiK1 and KcsA (closed state) provided structural contexts for evaluating mutant residues. The majority of mutations slowed deactivation, shifted conductance voltage curves to more negative potentials, or conferred a constitutive conductance over voltages that normally cause the channel to close. At the most intracellular extreme of the S6 region, Q664, Y667, and S668 were especially sensitive and together formed a ringed domain that occludes the pore in the closed state model. In contrast, mutation of S660, more than a full helical turn away and corresponding by alignment to a critical Shaker gate residue (V478), had little effect on gating. Multiple substitutions of chemically distinct amino acids at the adjacent V659 suggested that, upon closing, the native V659 side chain moves into a hydrophobic pocket but likely does not form the occluding gate itself. Overall, the study indicated that S6 mutagenesis disrupts the energetics primarily of channel closing and identified several residues critical for this process in the native channel.

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32

Gustina, Ahleah S., and Matthew C. Trudeau. "hERG potassium channel gating is mediated by N- and C-terminal region interactions." Journal of General Physiology 137, no. 3 (February 28, 2011): 315–25. http://dx.doi.org/10.1085/jgp.201010582.

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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 of the hERG channel. The mechanism for slow deactivation is unclear, however, because the other regions of the channel that participate in regulation of deactivation are not known. To identify other functional determinants of slow deactivation, we generated hERG channels with deletions of the cytoplasmic C-terminal regions. We report that hERG channels with deletions of the cyclic nucleotide–binding domain (CNBD) had accelerated deactivation kinetics that were similar to those seen in hERG channels lacking the PAS domain. Channels with dual deletions of the PAS domain and the CNBD did not show further acceleration in deactivation, indicating that the PAS domain and the CNBD regulate deactivation by a convergent mechanism. A recombinant PAS domain that we previously showed could directly regulate PAS domain–deleted channels did not regulate channels with dual deletions of the PAS domain and CNBD, suggesting that the PAS domain did not interact with CNBD-deleted channels. Biochemical protein interaction assays showed that glutathione S-transferase (GST)–PAS (but not GST) bound to a CNBD-containing fusion protein. Coexpression of PAS domain–deleted subunits (with intact C-terminal regions) and CNBD-deleted subunits (with intact N-terminal regions) resulted in channels with partially restored slow deactivation kinetics, suggesting regulatory intersubunit interactions between PAS domains and CNBDs. Together, these data suggest that the mechanism for regulation of slow deactivation in hERG channels is an interaction between the N-terminal PAS domain and the C-terminal CNBD.

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33

Codding, Sara J., and Matthew C. Trudeau. "The hERG potassium channel intrinsic ligand regulates N- and C-terminal interactions and channel closure." Journal of General Physiology 151, no. 4 (November 13, 2018): 478–88. http://dx.doi.org/10.1085/jgp.201812129.

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Human ether-à-go-go–related gene (hERG, KCNH2) voltage-activated potassium channels are critical for cardiac excitability. hERG channels have characteristic slow closing (deactivation), which is auto-regulated by a direct interaction between the N-terminal Per-Arnt-Sim (PAS) domain and the C-terminal cyclic nucleotide binding homology domain (CNBHD). hERG channels are not activated by the binding of extrinsic cyclic nucleotide ligands, but rather bind an “intrinsic ligand” that is composed of residues 860–862 within the CNBHD and mimics a cyclic nucleotide. The intrinsic ligand is located at the PAS–CNBHD interface, but its mechanism of action in hERG is not well understood. Here we use whole-cell patch-clamp electrophysiology and FRET spectroscopy to examine how the intrinsic ligand regulates gating. To carry out this work, we coexpress PAS (a PAS domain fused to cyan fluorescent protein) in trans with hERG “core” channels (channels with a deletion of the PAS domain fused to citrine fluorescent protein). The PAS domain in trans with hERG core channels has slow (regulated) deactivation, like that of WT hERG channels, as well as robust FRET, which indicates there is a direct functional and structural interaction of the PAS domain with the channel core. In contrast, PAS in trans with hERG F860A core channels has intermediate deactivation and intermediate FRET, indicating perturbation of the PAS domain interaction with the CNBHD. Furthermore, PAS in trans with hERG L862A core channels, or PAS in trans with hERG F860G,L862G core channels, has fast (nonregulated) deactivation and no measurable FRET, indicating abolition of the PAS and CNBHD interaction. These results indicate that the intrinsic ligand is necessary for the functional and structural interaction between the PAS domain and the CNBHD, which regulates the characteristic slow deactivation gating in hERG channels.

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34

McBride, Christie M., Jonathan Powell, Ashley Smith, and Brian P. Delisle. "Long QT-Linked HERG Mutations at R531 of the S4 Alter the Gating Properties of Wt-HERG." Biophysical Journal 100, no. 3 (February 2011): 427a. http://dx.doi.org/10.1016/j.bpj.2010.12.2525.

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35

Brelidze, Tinatin I. "N- and C-terminal interactions in KCNH channels: The spotlight on the intrinsic ligand." Journal of General Physiology 151, no. 4 (February 19, 2019): 400–403. http://dx.doi.org/10.1085/jgp.201812313.

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36

Fedida, D., Z. Es-Salah-Lamoureux, Y. Dou, and Z. Wang. "hERG Activation Gating Is Rapid: Evidence from Gating-Current Recordings and MTSET Modification of the Voltage Sensor." Heart Rhythm 9, no. 11 (November 2012): 1913–14. http://dx.doi.org/10.1016/j.hrthm.2012.09.102.

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37

Piper, D. R., A. Varghese, M. C. Sanguinetti, and M. Tristani-Firouzi. "Gating currents associated with intramembrane charge displacement in HERG potassium channels." Proceedings of the National Academy of Sciences 100, no. 18 (August 19, 2003): 10534–39. http://dx.doi.org/10.1073/pnas.1832721100.

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38

Tristani-Firouzi, M. "Structural determinants and biophysical properties of HERG and KCNQ1 channel gating." Journal of Molecular and Cellular Cardiology 35, no. 1 (January 2003): 27–35. http://dx.doi.org/10.1016/s0022-2828(02)00286-9.

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39

Bett, Glenna C. L., MiMi Liu, and Randall L. Rasmusson. "Histidine 562 on S5 is a pH Sensor for HERG Gating." Biophysical Journal 100, no. 3 (February 2011): 426a. http://dx.doi.org/10.1016/j.bpj.2010.12.2520.

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40

Colenso, Charlotte K., Yang Cao, Richard B. Sessions, Jules C. Hancox, and Christopher E. Dempsey. "Voltage Sensor Gating Charge Transfer in a hERG Potassium Channel Model." Biophysical Journal 107, no. 10 (November 2014): L25—L28. http://dx.doi.org/10.1016/j.bpj.2014.10.001.

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41

Jones, David K., Carol Harley, Anthony Amolo, Joao Morais-Cabral, and Gail A. Robertson. "The hERG PAS Domain Facilitates Gating Charge Deactivation at Physiological Temperature." Biophysical Journal 114, no. 3 (February 2018): 374a. http://dx.doi.org/10.1016/j.bpj.2017.11.2072.

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42

Fernández-Mariño, Ana I., and Kenton Swartz. "Conserved Voltage-Dependent Gating Elements between Shaker and HERG Kv Channels." Biophysical Journal 118, no. 3 (February 2020): 332a. http://dx.doi.org/10.1016/j.bpj.2019.11.1855.

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43

Tan, Peter S., Matthew D. Perry, Chai Ann Ng, Jamie I. Vandenberg, and Adam P. Hill. "Voltage-sensing domain mode shift is coupled to the activation gate by the N-terminal tail of hERG channels." Journal of General Physiology 140, no. 3 (August 13, 2012): 293–306. http://dx.doi.org/10.1085/jgp.201110761.

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Human ether-a-go-go–related gene (hERG) potassium channels exhibit unique gating kinetics characterized by unusually slow activation and deactivation. The N terminus of the channel, which contains an amphipathic helix and an unstructured tail, has been shown to be involved in regulation of this slow deactivation. However, the mechanism of how this occurs and the connection between voltage-sensing domain (VSD) return and closing of the gate are unclear. To examine this relationship, we have used voltage-clamp fluorometry to simultaneously measure VSD motion and gate closure in N-terminally truncated constructs. We report that mode shifting of the hERG VSD results in a corresponding shift in the voltage-dependent equilibrium of channel closing and that at negative potentials, coupling of the mode-shifted VSD to the gate defines the rate of channel closure. Deletion of the first 25 aa from the N terminus of hERG does not alter mode shifting of the VSD but uncouples the shift from closure of the cytoplasmic gate. Based on these observations, we propose the N-terminal tail as an adaptor that couples voltage sensor return to gate closure to define slow deactivation gating in hERG channels. Furthermore, because the mode shift occurs on a time scale relevant to the cardiac action potential, we suggest a physiological role for this phenomenon in maximizing current flow through hERG channels during repolarization.

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44

Wei, Mengyan, Pu Wang, Xiufang Zhu, Masaki Morishima, Yangong Liu, Mingqi Zheng, Gang Liu, et al. "Electrophysiological evaluation of an anticancer drug gemcitabine on cardiotoxicity revealing down-regulation and modification of the activation gating properties in the human rapid delayed rectifier potassium channel." PLOS ONE 18, no. 2 (February 2, 2023): e0280656. http://dx.doi.org/10.1371/journal.pone.0280656.

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Gemcitabine is an antineoplastic drug commonly used in the treatment of several types of cancers including pancreatic cancer and non–small cell lung cancer. Although gemcitabine-induced cardiotoxicity is widely recognized, the exact mechanism of cardiac dysfunction causing arrhythmias remains unclear. The objective of this study was to electrophysiologically evaluate the proarrhythmic cardiotoxicity of gemcitabine focusing on the human rapid delayed rectifier potassium channel, hERG channel. In heterologous hERG expressing HEK293 cells (hERG-HEK cells), hERG channel current (IhERG) was reduced by gemcitabine when applied for 24 h but not immediately after the application. Gemcitabine modified the activation gating properties of the hERG channel toward the hyperpolarization direction, while inactivation, deactivation or reactivation gating properties were unaffected by gemcitabine. When gemcitabine was applied to hERG-HEK cells in combined with tunicamycin, an inhibitor of N-acetylglucosamine phosphotransferase, gemcitabine was unable to reduce IhERG or shift the activation properties toward the hyperpolarization direction. While a mannosidase I inhibitor kifunensine alone reduced IhERG and the reduction was even larger in combined with gemcitabine, kifunensine was without effect on IhERG when hERG-HEK cells were pretreated with gemcitabine for 24 h. In addition, gemcitabine down-regulated fluorescence intensity for hERG potassium channel protein in rat neonatal cardiomyocyte, although hERG mRNA was unchanged. Our results suggest the possible mechanism of arrhythmias caused by gemcitabine revealing a down-regulation of IhERG through the post-translational glycosylation disruption possibly at the early phase of hERG channel glycosylation in the endoplasmic reticulum that alters the electrical excitability of cells.

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45

Wang, Yingyi, Zhengyi Luo, Sheng Lei, Shuji Li, Xiaowen Li, and Chunhua Yuan. "Effects and mechanism of gating modifier spider toxins on the hERG channel." Toxicon 189 (January 2021): 56–64. http://dx.doi.org/10.1016/j.toxicon.2020.11.008.

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46

Mullins, Franklin M., Svetlana Z. Stepanovic, Niloufar B. Gillani, Alfred L. George, and Jeffrey R. Balser. "Functional interaction between extracellular sodium, potassium and inactivation gating in HERG channels." Journal of Physiology 558, no. 3 (July 27, 2004): 729–44. http://dx.doi.org/10.1113/jphysiol.2004.065193.

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47

Vandenberg, Jamie I., Matthew D. Perry, Mark J. Perrin, Stefan A. Mann, Ying Ke, and Adam P. Hill. "hERG K+ Channels: Structure, Function, and Clinical Significance." Physiological Reviews 92, no. 3 (July 2012): 1393–478. http://dx.doi.org/10.1152/physrev.00036.2011.

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The human ether-a-go-go related gene (hERG) encodes the pore-forming subunit of the rapid component of the delayed rectifier K+ channel, Kv11.1, which are expressed in the heart, various brain regions, smooth muscle cells, endocrine cells, and a wide range of tumor cell lines. However, it is the role that Kv11.1 channels play in the heart that has been best characterized, for two main reasons. First, it is the gene product involved in chromosome 7-associated long QT syndrome (LQTS), an inherited disorder associated with a markedly increased risk of ventricular arrhythmias and sudden cardiac death. Second, blockade of Kv11.1, by a wide range of prescription medications, causes drug-induced QT prolongation with an increase in risk of sudden cardiac arrest. In the first part of this review, the properties of Kv11.1 channels, including biogenesis, trafficking, gating, and pharmacology are discussed, while the second part focuses on the pathophysiology of Kv11.1 channels.

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48

Gianulis, Elena C., Qiangni Liu, and Matthew C. Trudeau. "Direct interaction of eag domains and cyclic nucleotide–binding homology domains regulate deactivation gating in hERG channels." Journal of General Physiology 142, no. 4 (September 16, 2013): 351–66. http://dx.doi.org/10.1085/jgp.201310995.

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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 and a C-terminal C-linker/cyclic nucleotide–binding homology domain (CNBHD) are required for regulation of slow deactivation. The region between the S4 and S5 transmembrane domains (S4–S5 linker) is also implicated in this process, but the mechanism for regulation of slow deactivation is unclear. Here, using an eag domain–deleted channel (hERG Δeag) fused to Citrine fluorescent protein, we found that most channels bearing individual alanine mutations in the S4–S5 linker were directly regulated by recombinant eag domains fused to a cyan fluorescent protein (N-eag-CFP) and had robust Förster resonance energy transfer (FRET). Additionally, a channel bearing a group of eight alanine residues in the S4–S5 linker was not measurably regulated by N-eag-CFP domains, but robust FRET was measured. These findings demonstrate that the eag domain associated with all of the S4–S5 linker mutant channels. In contrast, channels that also lacked the CNBHD (hERG Δeag ΔCNBHD-Citrine) were not measurably regulated by N-eag-CFP nor was FRET detected, suggesting that the C-linker/CNBHD was required for eag domains to directly associate with the channel. In a FRET hybridization assay, N-eag-CFP had robust FRET with a C-linker/CNBHD-Citrine, suggesting a direct and specific interaction between the eag domain and the C-linker/CNBHD. Lastly, coexpression of a hERG subunit lacking the CNBHD and the distal C-terminal region (hERG ΔpCT-Citrine) with hERG Δeag-CFP subunits had FRET and partial restoration of slow deactivation. Collectively, these findings reveal that the C-linker/CNBHD, but not the S4–S5 linker, was necessary for the eag domain to associate with the channel, that the eag domain and the C-linker/CNBHD were sufficient for a direct interaction, and that an intersubunit interaction between the eag domain and the C-linker/CNBHD regulated slow deactivation in hERG channels at the plasma membrane.

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49

Dou, Ying, Samuel J. Goodchild, Robert Vander Velde, Yue Wu, and David Fedida. "The neutral, hydrophobic isoleucine at position I521 in the extracellular S4 domain of hERG contributes to channel gating equilibrium." American Journal of Physiology-Cell Physiology 305, no. 4 (August 15, 2013): C468—C478. http://dx.doi.org/10.1152/ajpcell.00147.2013.

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The human ether-a-go-go related (hERG) potassium channel has unusual functional characteristics in that the rates of channel activation and deactivation are much slower than inactivation, which is attributed to specific structural elements within the NH2 terminus and the S1–S4 voltage-sensing domains (VSD). Although the charged residues in the VSD have been extensively modified and mutated as a result, the role and importance of specific hydrophobic residues in the S4 has been much less explored in studies of hERG gating. We found that charged, but not neutral or hydrophobic, amino acid substitution of isoleucine 521 at the outer end of the S4 transmembrane domain resulted in channels activating at much more negative voltages associated with a marked hyperpolarization of the conductance-voltage ( G-V) relationship. The contributions of different physicochemical properties to this effect were probed by chemical modification of channels substituted with cysteine at position I521. When positively charged reagents including tetramethyl-rhodamine-5-maleimide (TMRM), 1-(2-maleimidylethyl)-4-[5-(4-methoxyphenyl)oxazol-2-yl] pyridinium methane-sulfonate (PyMPO), [2-(trimethylammonium)ethyl] methanethiosulfonate chloride (MTSET), and 2-aminoethyl methanethiosulfonate hydrobromide (MTSEA) were bound to the cysteine, I521C channels activated at more negative membrane potentials. To examine the contributions to hERG gating of other residues at the outer end of S4 (520–528), we performed a cysteine scan combined with MTSET modification. Only L520C, along with I521C, shows a substantial hyperpolarizing shift of the G-V relationship upon MTSET modification. The data indicate that the neutral, hydrophobic residue I521 at the extracellular end of S4 is critical for stabilizing the closed conformation of the hERG channel relative to the open state and by comparison with Shaker supports the alignment of hERG I521 with Shaker L361.

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50

Ottosson, Nina E., and Fredrik Elinder. "Trivalent lanthanides affect gating of the hERG potassium channel at low micromolar concentrations." Biophysical Journal 121, no. 3 (February 2022): 238a. http://dx.doi.org/10.1016/j.bpj.2021.11.1534.

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