Proton block of the pore underlies the inhibition of hERG cardiac K<sup>+</sup> channels during acidosis

Slyke, Aaron C. Van; Cheng, Yen May; Mafi, Pouya; Allard, Charlene R.; Hull, Christina M.; Shi, Yu; Claydon, Tom W.

doi:10.1152/ajpcell.00324.2011

Cited by 17 publications

(28 citation statements)

References 59 publications

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“…The Relaxed State of the Voltage Sensor Is Destabilized by Extracellular Protons hERG channel deactivation kinetics are sensitive to changes in the extracellular proton concentration and numerous studies have shown that acidosis accelerates deactivation rate (Anumonwo et al, 1999;Bérubé et al, 1999;Jiang et al, 1999;Terai et al, 2000;Bett and Rasmusson, 2003;Du et al, 2010;Zhou and Bett, 2010;Du et al, 2011;Van Slyke et al, 2012;Shi et al, 2014;Shi et al, 2019). pH reductions within the physiological range (as low as pH 6.5) accelerated both the fast and the slow components of deactivation with a pKa of~6.8 (Bett and Rasmusson, 2003;Shi et al, 2019) with little effect channel conductance, and other voltage-dependent gating parameters (Jiang et al, 1999;Bett and Rasmusson, 2003;Shi et al, 2019).…”

Section: Targeted Modulation Of Herg Voltage Sensor Relaxationmentioning

confidence: 99%

Modulation of hERG K+ Channel Deactivation by Voltage Sensor Relaxation

2020

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The hERG (human-ether-à-go-go-related gene) channel underlies the rapid delayed rectifier current, I kr , in the heart, which is essential for normal cardiac electrical activity and rhythm. Slow deactivation is one of the hallmark features of the unusual gating characteristics of hERG channels, and plays a crucial role in providing a robust current that aids repolarization of the cardiac action potential. As such, there is significant interest in elucidating the underlying mechanistic determinants of slow hERG channel deactivation. Recent work has shown that the hERG channel S4 voltage sensor is stabilized following activation in a process termed relaxation. Voltage sensor relaxation results in energetic separation of the activation and deactivation pathways, producing a hysteresis, which modulates the kinetics of deactivation gating. Despite widespread observation of relaxation behaviour in other voltage-gated K + channels, such as Shaker, Kv1.2 and Kv3.1, as well as the voltage-sensing phosphatase Ci-VSP, the relationship between stabilization of the activated voltage sensor by the open pore and voltage sensor relaxation in the control of deactivation has only recently begun to be explored. In this review, we discuss present knowledge and questions raised related to the voltage sensor relaxation mechanism in hERG channels and compare structure-function aspects of relaxation with those observed in related ion channels. We focus discussion, in particular, on the mechanism of coupling between voltage sensor relaxation and deactivation gating to highlight the insight that these studies provide into the control of hERG channel deactivation gating during their physiological functioning.

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Section: Targeted Modulation Of Herg Voltage Sensor Relaxationmentioning

confidence: 99%

Modulation of hERG K+ Channel Deactivation by Voltage Sensor Relaxation

2020

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“…Slowing of activation gating by external protons was reported for Kv10.1 (Terlau et al, 1996) and Kv11.1 (Zhou and Bett, 2010) but not Kv12.1 (Shi et al, 1998). Extracellular pH also accelerates Kv11.1 deactivation (Anumonwo et al, 1999; Jiang et al, 1999) and decreases its open channel conductance via proton pore block (Van Slyke et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

External pH modulates EAG superfamily K+ channels through EAG-specific acidic residues in the voltage sensor

Kazmierczak

Zhang

Chen

et al. 2013

Journal of General Physiology

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The Ether-a-go-go (EAG) superfamily of voltage-gated K+ channels consists of three functionally distinct gene families (Eag, Elk, and Erg) encoding a diverse set of low-threshold K+ currents that regulate excitability in neurons and muscle. Previous studies indicate that external acidification inhibits activation of three EAG superfamily K+ channels, Kv10.1 (Eag1), Kv11.1 (Erg1), and Kv12.1 (Elk1). We show here that Kv10.2, Kv12.2, and Kv12.3 are similarly inhibited by external protons, suggesting that high sensitivity to physiological pH changes is a general property of EAG superfamily channels. External acidification depolarizes the conductance–voltage (GV) curves of these channels, reducing low threshold activation. We explored the mechanism of this high pH sensitivity in Kv12.1, Kv10.2, and Kv11.1. We first examined the role of acidic voltage sensor residues that mediate divalent cation block of voltage activation in EAG superfamily channels because protons reduce the sensitivity of Kv12.1 to Zn2+. Low pH similarly reduces Mg2+ sensitivity of Kv10.1, and we found that the pH sensitivity of Kv11.1 was greatly attenuated at 1 mM Ca2+. Individual neutralizations of a pair of EAG-specific acidic residues that have previously been implicated in divalent block of diverse EAG superfamily channels greatly reduced the pH response in Kv12.1, Kv10.2, and Kv11.1. Our results therefore suggest a common mechanism for pH-sensitive voltage activation in EAG superfamily channels. The EAG-specific acidic residues may form the proton-binding site or alternatively are required to hold the voltage sensor in a pH-sensitive conformation. The high pH sensitivity of EAG superfamily channels suggests that they could contribute to pH-sensitive K+ currents observed in vivo.

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“…Effects of pH i on ion channel function have been suggested to play a role in vascular cells . In the context of the present study, it is relevant to note that most K + channels are inhibited at low rather than high pH i (Xu et al 1996;Schubert et al 2001;Mao et al 2003;Van Slyke et al 2012) and hence inhibition of IK and SK channels is an unlikely explanation for the reduced EDH. This conclusion is further supported by our observation that the EC hyperpolarisation upon acetylcholine stimulation was not significantly affected by CO 2 /HCO 3 − -free conditions.…”

Section: Figure 8 Intercellular Dye Coupling (Propidium Iodide) Is Amentioning

confidence: 82%

“…2001; Mao et al . 2003; Van Slyke et al . 2012) and hence inhibition of IK and SK channels is an unlikely explanation for the reduced EDH.…”

Section: Discussionmentioning

confidence: 99%

Endothelial alkalinisation inhibits gap junction communication and endothelium‐derived hyperpolarisations in mouse mesenteric arteries

Boedtkjer

Kim

Aalkjær

2013

The Journal of Physiology

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Key points• Gap junctions are important for coordination and transfer of signals between cells. Signals initiated in the vascular endothelium can spread through myoendothelial gap junctions and cause relaxation of coupled vascular smooth muscle cells.• The cellular level of acidity is important for control of vascular function. The mechanisms linking disturbed acid-base balance to changes in vascular tone have not been understood in detail.• We show that intracellular alkalinisation of endothelial cells in resistance arteries inhibits myoendothelial coupling and endothelium-dependent vasorelaxation. Although hyperpolarisations are generated in the endothelial cells under alkaline conditions, they are not transferred to the smooth muscle cells. Similarly, dye transfer between endothelial cells is inhibited during intracellular alkalinisation.• These results support the suggestion that intracellular pH is important for control of gap junction conductivity and intercellular communication. We describe a potential new molecular mechanism for development of vascular dysfunction in pathologies (e.g. diabetes, hypertension) involving altered myoendothelial signalling.Abstract Gap junctions mediate intercellular signalling in arteries and contribute to endothelium-dependent vasorelaxation, conducted vascular responses and vasomotion. Considering its putative role in vascular dysfunction, mechanistic insights regarding the control of gap junction conductivity are required. Here, we investigated the consequences of endothelial alkalinisation for gap junction communication and endothelium-dependent vasorelaxation in resistance arteries. We studied mesenteric arteries from NMRI mice by myography, confocal fluorescence microscopy and electrophysiological techniques. Removing CO 2 /HCO 3 − , reducing extracellular [Cl − ] or adding 4,4 -diisothiocyanatostilbene-2,2 -disulphonic acid inhibited or reversed Cl − /HCO 3 − exchange, alkalinised the endothelium by 0.2-0.3 pH units and inhibited acetylcholine-induced vasorelaxation. NO-synthase-dependent vasorelaxation was unaffected by endothelial alkalinisation whereas vasorelaxation dependent on small-and intermediate-conductance Ca 2+ -activated K + channels was attenuated by ∼75%. The difference in vasorelaxation between arteries with normal and elevated endothelial intracellular pH (pH i ) was abolished by the gap junction inhibitors 18β-glycyrrhetinic acid and carbenoxolone while other putative modulators of endothelium-derived hyperpolarisations -Ba 2+ , ouabain, iberiotoxin, 8Br-cAMP and polyethylene glycol catalase -had no effect. In the absence of CO 2 /HCO 3 − , addition of the Na acetylcholine were unaffected by omission of CO 2 /HCO 3 − . By contrast, dye transfer between endothelial cells and endothelium-derived hyperpolarisations of vascular smooth muscle cells stimulated by acetylcholine or the proteinase-activated receptor 2 agonist SLIGRL-amide were inhibited in the absence of CO 2 /HCO 3 − . We conclude that intracellular alkalinisation of endothelial cells attenu...

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Proton block of the pore underlies the inhibition of hERG cardiac K⁺ channels during acidosis

Abstract: Van Slyke AC, Cheng YM, Mafi P, Allard CR, Hull CM, Shi YP, Claydon TW. Proton block of the pore underlies the inhibition of hERG cardiac K ϩ channels during acidosis.

Cited by 17 publications

References 59 publications

Modulation of hERG K+ Channel Deactivation by Voltage Sensor Relaxation

Modulation of hERG K+ Channel Deactivation by Voltage Sensor Relaxation

External pH modulates EAG superfamily K+ channels through EAG-specific acidic residues in the voltage sensor

Endothelial alkalinisation inhibits gap junction communication and endothelium‐derived hyperpolarisations in mouse mesenteric arteries

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Proton block of the pore underlies the inhibition of hERG cardiac K+ channels during acidosis

Abstract: Van Slyke AC, Cheng YM, Mafi P, Allard CR, Hull CM, Shi YP, Claydon TW. Proton block of the pore underlies the inhibition of hERG cardiac K ϩ channels during acidosis.

Cited by 17 publications

References 59 publications

Modulation of hERG K+ Channel Deactivation by Voltage Sensor Relaxation

Modulation of hERG K+ Channel Deactivation by Voltage Sensor Relaxation

External pH modulates EAG superfamily K+ channels through EAG-specific acidic residues in the voltage sensor

Endothelial alkalinisation inhibits gap junction communication and endothelium‐derived hyperpolarisations in mouse mesenteric arteries

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Product

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Proton block of the pore underlies the inhibition of hERG cardiac K⁺ channels during acidosis