Zinc pyrithione-mediated activation of voltage-gated KCNQ potassium channels rescues epileptogenic mutants

Xiong, Qiaojie; Sun, Haiyan; Li, Min

doi:10.1038/nchembio874

Cited by 108 publications

(168 citation statements)

References 51 publications

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“…Retigabine, which activates KCNQ2, KCNQ3, KCNQ4, and KCNQ5, but not KCNQ1, channels (25), augmented the M-type current, as did ZnPy, a potent opener of all KCNQ channels except KCNQ3 (39). In addition to increasing M-type current amplitude at saturating voltages, both openers also produced hyperpolarizing shifts in V 1/2 and caused marked slowing of deactivation kinetics, effects that have been reported for KCNQ channels.…”

Section: Discussionmentioning

confidence: 85%

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Effects of KCNQ channel modulators on the M-type potassium current in primate retinal pigment epithelium

Pattnaik

Hughes

2012

American Journal of Physiology-Cell Physiology

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Pattnaik BR, Hughes BA. Effects of KCNQ channel modulators on the M-type potassium current in primate retinal pigment epithelium. Am J Physiol Cell Physiol 302: C821-C833, 2012. First published November 30, 2011 doi:10.1152/ajpcell.00269.2011Recently, we demonstrated the expression of KCNQ1, KCNQ4, and KCNQ5 transcripts in monkey retinal pigment epithelium (RPE) and showed that the M-type current in RPE cells is blocked by the specific KCNQ channel blocker XE991. Using patch-clamp electrophysiology, we investigated the pharmacological sensitivity of the M-type current in isolated monkey RPE cells to elucidate the subunit composition of the channel. Most RPE cells exhibited an M-type current with a voltage for half-maximal activation of approximately Ϫ35 mV. The M-type current activation followed a double-exponential time course and was essentially complete within 1 s. The M-type current was inhibited by micromolar concentrations of the nonselective KCNQ channel blockers linopirdine and XE991 but was relatively insensitive to block by 10 M chromanol 293B or 135 mM tetraethylammonium (TEA), two KCNQ1 channel blockers. The M-type current was activated by 1) 10 M retigabine, an opener of all KCNQ channels except KCNQ1, 2) 10 M zinc pyrithione, which augments all KCNQ channels except KCNQ3, and 3) 50 M N-ethylmaleimide, which activates KCNQ2, KCNQ4, and KCNQ5, but not KCNQ1 or KCNQ3, channels. Application of cAMP, which activates KCNQ1 and KCNQ4 channels, had no significant effect on the M-type current. Finally, diclofenac, which activates KCNQ2/3 and KCNQ4 channels but inhibits KCNQ5 channels, inhibited the M-type current in the majority of RPE cells but activated it in others. The results indicate that the M-type current in monkey RPE is likely mediated by channels encoded by KCNQ4 and KCNQ5 subunits. ion channels; patch clamp THE RETINAL PIGMENT EPITHELIUM (RPE) carries out a host of functions that are critical to the integrity of the adjacent photoreceptors, including the phagocytosis of outer segments, the regeneration of photopigment, and the supply of nutrients and removal of wastes (31). In addition, the RPE helps control the volume and ionic composition of fluid in the subretinal space, the extracellular compartment that is bounded by the photoreceptor outer segments and the apical aspects of the RPE and Müller (radial glial) cells (9). Photoreceptor function critically depends on the maintenance of subretinal K ϩ concentration within narrow limits, which is achieved by K ϩ transport mechanisms in the RPE and Müller cells.K ϩ channels in the RPE apical and basolateral membranes play pivotal roles in K ϩ secretion and absorption and strongly influence anion and fluid absorption, as well as mechanisms governing RPE intracellular Ca 2ϩ and pH homeostasis (9).Although various classes of K ϩ current have been described in cultured RPE cells (37), in native RPE cells there appear to be two principal types that are active at physiological voltages: an inwardly rectifying K ϩ current (11) and a sustained, outwardly ...

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Section: Discussionmentioning

confidence: 85%

“…ZnPy, a reversible and potent opener of all KCNQ channels except KCNQ3 (39), also augmented the M-type current in monkey RPE cells. The results are summarized in Fig.…”

Section: Resultsmentioning

confidence: 99%

Effects of KCNQ channel modulators on the M-type potassium current in primate retinal pigment epithelium

Pattnaik

Hughes

2012

American Journal of Physiology-Cell Physiology

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“…Several compounds that activate KCNQ channels have been described, including retigabine (17,18), R-L3 (19), and zinc pyrithione (20). Retigabine and R-L3 enhance the magnitude and slow the deactivation of KCNQ2-5 and KCNQ1 channel currents, respectively, and both compounds interact with residues in the S5 and S6 domains of the KCNQ subunits (17)(18)(19).…”

Section: Scanning Mutagenesis Identifies a Putative Binding Site For mentioning

confidence: 99%

Structural basis of action for a human ether-a-go-go-related gene 1 potassium channel activator

Perry

Sachse

Sanguinetti

2007

Proc. Natl. Acad. Sci. U.S.A.

133

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Activation of human ether-a-go-go-related gene 1 (hERG1) K ؉ channels mediates cardiac action potential repolarization. Drugs that activate hERG1 channels represent a mechanism-based approach for the treatment of long QT syndrome, a disorder of cardiac repolarization associated with ventricular arrhythmia and sudden death. Here, we characterize the mechanisms of action and the molecular determinants for binding of RPR260243 [(3R,4R)-4-[3-(6-methoxy-quinolin-4-yl)-3-oxo-propyl]-1-[3-(2,3,5-trifluorophenyl)-prop-2-ynyl]-piperidine-3-carboxylic acid] (RPR), a recently discovered hERG1 channel activator. Channels were heterologously expressed in Xenopus laevis oocytes, and currents were measured by using the two-microelectrode voltage-clamp technique. RPR induced a concentration-dependent slowing in the rate of channel deactivation and enhanced current magnitude by shifting the voltage dependence of inactivation to more positive potentials. This mechanism was confirmed by demonstrating that RPR slowed the rate of deactivation, but did not increase current magnitude of inactivation-deficient mutant channels. The effects of RPR on hERG1 kinetics and magnitude could be simulated by reducing three rate constants in a Markov model of channel gating. Point mutations of specific residues located in the S4 -S5 linker or cytoplasmic ends of the S5 and S6 domains greatly attenuated or ablated the effects of 3 M RPR on deactivation (five residues), inactivation (one residue), or both gating mechanisms (four residues). These findings define a putative binding site for RPR and confirm the importance of an interaction between the S4 -S5 linker and the S6 domain in electromechanical coupling of voltage-gated K ؉ channels.voltage clamp ͉ Xenopus ͉ long QT syndrome H uman ether-a-go-go-related gene 1 (hERG1) ␣-subunits coassemble to form channels that conduct I Kr (1-3), the rapid delayed rectifier K ϩ current that contributes to normal repolarization of cardiac action potentials (4). Loss-of-function mutations in hERG1 cause inherited long QT syndrome (LQTS), a disorder characterized by delayed repolarization of ventricular action potentials and prolonged QT interval of the body surface electrocardiogram (5). The acquired form of LQTS is more common and is most often caused by unintended block of hERG1 channels by a plethora of common medications (6). Inherited and acquired LQTS are associated with an increased risk of torsades de pointes, an arrhythmia that can degenerate into ventricular fibrillation and cause sudden death (7).Current treatments for inherited LQTS include the administration of ␤-adrenergic receptor blockers, left cardiac sympathetic denervation, or implantation of cardiac defibrillators for the most severe cases (8). However, pharmacologic treatment is not always effective (9) and surgery or devices are expensive and require invasive procedures. Acute episodes of drug-induced LQTS are treated with magnesium sulfate administration and discontinued use of the suspect medication. Activation of hERG1 could provide an...

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“…Acrylamide (S)-1 and meclofenamic acid also opens the channel [165,166]. Another recently described substance, zinc pyrithione (ZnPy), also opens KCNQ channels [167]. However, the mechanisms are different and the sites of action differ.…”

Section: Small-molecule K-channel Openersmentioning

confidence: 99%

“…[168,169]. ZnPy interacts with crucial residues in the outer end of S5 and the pore helix [167]. The effects of the two substances are additive [170].…”

Section: Small-molecule K-channel Openersmentioning

confidence: 99%

Structure, Function, and Modification of the Voltage Sensor in Voltage-Gated Ion Channels

Börjesson

Elinder

2008

Cell Biochem Biophys

121

146

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Voltage-gated ion channels are crucial for both neuronal and cardiac excitability. Decades of research have begun to unravel the intriguing machinery behind voltage sensitivity. Although the details regarding the arrangement and movement in the voltage-sensing domain are still debated, consensus is slowly emerging. There are three competing conceptual models: the helical-screw, the transporter, and the paddle model. In this review we explore the structure of the activated voltage-sensing domain based on the recent X-ray structure of a chimera between Kv1.2 and Kv2.1. We also present a model for the closed state. From this we conclude that upon depolarization the voltage sensor S4 moves ~13 Å outwards and rotates ~180º, thus consistent with the helical-screw model. S4 also moves relative to S3b which is not consistent with the paddle model. One interesting feature of the voltage sensor is that it partially faces the lipid bilayer and therefore can interact both with the membrane itself and with physiological and pharmacological molecules reaching the channel from the membrane.This type of channel modulation is discussed together with other mechanisms for how voltage-sensitivity is modified. Small effects on voltage-sensitivity can have profound effects on excitability. Therefore, medical drugs designed to alter the voltage dependence offer an interesting way to regulate excitability.3

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Zinc pyrithione-mediated activation of voltage-gated KCNQ potassium channels rescues epileptogenic mutants

Cited by 108 publications

References 51 publications

Effects of KCNQ channel modulators on the M-type potassium current in primate retinal pigment epithelium

Effects of KCNQ channel modulators on the M-type potassium current in primate retinal pigment epithelium

Structural basis of action for a human ether-a-go-go-related gene 1 potassium channel activator

Structure, Function, and Modification of the Voltage Sensor in Voltage-Gated Ion Channels

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