Chromanol 293B Binding in KCNQ1 (Kv7.1) Channels Involves Electrostatic Interactions with a Potassium Ion in the Selectivity Filter

Lerche, Christian; Bruhova, Iva; Lerche, Holger; Steinmeyer, Klaus; Wei, Aguan; Strutz‐Seebohm, Nathalie; Läng, Florian; Büsch, Andreas; Zhorov, Boris S.; Seebohm, Guiscard

doi:10.1124/mol.106.031682

Cited by 82 publications

(97 citation statements)

References 48 publications

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“…It has been stated that the KCNQ4 channel has an IC 50 for block by TEA of 3 mM (6), but a more recent study reported an IC 50 of ϳ50 mM (2); the latter value is in agreement with our results testing the effect of TEA on hKCNQ4_v1 and hKCNQ4_v2 channels expressed in Chinese hamster ovary cells (unpublished data). In addition, chromanol 293B, which blocks homomeric and heteromeric KCNQ1 channels with an IC 50 of Ͻ30 M (17), blocked only 44% of the M-type current at a concentration of 100 M. The low sensitivity of the M-type current to this drug is consistent with KCNQ4 and KCNQ5 channels, both of which are blocked moderately by 100 M chromanol 293B (17).…”

Section: Discussionsupporting

confidence: 52%

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: Discussionsupporting

confidence: 52%

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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“…KCNQ1/ KCNE3 ionic currents are reduced when the KCNQ1 channel blocker chromanol 293B is applied (Fig. S1A), indicating that the observed current is indeed conducted by channels with KCNQ1 subunits (34) conductance vs. voltage curve, G(V) (reflecting channel opening), in KCNQ1/KCNE3 channels are similarly shifted to negative voltages compared with KCNQ1 channels expressed alone [mean shift: G(V) = -87 ± 5.1 mV and F(V) = -100.7 ± 3.4 mV, n = 15] (Fig. 2C, arrow).…”

Section: Kcne3 Shifts the Equilibrium Of S4 Movement And Gate Opening Tomentioning

confidence: 91%

KCNE3 acts by promoting voltage sensor activation in KCNQ1

Barro-Soria

Perez

Larsson

2015

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

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KCNE β-subunits assemble with and modulate the properties of voltage-gated K + channels. In the colon, stomach, and kidney, KCNE3 coassembles with the α-subunit KCNQ1 to form K + channels important for K + and Cl − secretion that appear to be voltageindependent. How KCNE3 subunits turn voltage-gated KCNQ1 channels into apparent voltage-independent KCNQ1/KCNE3 channels is not completely understood. Different mechanisms have been proposed to explain the effect of KCNE3 on KCNQ1 channels. Here, we use voltage clamp fluorometry to determine how KCNE3 affects the voltage sensor S4 and the gate of KCNQ1. We find that S4 moves in KCNQ1/KCNE3 channels, and that inward S4 movement closes the channel gate. However, KCNE3 shifts the voltage dependence of S4 movement to extreme hyperpolarized potentials, such that in the physiological voltage range, the channel is constitutively conducting. By separating S4 movement and gate opening, either by a mutation or PIP 2 depletion, we show that KCNE3 directly affects the S4 movement in KCNQ1. Two negatively charged residues of KCNE3 (D54 and D55) are found essential for the effect of KCNE3 on KCNQ1 channels, mainly exerting their effects by an electrostatic interaction with R228 in S4. Our results suggest that KCNE3 primarily affects the voltage-sensing domain and only indirectly affects the gate.proteins with a variety of crucial physiological roles. Most Kv channels are expressed in excitable cells where, e.g., they regulate and modulate the resting potential and the threshold and duration of the action potential (1). The KCNQ1 channel (also called Kv7.1 or KvLQT1) differs from most other Kv channels in that it has key physiological roles in both excitable cells, such as cardiomyocytes (2, 3) and pancreatic β-cells (4, 5), and in nonexcitable cells, such as in epithelia (3, 6). The KCNQ1 channels display diverse biophysical properties in different cell types, a diversity thought to be mainly due to the KCNQ1 channel's association with five tissue-specific, single-transmembrane segment KCNE β-subunits (KCNE1-5) (7-13). KCNQ1 α-subunit expressed by itself forms a voltage-dependent K + channel that opens at negative voltages ( Fig. 1 A and D). However, coexpression of KCNQ1 with KCNE1 slows the kinetics of activation and shifts the voltage dependence of activation to positive voltages ( Fig. 1 B and D) (7, 8), thereby generating the slowly activating, voltage-dependent I Ks current that controls the repolarization phase of cardiac action potentials. In contrast, coexpression of KCNQ1 with KCNE3 results in a constitutively conducting channel in the physiological voltage range of -80 to +40 mV ( Fig. 1 C and D), which is important for transport of water and salt in epithelial tissues, including those of the colon, small intestine, and airways (9,14,15). In addition, mutations of KCNE3 have been associated with cardiac arrhythmia (16,17) and diseases in the inner ear, such as Meniere's disease and tinnitus (18,19). Because KCNQ1/KCNE3 channels are necessary for water and salt secretion...

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“…Collectively, these results indicate that the administration of 293B augments insulin secretion in a glucose-dependent manner at the level of islets and intact animal. As 293B has been shown to be an effective pharmacological blocker of KCNQ1 channel, 18,31 these data provide more evidence for the idea that the risk allele of KCNQ1 may increase the expression or up-regulate the function of KCNQ1 and thereby promote the development of T2D. 6 To generate an adequate secretory response, b-cells must receive multiple regulatory signals relaying information about changes in the internal and external environments.…”

Section: Discussionmentioning

confidence: 99%

Chromanol 293B, an inhibitor of KCNQ1 channels, enhances glucose-stimulated insulin secretion and increases glucagon-like peptide-1 level in mice

Liu

Wang

et al. 2014

Islets

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Glucose-stimulated insulin secretion (GSIS) is a highly regulated process involving complex interaction of multiple factors. Potassium voltage-gated channel subfamily KQT member 1 (KCNQ1) is a susceptibility gene for type 2 diabetes (T2D) and the risk alleles of the KCNQ1 gene appear to be associated with impaired insulin secretion. The role of KCNQ1 channel in insulin secretion has been explored by previous work in clonal pancreatic b-cells but has yet to be investigated in the context of primary islets as well as intact animals. Genetic studies suggest that altered incretin glucagon-like peptide-1 (GLP-1) secretion might be a potential link between KCNQ1 variants and impaired insulin secretion, but this hypothesis has not been verified so far. In the current study, we examined KCNQ1 expression in pancreas and intestine from normal mice and then investigated the effects of chromanol 293B, a KCNQ1 channel inhibitor, on insulin secretion in vitro and in vivo. By double-immunofluorescence staining, KCNQ1 was detected in insulin-positive b-cells and GLP-1-positive L-cells. Administration of chromanol 293B enhanced GSIS in cultured islets and intact animals. Along with the potentiated insulin secretion during oral glucose tolerance tests (OGTT), plasma GLP-1 level after gastric glucose load was increased in 293B treated mice. These data not only provided new evidence for the participation of KCNQ1 in GSIS at the level of pancreatic islet and intact animal but also indicated the potential linking role of GLP-1 between KCNQ1 and insulin secretion.

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Chromanol 293B Binding in KCNQ1 (Kv7.1) Channels Involves Electrostatic Interactions with a Potassium Ion in the Selectivity Filter

Cited by 82 publications

References 48 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

KCNE3 acts by promoting voltage sensor activation in KCNQ1

Chromanol 293B, an inhibitor of KCNQ1 channels, enhances glucose-stimulated insulin secretion and increases glucagon-like peptide-1 level in mice

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