KCNQ potassium channels: physiology, pathophysiology, and pharmacology

Robbins, Jon

doi:10.1016/s0163-7258(01)00116-4

Cited by 394 publications

(402 citation statements)

References 120 publications

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“…We tested the effect of several K ϩ channel blockers on the M-type current. Linopirdine, a relatively specific blocker of recombinant and native KCNQ channels (22), was an effective inhibitor of the M-type current in the micromolar range. Figure 3A shows families of whole cell currents recorded in the absence and presence of 300 nM linopirdine.…”

Section: Resultsmentioning

confidence: 99%

“…Figure 3C summarizes the results of five experiments in which various concentrations of linopirdine were tested. The smooth curve is the best fit of the data to a first-order equation describing 1:1 binding of linopirdine to the channel with an apparent IC 50 of 0.5 M. XE991, a structurally related and more potent inhibitor of KCNQ channels (22), blocked the M-type conductance with an apparent IC 50 of 0.3 Ϯ 0.1 M (n ϭ 3; not shown); at 10 M, XE991 completely blocked the M-type current (2.5 Ϯ 1.5% of control, n ϭ 9). Blockade of the M-type current by 10 M linopirdine and 10 M XE991 depolarized V 0 from Ϫ56.0 Ϯ 3.8 to Ϫ36.7 Ϯ 7.8 mV (P Ͻ 0.002, n ϭ 8) and from Ϫ54.4 Ϯ 4.7 to Ϫ40.5 Ϯ 8.1 mV (P Ͻ 0.005, n ϭ 8), respectively.…”

Section: Resultsmentioning

confidence: 99%

“…In addition to regulating excitability in neurons and cardiac myocytes, KCNQ/KCNE channels also help set the membrane potential in certain epithelia (22). Recently, we demonstrated that the M-type current in monkey RPE is blocked by the KCNQ channel blocker XE991 and that this tissue expresses transcripts for KCNQ1, KCNQ4, and KCNQ5 (41), establishing these subunits as candidates for the M-type channel.…”

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confidence: 99%

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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: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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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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“…Perhaps KCNQ4 coassembles with other subunits such as KCNQ5 to form a channel with relatively low TEA sensitivity. A further difference between I TEA in calyces and KCNQ currents is that KCNQ-mediated currents do not generally inactivate (Robbins 2001). However, recent studies have shown that currents mediated by KCNQ4 and 5 are increased by hyperpolarizing prepulses, indicating that inactivation can occur (Seebohm et al 2005;Jensen et al 2007).…”

Section: Tea-sensitive K + Currentmentioning

confidence: 98%

K+ Currents in Isolated Vestibular Afferent Calyx Terminals

Dhawan

Mann

Meredith

et al. 2010

JARO

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Vestibular hair cells transduce mechanical displacements of their hair bundles into an electrical receptor potential which modulates transmitter release and subsequent action potential firing in afferent neurons. To probe ionic mechanisms underlying sensory coding in vestibular calyces, we used the whole-cell patch-clamp technique to record action potentials and K + currents from afferent calyx terminals isolated from the semicircular canals of Mongolian gerbils. Calyx terminals showed minimal current at the mean zero-current potential (−60 mV), but two types of outward K + currents were identified at potentials above −50 mV. The first current was a rapidly activating and inactivating K + current that was blocked by 4-aminopyridine (4-AP, 2.5 mM) and BDS-I (up to 250 nM). The time constant for activation of this current decreased with membrane depolarization to a minimum value of ∼1 ms. The 4-AP-sensitive current showed steady-state inactivation with a half-inactivation of approximately −70 mV. A second, more slowly activating current (activation time constant was 8.5±0.7 ms at −8 mV) was sensitive to TEA (30 mM). The TEA-sensitive current also showed steady-state inactivation with a half-inactivation of −95.4±1.4 mV, following 500-ms duration conditioning pulses. A combination of 4-AP and TEA blocked ∼90% of the total outward current.In current clamp, single Na + -dependent action potentials were evoked following hyperpolarization to potentials more negative than the resting potential. 4-AP application increased action potential width, whereas TEA both increased the width and greatly reduced repolarization of the action potential.

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“…K v 7.1 is found in the heart (Yang et al, 1997) and in epithelial tissues (Schroeder et al, 2000b), whereas K v 7.2 to K v 7.5 are expressed primarily in neurons and are therefore collectively referred to as neuronal (Biervert et al, 1998;Singh et al, 1998;Yang et al, 1998;Kharkovets et al, 2000). All K v 7 channels, with the exception of K v 7.5, have been linked with hereditary diseases: K v 7.1 with cardiac long QT syndrome, K v 7.2 and K v 7.3 with benign neonatal familial convulsions, and K v 7.4 with deafness (for reviews, see Robbins, 2001;Gribkoff, 2003).…”

mentioning

confidence: 99%

Anxiolytic Effects of Maxipost (BMS-204352) and Retigabine via Activation of Neuronal K_v7 Channels

Korsgaard

Hartz²,

Brown³

et al. 2005

J Pharmacol Exp Ther

126

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Neuronal K v 7 channels are recognized as potential drug targets for treating hyperexcitability disorders such as pain, epilepsy, and mania. Hyperactivity of the amygdala has been described in clinical and preclinical studies of anxiety, and therefore, neuronal K v 7 channels may be a relevant target for this indication. In patch-clamp electrophysiology on cell lines expressing K v 7 channel subtypes, Maxipost (BMS-204352) exerted positive modulation of all neuronal K v 7 channels, whereas its Renantiomer was a negative modulator. By contrast, at the K v 7.1 and the large conductance Ca 2ϩ -activated potassium channels, the two enantiomers showed the same effect, namely, negative and positive modulation at the two channels, respectively. At GABA A receptors (␣ 1 ␤ 2 ␥ 2s and ␣ 2 ␤ 2 ␥ 2s ) expressed in Xenopus oocytes, BMS-204352 was a negative modulator, and the R-enantiomer was a positive modulator. The observation that the S-and R-forms exhibited opposing effects on neuronal K v 7 channel subtypes allowed us to assess the potential role of K v 7 channels in anxiety. In vivo, BMS-204352 (3-30 mg/kg) was anxiolytic in the mouse zero maze and marble burying models of anxiety, with the effect in the burying model antagonized by the R-enantiomer (3 mg/kg). Likewise, the positive K v 7 channel modulator retigabine was anxiolytic in both models, and its effect in the burying model was blocked by the K v 7 channel inhibitor 10,10-bis-pyridin-4-ylmethyl-10H-anthracen-9-one (XE-991) (1 mg/kg). Doses at which BMS-204352 and retigabine induce anxiolysis could be dissociated from effects on sedation or memory impairment. In conclusion, these in vitro and in vivo studies provide compelling evidence that neuronal K v 7 channels are a target for developing novel anxiolytics.

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KCNQ potassium channels: physiology, pathophysiology, and pharmacology

Cited by 394 publications

References 120 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

K+ Currents in Isolated Vestibular Afferent Calyx Terminals

Anxiolytic Effects of Maxipost (BMS-204352) and Retigabine via Activation of Neuronal K_v7 Channels

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KCNQ potassium channels: physiology, pathophysiology, and pharmacology

Cited by 394 publications

References 120 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

K+ Currents in Isolated Vestibular Afferent Calyx Terminals

Anxiolytic Effects of Maxipost (BMS-204352) and Retigabine via Activation of Neuronal Kv7 Channels

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Anxiolytic Effects of Maxipost (BMS-204352) and Retigabine via Activation of Neuronal K_v7 Channels