KCNQ5, a Novel Potassium Channel Broadly Expressed in Brain, Mediates M-type Currents

Schroeder, Björn C.; Hechenberger, Mirko; Weinreich, Frank; Kubisch, Christian; Jentsch, Thomas J.

doi:10.1074/jbc.m003245200

Cited by 360 publications

(410 citation statements)

References 41 publications

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“…Figure 2 shows that heterologous expression of homomeric WT Kv7.5 channels yielded voltage-dependent K þ currents that activated slowly upon depolarization with a V 1/2 of activation of À46.2 5 1.8 mV (n ¼ 7), as has been described previously. 8,21 All four aberrant proteins exhibited robust functional expression when expressed as homomers. Compared with WT channels, each altered channel modified gating properties (Figures 2 and 3), and this was evident in the activation (Figure 2A) and deactivation ( Figure 3A) current traces.…”

Section: Resultsmentioning

confidence: 99%

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Loss-of-Function and Gain-of-Function Mutations in KCNQ5 Cause Intellectual Disability or Epileptic Encephalopathy

Lehman

Thouta

Mancini

et al. 2017

The American Journal of Human Genetics

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Section: Resultsmentioning

confidence: 99%

“…Kv7.5 subunits might also co-assemble with Kv7.3 subunits in vivo to contribute to the M-current, 8,21 as well as KCNE1 and KCNE3 (MIM: 604433), which are endogenously expressed in Xenopus oocytes, and we have not explored the effect of the de novo mutations in such protein complexes.…”

Section: Discussionmentioning

confidence: 99%

Loss-of-Function and Gain-of-Function Mutations in KCNQ5 Cause Intellectual Disability or Epileptic Encephalopathy

Lehman

Thouta

Mancini

et al. 2017

The American Journal of Human Genetics

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“…Linopirdine and its more potent analog XE991 have been useful in the study of heterologously ex- M. Although linopirdine and XE991 also block other voltagedependent currents (5,26,38), they do so at higher concentrations (IC 50 Ͼ100 M). We found that the M-type current in RPE cells was quite sensitive to block by linopirdine, with an apparent IC 50 of 0.5 M. Consistent with our previous finding (41), XE991 was also effective, with an apparent IC 50 of 0.3 M. The IC 50 values for the block of the M-type current by linopirdine and XE991 are similar to those of KCNQ1, with IC 50 for block of 9 and 0.8 M, respectively (35), but are about an order of magnitude lower than those of homomeric KCNQ4 and KCNQ5 channels, with IC 50 of 6 -14 and 16 -75 M, respectively (18,27,30). This would seem to argue against the involvement of KCNQ4 or KCNQ5 channels in the M-type current and in favor of KCNQ1, but it is possible that the M-type channel sensitivity to these blockers is influenced by interactions with KCNE subunits or other factors.…”

Section: Discussionmentioning

confidence: 98%

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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“…This profile holds true for all the neuronal K v 7 channel subtypes, whereas for the K v 7.1 subtype both enantiomers block the current. In light of the presence of K v 7.2/7.3 (Saganich et al, 2001) and K v 7.5 (Schroeder et al, 2000a) in the amygdala, and the absence of K v 7.1 in the brain, this implies positive modulators of these channels have a potential as anxiolytics.…”

Section: Discussionmentioning

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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KCNQ5, a Novel Potassium Channel Broadly Expressed in Brain, Mediates M-type Currents

Cited by 360 publications

References 41 publications

Loss-of-Function and Gain-of-Function Mutations in KCNQ5 Cause Intellectual Disability or Epileptic Encephalopathy

Loss-of-Function and Gain-of-Function Mutations in KCNQ5 Cause Intellectual Disability or Epileptic Encephalopathy

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

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

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KCNQ5, a Novel Potassium Channel Broadly Expressed in Brain, Mediates M-type Currents

Cited by 360 publications

References 41 publications

Loss-of-Function and Gain-of-Function Mutations in KCNQ5 Cause Intellectual Disability or Epileptic Encephalopathy

Loss-of-Function and Gain-of-Function Mutations in KCNQ5 Cause Intellectual Disability or Epileptic Encephalopathy

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

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

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Product

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