KCNQ4 channels expressed in mammalian cells: functional characteristics and pharmacology

Søgaard, Rikke; Ljungstrøm, Trine; Pedersen, Kamilla Angelo; Olesen, Søren‐Peter; Jensen, Bo

doi:10.1152/ajpcell.2001.280.4.c859

Cited by 91 publications

(73 citation statements)

References 30 publications

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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: 88%

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: 88%

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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“…All other chemicals were purchased from Sigma Aldrich. HEK293 cells stably expressing Kv7.4 were a gift from the University of Copenhagen (19).…”

Section: Methodsmentioning

confidence: 99%

G-protein βγ subunits are positive regulators of Kv7.4 and native vascular Kv7 channel activity

Stott¹,

Povstyan²,

Carr³

et al. 2015

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

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Kv7.4 channels are a crucial determinant of arterial diameter both at rest and in response to endogenous vasodilators. However, nothing is known about the factors that ensure effective activity of these channels. We report that G-protein βγ subunits increase the amplitude and activation rate of whole-cell voltage-dependent K + currents sensitive to the Kv7 blocker linopirdine in HEK cells heterologously expressing Kv7.4, and in rat renal artery myocytes. In excised patch recordings, Gβγ subunits (2-250 ng /mL) enhanced the open probability of Kv7.4 channels without changing unitary conductance. Kv7 channel activity was also augmented by stimulation of G-protein-coupled receptors. Gallein, an inhibitor of Gβγ subunits, prevented these stimulatory effects. Moreover, gallein and two other structurally different Gβγ subunit inhibitors (GRK2i and a β-subunit antibody) abolished Kv7 channel currents in the absence of either Gβγ subunit enrichment or G-protein-coupled receptor stimulation. Proximity ligation assay revealed that Kv7.4 and Gβγ subunits colocalized in HEK cells and renal artery smooth muscle cells. Gallein disrupted this colocalization, contracted whole renal arteries to a similar degree as the Kv7 inhibitor linopirdine, and impaired isoproterenol-induced relaxations. Furthermore, mSIRK, which disassociates Gβγ subunits from α subunits without stimulating nucleotide exchange, relaxed precontracted arteries in a linopirdine-sensitive manner. These results reveal that Gβγ subunits are fundamental for Kv7.4 activation and crucial for vascular Kv7 channel activity, which has major consequences for the regulation of arterial tone.Kv7 channels | KCNQ genes | G-protein beta gamma subunits | electrophysiology | vascular biology

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“…These differences include activation of channels at very negative potentials, which was never observed for cloned KCNQ channels, and the activation kinetics, which are much slower in recombinant channels (Wang et al, 1998;Kubisch et al, 1999;Schroeder et al, 2000;Sogaard et al, 2001). The molecular determinants of these differences in channel gating are currently unknown.…”

Section: Kcnq4 Currents In Ihcsmentioning

confidence: 99%

Resting Potential and Submembrane Calcium Concentration of Inner Hair Cells in the Isolated Mouse Cochlea Are Set by KCNQ-Type Potassium Channels

Knipper²,

et al. 2003

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KCNQ4 channels expressed in mammalian cells: functional characteristics and pharmacology

Cited by 91 publications

References 30 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

G-protein βγ subunits are positive regulators of Kv7.4 and native vascular Kv7 channel activity

Resting Potential and Submembrane Calcium Concentration of Inner Hair Cells in the Isolated Mouse Cochlea Are Set by KCNQ-Type Potassium Channels

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