Activation of Expressed KCNQ Potassium Currents and Native Neuronal M-Type Potassium Currents by the Anti-Convulsant Drug Retigabine

Tatulian, Lucine; Delmas, Patrick; Abogadie, Fe C.; Da, Brown

doi:10.1523/jneurosci.21-15-05535.2001

Cited by 379 publications

(460 citation statements)

References 38 publications

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“…Retigabine, an antiepileptic drug that was recently approved for clinical use, has been shown to activate native M-type currents (34), as well as KCNQ2, KCNQ3, KCNQ4, and KCNQ5 currents (25). A tryptophan residue in the S5 segment of KCNQ subunits is crucial for the effects of retigabine (25), although additional residues have also been implicated (16).…”

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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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%

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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“…Retigabine was subsequently shown to activate all four KCNQ isoforms expressed in the brain (KCNQ2-5), but not the isoform responsible for the cardiac M-current (KCNQ1). 151 Study of chimeras derived from KCNQ1-KCNQ2 152 or KCNQ1-KCNQ3 151 showed that S5, S6, and the pore loop contribute to retigabine sensitivity. Point mutations further indicated that a tryptophan residue on the cytoplasmic end of S5 is essential for the action of retigabine.…”

Section: Voltage-gated Potassium Channelsmentioning

confidence: 99%

Molecular Targets for Antiepileptic Drug Development

2007

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Summary:This review considers how recent advances in the physiology of ion channels and other potential molecular targets, in conjunction with new information on the genetics of idiopathic epilepsies, can be applied to the search for improved antiepileptic drugs (AEDs). Marketed AEDs predominantly target voltage-gated cation channels (the ␣ subunits of voltagegated Na ϩ channels and also T-type voltage-gated Ca 2ϩ channels) or influence GABA-mediated inhibition. Recently, ␣2-␦ voltage-gated Ca 2ϩ channel subunits and the SV2A synaptic vesicle protein have been recognized as likely targets. Genetic studies of familial idiopathic epilepsies have identified numerous genes associated with diverse epilepsy syndromes, including genes encoding Na ϩ channels and GABA A receptors, which are known AED targets. A strategy based on genes associated with epilepsy in animal models and humans suggests other potential AED targets, including various voltage-gated Ca 2ϩ channel subunits and auxiliary proteins, A-or M-type voltage-gated K ϩ channels, and ionotropic glutamate receptors. Recent progress in ion channel research brought about by molecular cloning of the channel subunit proteins and studies in epilepsy models suggest additional targets, including G-protein-coupled receptors, such as GABA B and metabotropic glutamate receptors; hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channel subunits, responsible for hyperpolarization-activated current I h ; connexins, which make up gap junctions; and neurotransmitter transporters, particularly plasma membrane and vesicular transporters for GABA and glutamate. New information from the structural characterization of ion channels, along with better understanding of ion channel function, may allow for more selective targeting. For example, Na ϩ channels underlying persistent Na ϩ currents or GABA A receptor isoforms responsible for tonic (extrasynaptic) currents represent attractive targets. The growing understanding of the pathophysiology of epilepsy and the structural and functional characterization of the molecular targets provide many opportunities to create improved epilepsy therapies.

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“…In heterologous expression systems, it primarily targets KCNQ3-containing channels and, to a lesser extent, KCNQ2 homomers (9). Bath application of retigabine to hippocampal CA1 pyramidal cells from wild-type mice led to the rapid development of an outward current reflecting the opening of KCNQ channels ( Fig.…”

Section: Role Of Kcnq3 In the Imahp In Hippocampusmentioning

confidence: 99%

Contribution of KCNQ2 and KCNQ3 to the medium and slow afterhyperpolarization currents

Tzingounis

Nicoll

2008

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

125

143

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Benign familial neonatal convulsion (BNFC) is a neurological disorder caused by mutations in the potassium channel genes KCNQ2 and KCNQ3, which are thought to contribute to the medium afterhyperpolarization (mAHP). Despite their importance in normal brain function, it is unknown whether they invariably function as heteromeric complexes. Here, we examined the contribution of KCNQ3 and KCNQ2 in mediating the apamin-insensitive mAHP current (ImAHP) in hippocampus. The ImAHP was not impaired in CA1 pyramidal neurons from mice genetically deficient for either KCNQ3 or KCNQ2 but was reduced Ϸ50% in dentate granule cells. While recording from KCNQ-deficient mice, we observed that the calcium-activated slow afterhyperpolarization current (IsAHP) was also reduced in dentate granule cells, suggesting that KCNQ channels might also contribute to this potassium current whose molecular identity is unknown. Further pharmacological and molecular experiments manipulating KCNQ channels provided evidence in support of this possibility. Together our data suggest that multiple KCNQ subunit compositions can mediate the ImAHP, and that the very same subunits may also contribute to the IsAHP. We also present data suggesting that the neuronal calcium sensor protein hippocalcin may allow for these dual signaling processes.Epilepsy ͉ KCNQ ͉ M-current ͉ Retigabine ͉ sAHP

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Activation of Expressed KCNQ Potassium Currents and Native Neuronal M-Type Potassium Currents by the Anti-Convulsant Drug Retigabine

Cited by 379 publications

References 38 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

Molecular Targets for Antiepileptic Drug Development

Contribution of KCNQ2 and KCNQ3 to the medium and slow afterhyperpolarization currents

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