Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Mol Pharmacol
2018 Oct 18;944:1155-1163. doi: 10.1124/mol.118.112953.
Show Gene links
Show Anatomy links
Gabapentin Is a Potent Activator of KCNQ3 and KCNQ5 Potassium Channels.
Manville RW
,
Abbott GW
.
???displayArticle.abstract???
Synthetic gabapentinoids, exemplified by gapapentin and pregabalin, are in extensive clinical use for indications including epilepsy, neuropathic pain, anxiety, and alcohol withdrawal. Their mechanisms of action are incompletely understood, but are thought to involve inhibition of α2δ subunit-containing voltage-gated calcium channels. Here, we report that gabapentin is a potent activator of the heteromeric KCNQ2/3 voltage-gated potassium channel, the primary molecular correlate of the neuronal M-current, and also homomeric KCNQ3 and KCNQ5 channels. In contrast, the structurally related gabapentinoid, pregabalin, does not activate KCNQ2/3, and at higher concentrations (≥10 µM) is inhibitory. Gabapentin activation of KCNQ2/3 (EC50 = 4.2 nM) or homomeric KCNQ3* (EC50 = 5.3 nM) channels requires KCNQ3-W265, a conserved tryptophan in KCNQ3 transmembrane segment 5. Homomeric KCNQ2 or KCNQ4 channels are insensitive to gabapentin, whereas KCNQ5 is highly sensitive (EC50 = 1.9 nM). Given the potent effects and the known anticonvulsant, antinociceptive, and anxiolytic effects of M-channel activation, our findings suggest the possibility of an unexpected role for M-channel activation in the mechanism of action of gabapentin.
Alles,
Etiology and Pharmacology of Neuropathic Pain.
2018, Pubmed
Alles,
Etiology and Pharmacology of Neuropathic Pain.
2018,
Pubmed
Asano,
Prevention of the agonist binding to gamma-aminobutyric acid B receptors by guanine nucleotides and islet-activating protein, pertussis toxin, in bovine cerebral cortex. Possible coupling of the toxin-sensitive GTP-binding proteins to receptors.
1985,
Pubmed
Ben-Menachem,
Seizure frequency and CSF parameters in a double-blind placebo controlled trial of gabapentin in patients with intractable complex partial seizures.
1995,
Pubmed
Ben-Menachem,
Selected CSF biochemistry and gabapentin concentrations in the CSF and plasma in patients with partial seizures after a single oral dose of gabapentin.
1992,
Pubmed
Ben-Menachem,
Pregabalin pharmacology and its relevance to clinical practice.
2004,
Pubmed
Berry,
The absorption of gabapentin following high dose escalation.
2003,
Pubmed
Bertrand,
Gabapentin actions on Kir3 currents and N-type Ca2+ channels via GABAB receptors in hippocampal pyramidal cells.
2003,
Pubmed
Bertrand,
Different actions of gabapentin and baclofen in hippocampus from weaver mice.
2003,
Pubmed
Blackburn-Munro,
Retigabine: chemical synthesis to clinical application.
2005,
Pubmed
Brown,
Cloning and deletion mutagenesis of the alpha2 delta calcium channel subunit from porcine cerebral cortex. Expression of a soluble form of the protein that retains [3H]gabapentin binding activity.
1998,
Pubmed
Brown,
Muscarinic suppression of a novel voltage-sensitive K+ current in a vertebrate neurone.
1980,
Pubmed
Brown,
Gabapentin fails to alter P/Q-type Ca2+ channel-mediated synaptic transmission in the hippocampus in vitro.
2005,
Pubmed
Calandre,
Alpha2delta ligands, gabapentin, pregabalin and mirogabalin: a review of their clinical pharmacology and therapeutic use.
2016,
Pubmed
Chen,
The α2δ-1-NMDA Receptor Complex Is Critically Involved in Neuropathic Pain Development and Gabapentin Therapeutic Actions.
2018,
Pubmed
Field,
Identification of the alpha2-delta-1 subunit of voltage-dependent calcium channels as a molecular target for pain mediating the analgesic actions of pregabalin.
2006,
Pubmed
Freiman,
Modulation of K+-evoked [3H]-noradrenaline release from rat and human brain slices by gabapentin: involvement of KATP channels.
2001,
Pubmed
Fuller-Bicer,
Targeted disruption of the voltage-dependent calcium channel alpha2/delta-1-subunit.
2009,
Pubmed
Gee,
The novel anticonvulsant drug, gabapentin (Neurontin), binds to the alpha2delta subunit of a calcium channel.
1996,
Pubmed
Grosdidier,
Fast docking using the CHARMM force field with EADock DSS.
2011,
Pubmed
Grosdidier,
SwissDock, a protein-small molecule docking web service based on EADock DSS.
2011,
Pubmed
Guyon,
Baclofen and other GABAB receptor agents are allosteric modulators of the CXCL12 chemokine receptor CXCR4.
2013,
Pubmed
,
Xenbase
Hoppa,
α2δ expression sets presynaptic calcium channel abundance and release probability.
2012,
Pubmed
Jensen,
The anticonvulsant gabapentin (neurontin) does not act through gamma-aminobutyric acid-B receptors.
2002,
Pubmed
,
Xenbase
Johansson,
Defining and searching for structural motifs using DeepView/Swiss-PdbViewer.
2012,
Pubmed
Kang,
Ethanol Withdrawal Drives Anxiety-Related Behaviors by Reducing M-type Potassium Channel Activity in the Lateral Habenula.
2017,
Pubmed
Kim,
Atomic basis for therapeutic activation of neuronal potassium channels.
2015,
Pubmed
,
Xenbase
Lanneau,
Gabapentin is not a GABAB receptor agonist.
2001,
Pubmed
Manville,
Direct neurotransmitter activation of voltage-gated potassium channels.
2018,
Pubmed
,
Xenbase
Marrion,
Muscarinic suppression of the M-current in the rat sympathetic ganglion is mediated by receptors of the M1-subtype.
1989,
Pubmed
Martin,
Gabapentin-mediated inhibition of voltage-activated Ca2+ channel currents in cultured sensory neurones is dependent on culture conditions and channel subunit expression.
2002,
Pubmed
Mason,
Gabapentin for the treatment of alcohol use disorder.
2018,
Pubmed
McClelland,
A study comparing the actions of gabapentin and pregabalin on the electrophysiological properties of cultured DRG neurones from neonatal rats.
2004,
Pubmed
Ng,
Gamma-aminobutyric acid type B receptors with specific heterodimer composition and postsynaptic actions in hippocampal neurons are targets of anticonvulsant gabapentin action.
2001,
Pubmed
,
Xenbase
Okada,
Age-dependent modulation of hippocampal excitability by KCNQ-channels.
2003,
Pubmed
Parker,
Gabapentin activates presynaptic GABAB heteroreceptors in rat cortical slices.
2004,
Pubmed
Peng,
Gabapentin promotes inhibition by enhancing hyperpolarization-activated cation currents and spontaneous firing in hippocampal CA1 interneurons.
2011,
Pubmed
Rock,
Gabapentin actions on ligand- and voltage-gated responses in cultured rodent neurons.
1993,
Pubmed
Schenzer,
Molecular determinants of KCNQ (Kv7) K+ channel sensitivity to the anticonvulsant retigabine.
2005,
Pubmed
,
Xenbase
Schumacher,
Effects of phenytoin, carbamazepine, and gabapentin on calcium channels in hippocampal granule cells from patients with temporal lobe epilepsy.
1998,
Pubmed
Sills,
The mechanisms of action of gabapentin and pregabalin.
2006,
Pubmed
Stefani,
The effects of gabapentin on different ligand- and voltage-gated currents in isolated cortical neurons.
2001,
Pubmed
Stefani,
Gabapentin inhibits calcium currents in isolated rat brain neurons.
1998,
Pubmed
Stringer,
The reduction in paired-pulse inhibition in the rat hippocampus by gabapentin is independent of GABA(B) receptor receptor activation.
1999,
Pubmed
Sun,
Cryo-EM Structure of a KCNQ1/CaM Complex Reveals Insights into Congenital Long QT Syndrome.
2017,
Pubmed
,
Xenbase
Surges,
Gabapentin increases the hyperpolarization-activated cation current Ih in rat CA1 pyramidal cells.
2003,
Pubmed
Tae,
Gabapentin Modulates HCN4 Channel Voltage-Dependence.
2017,
Pubmed
,
Xenbase
Tatulian,
Activation of expressed KCNQ potassium currents and native neuronal M-type potassium currents by the anti-convulsant drug retigabine.
2001,
Pubmed
Taylor,
Mechanisms of action of gabapentin.
1997,
Pubmed
Tinel,
The KCNQ2 potassium channel: splice variants, functional and developmental expression. Brain localization and comparison with KCNQ3.
1998,
Pubmed
Wang,
KCNQ2 and KCNQ3 potassium channel subunits: molecular correlates of the M-channel.
1998,
Pubmed
,
Xenbase
Zaika,
Determinants within the turret and pore-loop domains of KCNQ3 K+ channels governing functional activity.
2008,
Pubmed
