Gabapentin Is a Potent Activator of KCNQ3 and KCNQ5 Potassium Channels

Molecular Pharmacology
Rían W Manville, Geoffrey W Abbott

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.

References

Jul 29, 1998·Neuropharmacology·A StefaniG Bernardi
Jun 1, 2001·Naunyn-Schmiedeberg's Archives of Pharmacology·T M FreimanT J Feuerstein
Dec 19, 2001·Neuropharmacology·C LanneauM N Pangalos
May 22, 2002·Molecular Pharmacology·Anders A JensenHans Bräuner-Osborne
Dec 24, 2002·Seizure : the Journal of the British Epilepsy Association·David J BerryWai Tak Hung
Feb 11, 2003·Epilepsy Research·Motohiro OkadaSunao Kaneko
Jul 3, 2003·Hippocampus·Sandrine BertrandJean-Claude Lacaille
Jul 14, 2004·European Journal of Pharmacology·David A S ParkerDavid I B Kerr
Aug 19, 2004·Epilepsia·Elinor Ben-Menachem
May 4, 2005·CNS Drug Reviews·G Blackburn-MunroR E Blackburn-Munro
May 20, 2005·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Anne SchenzerMichael Schwake
Dec 27, 2005·Current Opinion in Pharmacology·Graeme J Sills
Nov 8, 2006·Proceedings of the National Academy of Sciences of the United States of America·Mark J FieldDic Williams
May 12, 2009·American Journal of Physiology. Heart and Circulatory Physiology·Geraldine A Fuller-BicerArnold Schwartz
May 5, 2011·Journal of Computational Chemistry·Aurélien GrosdidierOlivier Michielin
Jun 1, 2011·Nucleic Acids Research·Aurélien GrosdidierOlivier Michielin
Jul 25, 2012·BMC Bioinformatics·Maria U JohanssonNicolas Guex
Jul 12, 2013·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Alice GuyonJean-Louis Nahon
Sep 4, 2015·Nature Communications·Robin Y KimHarley T Kurata
Apr 8, 2017·Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology·Seungwoo KangJiang-Hong Ye
Sep 6, 2017·Frontiers in Pharmacology·Han-Shen TaeChristopher A Reid
Dec 16, 2017·Expert Opinion on Investigational Drugs·Barbara J MasonFarhad Shadan
Mar 4, 2018·Pharmacological Reviews·Sascha R A Alles, Peter A Smith
May 12, 2018·Nature Communications·Rían W ManvilleGeoffrey W Abbott

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Citations

Mar 19, 2019·Pharmacogenomics·Josiah D Allen, Jeffrey R Bishop
Mar 29, 2020·The Journal of Pharmacology and Experimental Therapeutics·Rían W Manville, Geoffrey W Abbott
Jul 18, 2019·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Rían W Manville, Geoffrey W Abbott
Oct 22, 2019·Assay and Drug Development Technologies·Benjamin WilenkinBirgit T Priest
Jul 10, 2020·Communications Biology·Kaitlyn E Redford, Geoffrey W Abbott
Jul 18, 2020·Frontiers in Physiology·Gema Mondejar-ParreñoAngel Cogolludo
May 3, 2019·Current Pain and Headache Reports·Omar ViswanathAlan D Kaye
Oct 24, 2020·Frontiers in Cellular Neuroscience·Peter A Smith
Mar 24, 2021·Expert Opinion on Therapeutic Targets·E S Nikitin, L V Vinogradova
May 7, 2021·PeerJ·Preeti ManandharMarina Santiago
May 29, 2021·RSC Medicinal Chemistry·Matteo BorginiPeter Wipf
Nov 16, 2021·British Journal of Clinical Pharmacology·Carla Marini, Maria Giardino
Sep 14, 2021·Annual Review of Pharmacology and Toxicology·Kaitlyn E Redford, Geoffrey W Abbott

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