Direct neurotransmitter activation of voltage-gated potassium channels

Nature Communications
Rían W ManvilleGeoffrey W Abbott

Abstract

Voltage-gated potassium channels KCNQ2-5 generate the M-current, which controls neuronal excitability. KCNQ2-5 subunits each harbor a high-affinity anticonvulsant drug-binding pocket containing an essential tryptophan (W265 in human KCNQ3) conserved for >500 million years, yet lacking a known physiological function. Here, phylogenetic analysis, electrostatic potential mapping, in silico docking, electrophysiology, and radioligand binding assays reveal that the anticonvulsant binding pocket evolved to accommodate endogenous neurotransmitters including γ-aminobutyric acid (GABA), which directly activates KCNQ5 and KCNQ3 via W265. GABA, and endogenous metabolites β-hydroxybutyric acid (BHB) and γ-amino-β-hydroxybutyric acid (GABOB), competitively and differentially shift the voltage dependence of KCNQ3 activation. Our results uncover a novel paradigm: direct neurotransmitter activation of voltage-gated ion channels, enabling chemosensing of the neurotransmitter/metabolite landscape to regulate channel activity and cellular excitability.

References

Oct 5, 1990·Journal of Molecular Biology·S F AltschulD J Lipman
Feb 7, 1998·Science·C BiervertO K Steinlein
Jan 23, 2004·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Maria MartireMaurizio Taglialatela
May 26, 2004·Biochemical Society Transactions·T L KashN L Harrison
Jun 17, 2004·The Journal of Biological Chemistry·Ingo BöhmeHartmut Lüddens
May 20, 2005·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Anne SchenzerMichael Schwake
Mar 24, 2006·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Vijayalakshmi SanthakumarThomas S Otis
Nov 15, 2006·Comparative Biochemistry and Physiology. Part A, Molecular & Integrative Physiology·G Kass-Simon, Paola Pierobon
Aug 25, 2007·Anesthesia and Analgesia·Liya YangJames M Sonner
Jan 22, 2008·Trends in Pharmacological Sciences·Qiaojie XiongMin Li
Oct 16, 2009·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Delia BelelliDavid W Cope
Jun 11, 2010·Proceedings of the National Academy of Sciences of the United States of America·Anastassios V TzingounisThomas J Jentsch
Oct 12, 2010·Science·Soojung LeeC Justin Lee
May 5, 2011·Journal of Computational Chemistry·Aurélien GrosdidierOlivier Michielin
May 18, 2011·Proceedings of the National Academy of Sciences of the United States of America·Yang LiJianmin Cui
Jun 1, 2011·Nucleic Acids Research·Aurélien GrosdidierOlivier Michielin
Jul 27, 2011·NeuroImage·Felicia KlingerMark S Shapiro
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
Jun 6, 2014·FEMS Microbiology Reviews·Peter LundDaniela De Biase
Nov 29, 2014·Journal of Biosciences·Tae Kyung HyunJu-Sung Kim
Feb 19, 2015·Proceedings of the National Academy of Sciences of the United States of America·Xiaofan LiTimothy Jegla
Sep 4, 2015·Nature Communications·Robin Y KimHarley T Kurata
Feb 19, 2016·Pflügers Archiv : European journal of physiology·Alejandra G PalmaGabriela I Marino

❮ Previous
Next ❯

Citations

Jul 20, 2018·Molecular Pharmacology·Rían W Manville, Geoffrey W Abbott
Oct 2, 2019·Proceedings of the National Academy of Sciences of the United States of America·Rían W ManvilleGeoffrey W Abbott
Nov 24, 2019·The Journal of Pharmacology and Experimental Therapeutics·Rían W ManvilleGeoffrey W Abbott
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
Jul 12, 2020·Epilepsia·Richard KanyoHarley T Kurata
Jun 3, 2020·The Journal of General Physiology·Harley T Kurata
Sep 23, 2018·Nature Communications·Rían W Manville, Geoffrey W Abbott
Feb 26, 2019·Future Medicinal Chemistry·Christian Bock, Andreas Link
Mar 1, 2020·Communications Biology·Rίan W Manville, Geoffrey W Abbott
Oct 22, 2019·Assay and Drug Development Technologies·Benjamin WilenkinBirgit T Priest
Mar 15, 2020·The Journal of Membrane Biology·Sai ShiHailong An
Jul 14, 2020·Frontiers in Physiology·Geoffrey W Abbott
Jul 18, 2020·Frontiers in Physiology·Gema Mondejar-ParreñoAngel Cogolludo
Jun 6, 2020·Frontiers in Pharmacology·Kenny M Van TheemscheAlain J Labro
Jul 10, 2020·Communications Biology·Kaitlyn E Redford, Geoffrey W Abbott
Dec 29, 2020·Epilepsy & Behavior : E&B·Priya MishraSatyendra Kumar Rajput
Dec 17, 2020·International Journal of Molecular Sciences·Xiaoan Wu, H Peter Larsson
May 29, 2021·RSC Medicinal Chemistry·Matteo BorginiPeter Wipf
Jun 27, 2021·European Journal of Pharmacology·Moawiah M Naffaa, Ola A Al-Ewaidat
Oct 16, 2021·Experimental Biology and Medicine·Debanjan BhattacharyaSoma Sengupta
Dec 14, 2021·Frontiers in Molecular Neuroscience·Elva Martin-BatistaTeresa Giraldez
Sep 14, 2021·Annual Review of Pharmacology and Toxicology·Kaitlyn E Redford, Geoffrey W Abbott

❮ Previous
Next ❯

Methods Mentioned

BETA
saturation binding
in vitro transcription
dissection
transfection

Software Mentioned

SwissDock
GraphPad prism
Clampfit
Jmol
BLAST
DeepView
pClamp8
ImageJ
GROMOS
CHARMM

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.