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Cited by 523Ion channel regulation and functionIon Transport and Channel RegulationNeuroscience and Neuropharmacology Research

PIP2 Activates KCNQ Channels, and Its Hydrolysis Underlies Receptor-Mediated Inhibition of M Currents

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Zhang, Hailin, Craciun, Liviu C, Mirshahi, Tooraj, Rohács, Tibor, Lopes, Coeli M.B, Jin, Taihao, Logothetis, Diomedes E·2003·Neuron
DOI 10.1016/s0896-6273(03)00125-9
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Abstract

KCNQ channels belong to a family of potassium ion channels with crucial roles in physiology and disease. Heteromers of KCNQ2/3 subunits constitute the neuronal M channels. Inhibition of M currents, by pathways that stimulate phospholipase C activity, controls excitability throughout the nervous system. Here we show that a common feature of all KCNQ channels is their activation by the signaling membrane phospholipid phosphatidylinositol-bis-phosphate (PIP(2)). We show that wortmannin, at concentrations that prevent recovery from receptor-mediated inhibition of M currents, blocks PIP(2) replenishment to the cell surface. Moreover, we identify a C-terminal histidine residue, immediately proximal to the plasma membrane, mutation of which renders M channels less sensitive to PIP(2) and more sensitive to receptor-mediated inhibition. Finally, native or recombinant channels inhibited by muscarinic agonists can be activated by PIP(2). Our data strongly suggest that PIP(2) acts as a membrane-diffusible second messenger to regulate directly the activity of KCNQ currents.

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  • KCNQ channels are maintained in the open state by PI(4,5)P2; M1 receptor activation via Gαq/PLCβ1 causes a robust decrease in PI(4,5)P2 and channel closure; IP3 and DAG do not directly contribute; PI(4,5)P2 resynthesis reopens the channels.

    “The best characterised example is the KCNQ channels which are maintained in the open state allowing K+ to move freely (Figure 6B). Upon stimulation with the muscarinic agonist, M1 receptors are activated which couple to Gαq and activate PLCβ1. A robust decrease in PI(4,5)P2 causes channel closure; the PI(4,5)P2 hydrolysis products IP3 and DAG do not contribute directly to channel regulation. Res”

    From Phosphatidylinositol(4,5)bisphosphate: diverse functions at the plasma membrane (2020) · cites this paper as [116]

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Authors
Zhang, H., Craciun, L. C., Mirshahi, T., Rohács, T., Lopes, C. M. B., Jin, T., & Logothetis, D. E.
Affiliations
New York University (US)
Corresponding author
Logothetis, Diomedes E
ORCID
Venue
Neuron
Publisher
Elsevier BV
Published
2003-03
Volume
37
Issue
6
Pages
963-975
ISSN
0896-6273 (ISSN-L)
DOI
10.1016/s0896-6273(03)00125-9
OpenAlex
W2171553829
Cited by
523
References
0
Citations by year
2026: 7 · 2025: 14 · 2024: 14 · 2023: 14 · 2022: 23 · 2021: 27 · 2020: 28 · 2019: 16 · 2018: 21 · 2017: 19 · 2016: 16 · 2015: 24 · 2014: 27 · 2013: 34 · 2012: 24
FWCI
9.79
Type
journal article
Language
en
Open access
Licence
Locations
  • Neuron (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health (1f32gm020856-01, 5f32hl010307-02)
  • National Heart, Lung, and Blood Institute (HL10307, HL 59949, R01HL059949)
  • National Institute of General Medical Sciences (GM20856)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion Transport and Channel Regulation
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
KCNQ channels, M-current, phosphatidylinositol bisphosphate, PIP2 hydrolysis, wortmannin, muscarinic agonists, phospholipase C, neuronal excitability, potassium channels
MeSH terms
Wortmannin, Phosphoinositide-3 Kinase Inhibitors, Androstadienes, Animals, Bradykinin, Cells, Cultured, Electric Conductivity, Enzyme Inhibitors, Female, Cricetinae, Hydrolysis, Mutation, Neurons, Receptors, Muscarinic, Recombinant Proteins, Transfection, Xenopus laevis, Potassium Channels, Second Messenger Systems, Signal Transduction, CHO Cells, Rats, Sprague-Dawley, Superior Cervical Ganglion, Patch-Clamp Techniques, Microscopy, Confocal, Phosphatidylinositol 4,5-Diphosphate, Tetraethylammonium, Potassium Channels, Voltage-Gated, Receptor, Muscarinic M1, Rats, KCNQ2 Potassium Channel, KCNQ3 Potassium Channel

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