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Cited by 85Lipid Membrane Structure and BehaviorIon channel regulation and functionCellular transport and secretion

Tools for Understanding Nanoscale Lipid Regulation of Ion Channels

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Robinson, Carol V., Rohacs, Tibor, Hansen, Scott B.·2019·Trends in Biochemical Sciences
DOI 10.1016/j.tibs.2019.04.001PMC PMC6729126
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Abstract

Anionic phospholipids are minor but prominent components of the plasma membrane that are necessary for ion channel function. Their persistence in bulk membranes, in particular phosphatidylinositol 4,5-bisphosphate (PIP 2), initially suggested they act as channel cofactors. However, recent technologies have established an emerging system of nanoscale signaling to ion channels based on lipid compartmentalization (clustering), direct lipid binding, and local lipid dynamics that allow cells to harness lipid heterogeneity to gate ion channels. The new tools to study lipid binding are set to transform our view of the membrane and answer important questions surrounding ion channel-delimited processes such as mechanosensation.

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Crossref · 10.1016/j.tibs.2019.04.001

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  • PI(4,5)P2 is a substrate for PLC and PI3K.

    “PI(4,5)P2 is a substrate for two signalling pathways.”

    From Phosphatidylinositol(4,5)bisphosphate: diverse functions at the plasma membrane (2020) · cites this paper as [13]

    The ‘Direct versus indirect lipid regulation’ section discusses PIP2-depleting enzymes and identifies phospholipase C (PLC), supporting the PLC part of the paraphrase. Our copy does not identify PI3K or state that PIP2 is its substrate, so it does not establish the claimed two pathways. (LLM, conf=0.80)

    Experimental — accuracy not yet measured

  • PLC hydrolysis of PI(4,5)P2 generates IP3 and DAG.

    “Phospholipase C (PLC) leads to the generation of two second messengers, inositol(1,4,5)trisphosphate (I(1,4,5)P3), known trigger for mobilising Ca2+ from endoplasmic reticulum (ER) stores and diacylglycerol (DAG), an activator for protein kinase C (PKC).”

    From Phosphatidylinositol(4,5)bisphosphate: diverse functions at the plasma membrane (2020) · cites this paper as [13]

    The “Direct versus indirect lipid regulation” section says PIP2 generates second-messenger signals and describes PLC as a PIP2-depleting enzyme. It does not identify IP3 or DAG as the products, or describe their effects on ER calcium release and PKC activation. No page number is available in our copy. (LLM, conf=0.78)

    Experimental — accuracy not yet measured

  • PI(4,5)P2 as an intact lipid regulates cytoskeletal organisation, membrane trafficking including endocytosis and exocytosis, and ion channel regulation.

    “This is important as PI(4,5)P2 as an intact lipid regulates diverse cellular functions, including cytoskeletal organisation and membrane trafficking (including endocytosis and exocytosis) and ion channel regulation [10–13].”

    From Phosphatidylinositol(4,5)bisphosphate: diverse functions at the plasma membrane (2020) · cites this paper as [13]

    The ‘Challenges and opportunities’ and ‘Direct versus indirect lipid regulation’ sections describe PIP2 as a membrane lipid that regulates ion channels, including through direct binding. Our copy does not establish the claimed roles in cytoskeletal organisation or membrane trafficking, including endocytosis and exocytosis. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • The GABAA receptor is a pentamer with two PI(4,5)P2 molecules constitutively associated; the PI(4,5)P2 headgroup occupies a positively charged pocket in the intracellular juxta-membrane region, and PI(4,5)P2 does not regulate channel function.

    “The GABAA receptor is a pentamer and two molecules of PI(4,5)P2 are constitutively associated with the receptor. The negatively charged headgroup of PI(4,5)P2 occupies a positively charged pocket in the intracellular juxta-membrane region of one of the subunits. The function of PI(4,5)P2 is not to regulate channel function.”

    From Phosphatidylinositol(4,5)bisphosphate: diverse functions at the plasma membrane (2020) · cites this paper as [13]

    Split into 3 atoms — 0 confirmed, 3 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

    Experimental — accuracy not yet measured

  • Kir2.2 channel is maintained open by PI(4,5)P2; a crystal structure shows each subunit coordinates a single PI(4,5)P2 molecule in a conserved basic pocket.

    “Another example is the Kir2.2 channel, which is maintained in the open state to allow inflow of K+. A crystal structure of the inward rectifier Kir2.2 channel shows that each subunit directly coordinates a single PI(4,5)P2 molecule in a conserved basic pocket to keep the channel open [12,13].”

    From Phosphatidylinositol(4,5)bisphosphate: diverse functions at the plasma membrane (2020) · cites this paper as [13]

    The CryoEM section (page unavailable) describes an X-ray structure of PIP2 bound at a specific site in Kir2.2 and a conformational change consistent with lipid gating. It does not say that each subunit coordinates exactly one PIP2 molecule in a conserved basic pocket, or establish that PIP2 maintains the channel in an open state. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

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Cites

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Research works printed but not linked: 83

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Cited by

Sorted by citations

Authors
Robinson, C. V., Rohacs, T., & Hansen, S. B.
Affiliations
  • University of Oxford (GB)
  • Scripps Research Institute (US)
Corresponding author
Hansen, Scott B.
ORCID
Venue
Trends in Biochemical Sciences
Publisher
Elsevier BV
Published
2019-09
Volume
44
Issue
9
Pages
795-806
ISSN
0968-0004 (ISSN-L)
DOI
10.1016/j.tibs.2019.04.001
PMC
PMC6729126
OpenAlex
W2943777537
Cited by
85
References
0
Citations by year
2026: 5 · 2025: 7 · 2024: 6 · 2023: 18 · 2022: 15 · 2021: 8 · 2020: 19 · 2019: 5 · 2018: 2
FWCI
1.04
Type
journal article
Language
en
Open access
Licence
Locations
  • Trends in Biochemical Sciences (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Institutes of Health
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Lipid Membrane Structure and Behavior
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
Keywords
anionic phospholipids, ion channels, phosphatidylinositol 4,5-bisphosphate, lipid signaling, lipid clustering, lipid binding, membrane heterogeneity, channel gating, mechanosensing, plasma membrane
MeSH terms
Humans, Ion Channels, Phospholipids, Nanotechnology

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