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Cited by 146Ion channel regulation and functionLipid Membrane Structure and BehaviorProtein Kinase Regulation and GTPase Signaling

Lipid agonism: The PIP2 paradigm of ligand-gated ion channels

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Hansen, Scott B.·2015·Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids
DOI 10.1016/j.bbalip.2015.01.011PMC PMC4540326
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Abstract

The past decade, membrane signaling lipids emerged as major regulators of ion channel function. However, the molecular nature of lipid binding to ion channels remained poorly described due to a lack of structural information and assays to quantify and measure lipid binding in a membrane. How does a lipid-ligand bind to a membrane protein in the plasma membrane, and what does it mean for a lipid to activate or regulate an ion channel? How does lipid binding compare to activation by soluble neurotransmitter? And how does the cell control lipid agonism? This review focuses on lipids and their interactions with membrane proteins, in particular, ion channels. I discuss the intersection of membrane lipid biology and ion channel biophysics. A picture emerges of membrane lipids as bona fide agonists of ligand-gated ion channels. These freely diffusing signals reside in the plasma membrane, bind to the transmembrane domain of protein, and cause a conformational change that allosterically gates an ion channel. The system employs a catalog of diverse signaling lipids ultimately controlled by lipid enzymes and raft localization. I draw upon pharmacology, recent protein structure, and electrophysiological data to understand lipid regulation and define inward rectifying potassium channels (Kir) as a new class of PIP2 lipid-gated ion channels.

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  • IP3 mobilises Ca2+ from ER stores.

    “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 [12]

    Section 4.2 identifies IP3 as a second messenger in PLC signaling, and section 4.3 says the IP3 receptor co-localizes with PLC to regulate calcium release. The paper does not specify that this calcium is mobilized from ER stores or explicitly describe IP3 as the trigger. (LLM, conf=0.76)

    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 [12]

    Section 4.2 says PLC activation hydrolyzes PIP2 and links PLC to IP3 second-messenger signaling; section 4.4 says PLC activation generates diacylglycerol. Section 4.3 links the IP3 receptor and PLC to calcium release, but the cited passages do not specify ER stores or say that DAG activates PKC. No page numbers are available in our copy. (LLM, conf=0.83)

    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 [12]

    Section 4.2 describes intact PIP2 as an ion-channel activator, supporting the ion-channel part of the claim. Section 4.4 discusses endocytosis recycling lipid microdomains after signaling, but does not say PIP2 regulates endocytosis; the passages found also do not establish cytoskeletal organisation or exocytosis as PIP2-regulated functions. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • PI3K generates PI(3,4,5)P3, a lipid with wide-ranging functions.

    “The second pathway is phosphoinositide-3-kinase (PI3K) to make PI(3,4,5)P3, a lipid with wide-ranging functions.”

    From Phosphatidylinositol(4,5)bisphosphate: diverse functions at the plasma membrane (2020) · cites this paper as [12]

    Section 4.1 identifies PI3 kinase as the enzyme that generates PIP3 from PIP2, supporting the pathway described. The paper mentions PIP3 signaling in Section 4.5 but does not substantiate the claim that PIP3 has wide-ranging functions. (LLM, conf=0.84)

    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 [12]

    Section 2.3 describes a Kir2.2–PIP2 crystal structure, direct contact with basic residues, and a conformational change that appeared to open the ion pathway. Section 4.5 describes four binding sites in the tetramer, but says one PIP2 molecule is sufficient to activate the channel; it does not establish that each subunit must coordinate one PIP2 molecule to keep it open. The cited passages also do not describe the pocket as conserved. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

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References 117 · Cited by 146

Research works printed but not linked: 117

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Authors
Hansen, S. B.
Affiliations
Scripps Research Institute (US)
Corresponding author
Hansen, Scott B.
ORCID
Hansen, Scott B.
Venue
Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids
Publisher
Elsevier BV
Published
2015-05
Volume
1851
Issue
5
Pages
620-628
ISSN
1388-1981 (ISSN-L)
DOI
10.1016/j.bbalip.2015.01.011
PMC
PMC4540326
OpenAlex
W2013853780
Cited by
146
References
117
Citations by year
2026: 6 · 2025: 12 · 2024: 11 · 2023: 15 · 2022: 9 · 2021: 13 · 2020: 20 · 2019: 23 · 2018: 12 · 2017: 11 · 2016: 11 · 2015: 3
FWCI
1.20
Type
journal article
Language
en
Open access
Licence
Locations
  • Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • SBH (1DP2NS087943-01)
  • NIH Common Fund
  • National Institute of Neurological Disorders and Stroke (NINDS)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Lipid Membrane Structure and Behavior
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Keywords
phosphatidylinositol 2, ligand-gated ion channels, protein-lipid interactions, allosteric gating, inwardly rectifying potassium channels, lipid rafts, plasma membrane, ion channel modulation
MeSH terms
Animals, Humans, Ligands, Membrane Potentials, Models, Molecular, Protein Conformation, Structure-Activity Relationship, Ion Channel Gating, Phosphatidylinositol 4,5-Diphosphate, Membrane Microdomains, Potassium Channels, Inwardly Rectifying, Ligand-Gated Ion Channels

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