Lipid-Dependent Regulation of Ion Channels and G Protein–Coupled Receptors: Insights from Structures and Simulations
Abstract
Ion channels and G protein-coupled receptors (GPCRs) are regulated by lipids in their membrane environment. Structural studies combined with biophysical and molecular simulation investigations reveal interaction sites for specific lipids on membrane protein structures. For K channels, PIP 2 plays a key role in regulating Kv and Kir channels. Likewise, several recent cryo-EM structures of TRP channels have revealed bound lipids, including PIP 2 and cholesterol. Among the pentameric ligand-gated ion channel family, structural and biophysical studies suggest the M4 TM helix may act as a lipid sensor, e.g., forming part of the binding sites for neurosteroids on the GABA A receptor. Structures of GPCRs have revealed multiple cholesterol sites, which may modulate both receptor dynamics and receptor oligomerization. PIP 2 also interacts with GPCRs and may modulate their interactions with G proteins. Overall, it is evident that multiple lipid binding sites exist on channels and receptors that modulate their function allosterically and are potential druggable sites.
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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 [11]
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 [11]
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 [11]
DAG activates PKC.
“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 [11]
PI(4,5)P2 is highly negatively charged and can bind unstructured clusters of basic residues on membrane proteins such as ion channels, receptors and cytoskeletal proteins.
“In addition, PI(4,5)P2 is a highly negatively charged lipid and therefore can bind unstructured clusters of basic residues on numerous membrane proteins (for example, ion channels, receptors and cytoskeletal proteins) [3,11] (see Figure 1C).”
From Phosphatidylinositol(4,5)bisphosphate: diverse functions at the plasma membrane (2020) · cites this paper as [11]
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 [11]
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 [11]
Aberrant functions of different PLCs and PI3Ks in disease development are well established.
“Although not covered in this review, the importance of aberrant functions of different PLCs and PI3Ks in disease development is well established and continues to expand [11,62,67,72,134–138].”
From Phosphatidylinositol(4,5)bisphosphate: diverse functions at the plasma membrane (2020) · cites this paper as [11]
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References 176 · Cited by 158
- Authors
- Duncan, A. L., Song, W., & Sansom, M. S. P.
- Affiliations
- University of Oxford (GB)
- Corresponding author
- Sansom, Mark S.P.
- Venue
- Annual Review of Pharmacology and Toxicology
- Publisher
- Annual Reviews
- Published
- 2020-01-06
- Volume
- 60
- Issue
- 1
- Pages
- 31-50
- ISSN
- 0362-1642 (ISSN-L)
- 1545-4304
- OpenAlex
- W2973024451
- Cited by
- 158
- References
- 176
- Citations by year
- 2026: 13 · 2025: 21 · 2024: 23 · 2023: 26 · 2022: 24 · 2021: 29 · 2020: 18 · 2019: 4
- FWCI
- 1.65
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Annual Review of Pharmacology and Toxicology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Wellcome Trust
- Engineering and Physical Sciences Research Council (EP/R029407/1)
- Biotechnology and Biological Sciences Research Council (BB/R00126X/1, 1594364)
- 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 › Molecular Biology › Receptor Mechanisms and Signaling
- Keywords
- G protein-coupled receptors, phosphatidylinositol 4,5-bisphosphate, potassium channels, voltage-gated potassium channels, inwardly rectifying potassium channels, TRP channels, cholesterol binding sites, GABAA receptor, neurosteroids, allosteric regulation, GPCR-G protein coupling, receptor oligomerization
- MeSH terms
- Animals, Binding Sites, Cholesterol, Computer Simulation, Humans, Ion Channels, Ligands, Lipids, Receptors, G-Protein-Coupled
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