PI(4,5)P2 and Cholesterol: Synthesis, Regulation, and Functions

Rosenhouse‐Dantsker, Avia; Gazgalis, Dimitris; Logothetis, Diomedes E.

doi:10.1007/978-3-031-21547-6_1

Cited by 3 publications

(2 citation statements)

References 518 publications

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“…The blood toxicity of AmB is dependent on the destruction of the erythrocyte membrane by AmB. In red blood cells, the proportion of cholesterol molecules in membrane lipids is as high as 50 mol% ( Rosenhouse-Dantsker et al, 2023 ). Cholesterol is a regulator of signaling molecules and functional proteins, and it also happens to be the binding site of AmB affinity to cell membranes.…”

Section: Introductionmentioning

confidence: 99%

Effect of high sodium ion level on the interaction of AmB with a cholesterol-rich phospholipid monolayer

Wang,

Qiang,

et al. 2024

Front. Mol. Biosci.

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Invasive fungal infections are a primary reason for high mortality in immunocompromised people, especially in critically ill patients, such as intensive care unit (ICU) patients, advanced cancer patients, or severe burn patients. Hypernatremia also can increase mortality in severely ill patients. Amphotericin B (AmB) is the gold standard for treating infections, but in severely ill patients, AmB can cause hematotoxicity when administered intravenously due to its interaction with cholesterol on red blood cell membranes. This results in limited doses of AmB and affects the treatment of infections. The proportion of cholesterol molecules in membrane lipids in red blood cells is as high as 50 mol%, and the sodium ions can influence the interaction between AmB and lipids on the membrane. Therefore, in the complex clinical situation of a severely ill patient with a fungal infection and hypernatremia, the interaction between amphotericin B and the red blood cell membranes is worth studying in depth. In this work, the interaction between AmB and the dipalmitoyl phosphatidylcholine (DPPC)/cholesterol mixed monolayer in the presence of high sodium ion levels was studied when the proportion of cholesterol was 50%. The results show that the effect of AmB on reducing the monolayer’s area at a high level of sodium ions is slightly stronger at 30 mN/m. The effect of AmB on reducing the elastic modulus of the DPPC/Chol monolayer is significantly weakened by a high sodium ion level, compared with the level of sodium ions at normal physiological concentration. The higher the sodium ion concentration, the weaker the intermolecular force of the DPPC/Chol/AmB mixed monolayers. The scanning electron microscope (SEM) and atomic force microscopy (AFM) observations suggest that at a high sodium ion level, the presence of AmB significantly reduces the surface roughness of the DPPC/Chol monolayer. AmB may bind to cholesterol molecules, and it isolates cholesterol from the monolayer, resulting in a reduced height of the cholesterol-rich monolayer and an increasingly dispersed monolayer region. The results are beneficial to understanding the mechanism of impact of a high sodium ion level on the relationship between AmB and red blood cell membranes rich in cholesterol and are valuable for understanding the hemolytic toxicity of AmB to red blood cells at a high sodium ion level.

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Section: Introductionmentioning

confidence: 99%

Effect of high sodium ion level on the interaction of AmB with a cholesterol-rich phospholipid monolayer

Wang,

Qiang,

et al. 2024

Front. Mol. Biosci.

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“…Transient receptor potential (TRP) channels constitute a superfamily of Ca 2+ -permeable cation channels, which feature striking functional and regulatory heterogeneity 1 . As for other transmembrane proteins, the function of TRP channels is intimately intertwined with the lipid environment, and TRP channels are critically controlled by lipid mediators [2][3][4] . In this regard, transient receptor potential canonical 3 (TRPC3) represents a paradigm for primarily lipid-gated ion channels.…”

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confidence: 99%

PIP2 modulates TRPC3 activity via TRP helix and S4-S5 linker

Clarke,

Skerjanz,

Gsell

et al. 2024

Nat Commun

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The transient receptor potential canonical type 3 (TRPC3) channel plays a pivotal role in regulating neuronal excitability in the brain via its constitutive activity. The channel is intricately regulated by lipids and has previously been demonstrated to be positively modulated by PIP2. Using molecular dynamics simulations and patch clamp techniques, we reveal that PIP2 predominantly interacts with TRPC3 at the L3 lipid binding site, located at the intersection of pre-S1 and S1 helices. We demonstrate that PIP2 sensing involves a multistep mechanism that propagates from L3 to the pore domain via a salt bridge between the TRP helix and S4-S5 linker. Notably, we find that both stimulated and constitutive TRPC3 activity require PIP2. These structural insights into the function of TRPC3 are invaluable for understanding the role of the TRPC subfamily in health and disease, in particular for cardiovascular diseases, in which TRPC3 channels play a major role.

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RAS G-domains allosterically contribute to the recognition of lipid headgroups and acyl chains

Arora,

Mu,

Liang

et al. 2024

Journal of Cell Biology

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Mutant RAS are major contributors to cancer and signal primarily from nanoclusters on the plasma membrane (PM). Their C-terminal membrane anchors are main features of membrane association. However, the same RAS isoform bound to different guanine nucleotides spatially segregate. Different RAS nanoclusters all enrich a phospholipid, phosphatidylserine (PS). These findings suggest more complex membrane interactions. Our electron microscopy-spatial analysis shows that wild-types, G12V mutants, and membrane anchors of isoforms HRAS, KRAS4A, and KRAS4B prefer distinct PS species. Mechanistically, reorientation of KRAS4B G-domain exposes distinct residues, such as Arg 135 in orientation state 1 (OS1) and Arg 73/Arg 102 in OS2, to the PM and differentially facilitates the recognition of PS acyl chains. Allele-specific oncogenic mutations of KRAS4B also shift G-domain reorientation equilibrium. Indeed, KRAS4BG12V, KRAS4BG12D, KRAS4BG12C, KRAS4BG13D, and KRAS4BQ61H associate with PM lipids with headgroup and acyl chain specificities. Distribution of these KRAS4B oncogenic mutants favors different nanoscale membrane topography. Thus, RAS G-domains allosterically facilitate membrane lateral distribution.

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PI(4,5)P2 and Cholesterol: Synthesis, Regulation, and Functions

Cited by 3 publications

References 518 publications

Effect of high sodium ion level on the interaction of AmB with a cholesterol-rich phospholipid monolayer

Effect of high sodium ion level on the interaction of AmB with a cholesterol-rich phospholipid monolayer

PIP2 modulates TRPC3 activity via TRP helix and S4-S5 linker

RAS G-domains allosterically contribute to the recognition of lipid headgroups and acyl chains

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