Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2022 Jul 23;12(8):727.
doi: 10.3390/membranes12080727.

Inimitable Impacts of Ceramides on Lipid Rafts Formed in Artificial and Natural Cell Membranes

Masanao Kinoshita  1 , Nobuaki Matsumori  1
Affiliations
Review

Inimitable Impacts of Ceramides on Lipid Rafts Formed in Artificial and Natural Cell Membranes

Masanao Kinoshita et al. Membranes (Basel). .

Abstract

Ceramide is the simplest precursor of sphingolipids and is involved in a variety of biological functions ranging from apoptosis to the immune responses. Although ceramide is a minor constituent of plasma membranes, it drastically increases upon cellular stimulation. However, the mechanistic link between ceramide generation and signal transduction remains unknown. To address this issue, the effect of ceramide on phospholipid membranes has been examined in numerous studies. One of the most remarkable findings of these studies is that ceramide induces the coalescence of membrane domains termed lipid rafts. Thus, it has been hypothesised that ceramide exerts its biological activity through the structural alteration of lipid rafts. In the present article, we first discuss the characteristic hydrogen bond functionality of ceramides. Then, we showed the impact of ceramide on the structures of artificial and cell membranes, including the coalescence of the pre-existing lipid raft into a large patch called a signal platform. Moreover, we proposed a possible structure of the signal platform, in which sphingomyelin/cholesterol-rich and sphingomyelin/ceramide-rich domains coexist. This structure is considered to be beneficial because membrane proteins and their inhibitors are separately compartmentalised in those domains. Considering the fact that ceramide/cholesterol content regulates the miscibility of those two domains in model membranes, the association and dissociation of membrane proteins and their inhibitors might be controlled by the contents of ceramide and cholesterol in the signal platform.

Keywords: apoptosis; lipid membranes; lipid rafts; phase separation; signal platforms; transmembrane signalling.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Chemical structures of ceramides, diacylglycerols, phospholipids and cholesterol described in the present article.
Figure 2
Figure 2
Fluorescence micrographs of binary-component giant unilamellar vesicles (GUVs) that underwent phase separation between the ceramide-rich and ceramide-poor (thus, phospholipid-rich) domains. (A) C16:0SM/C16:0Cer (95:5, molar ratio) GUVs containing 0.2 mol % 594neg-PCer1 (ceramide-rich domain marker) and 0.2 mol % 488neg-SM (SM-rich domain marker). (B) Palmitoyl-oleoyl–phosphatidycholine (POPC)/C16:0Cer (95:5, mole ratio) GUVs containing 0.2 mol % 594neg-PCer1 and BODIPY-PC (POPC-rich fluid phase marker). Bars indicate 10 μm. Image brightness and contrast were adjusted for clarity. This figure was adapted with permission from [41]. Copyright 2019 American Chemical Society.
Figure 3
Figure 3
Real-time sphingomyelinase (SMase)-induced coalescence of raft-like ordered domains visualised using total internal reflection fluorescence (TIRF) microscopy. Egg-SM/Chol/dioleoylphosphatidylcholine (DOPC) (5:1:5 in molar ratio) bilayers, which contained 0.5% fluorescently labelled dipalmitoylphosphatidylethanolamine (a non-raft domain marker), were imaged before (A) and at various times after (B–H) injection of 1 U/mL SMase. The dark regions correspond to raft-like domains. (I) Areas of “domains” 1–5 (outlined in panel F) were plotted as a function of time after enzyme injection; the inset shows initial slopes of the curves. The graphs show expansion of the dark patches during the first 0–15 min. This figure was redrawn from [58] with permission from Elsevier (License No. 5334110330270).
Figure 4
Figure 4
AFM images of C16:0SM/Chol/DOPC (2:1:2 molar ratio) bilayers containing 0 (A), 5 (B), and 10 (C) mol % of C16:0Cer. The total mole percentage of SM plus ceramide was kept constant at 40%. All images are 5 × 5 µm with a z-scale of 5 nm. Cross-sections for lines indicated in images (A–C) are shown in a, b, and c, respectively. The Lo domains showed higher membrane thickness while the Ld domains showed lower. Thus, the brighter and darker regions correspond to the Lo and Ld domains, respectively, in these AFM images. Some examples of the convex subdomains for 10% ceramide are indicated by arrows in image C and cross-section c. This figure was adapted with permission from [61]. Copyright 2006 American Chemical Society.
Figure 5
Figure 5
(A,B) Time-of-flight secondary ion mass spectrometry (ToF-SIMS) images for C16:0SM/Chol/DOPC/C16:0Cer-d31 (3:2:4:1 molar ratio) monolayers deposited on the substrate at 30 mN/m. (A) shows distribution of m/z 2 signals due to deuterium in the negative ion mode that is used to monitor the location of deuterated ceramide. (B) shows distribution of m/z 281 signals due to the oleate fragment that was used to monitor DOPC. (C) illustrates chemical structures of newly developed fluorescent ceramide analogues 594neg-PCer1 and 594neg-PCer2 (inclusively termed 594neg-PCer). (D) Fluorescence micrographs of C16:0SM/Chol/DOPC (1:1:1 molar ratio) ternary component GUVs that underwent phase separation between the Lo and Ld domains. This sample contained 0.2 mol % 594neg-PCer1 and BODIPY-PC (Ld marker). (E) Fluorescence micrographs of C16:0SM/Chol/DOPC/C16:0Cer (1:1:1:0.3 mole ratio) quaternary component GUVs. This sample contained (top) 0.2 mol % 594neg-PCer1 and 0.2 mol % NBD-Cer (both Lo and Ld marker) and (bottom) 0.2 mol % Texas Red-DPPE (Ld marker) and 0.2 mol % NBD-Cer. White and yellow arrows indicate the ceramide-rich subdomains and Lo domains, respectively. Bars indicate 10 μm. This figure was adapted with permission from [41,65]. Copyright 2008 and 2019 American Chemical Society.
Figure 6
Figure 6
Chemical structures of 1-OH group substituted ceramide analogues developed in [102,103]. Protective groups are indicated by red colour.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Shabbir M.A., Mehak F., Khan Z.M., Ahmad W., Khan M.R., Zia S., Rahaman A., Aadil R.M. Interplay between ceramides and phytonutrients: New insights in metabolic syndrome. Trends Food Sci. Technol. 2021;111:483–494. doi: 10.1016/j.tifs.2021.03.010. - DOI
    1. Skácel J., Slusher B.S., Tsukamoto T. Small molecule inhibitors targeting biosynthesis of ceramide, the central hub of the sphingolipid network. J. Med. Chem. 2021;64:279–297. doi: 10.1021/acs.jmedchem.0c01664. - DOI - PMC - PubMed
    1. Pant D.C., Aguilera-Albesa S., Pujol A. Ceramide signalling in inherited and multifactorial brain metabolic diseases. Neurobiol. Dis. 2020;143:105014. doi: 10.1016/j.nbd.2020.105014. - DOI - PubMed
    1. Taniguchi M., Okazaki T. Role of ceramide/sphingomyelin (SM) balance regulated through “SM cycle” in cancer. Cell. Signal. 2021;87:110119. doi: 10.1016/j.cellsig.2021.110119. - DOI - PubMed
    1. Stith J.L., Velazquez F.N., Obeid L.M. Advances in determining signaling mechanisms of ceramide and role in disease. J. Lipid Res. 2019;60:913–918. doi: 10.1194/jlr.S092874. - DOI - PMC - PubMed

Grants and funding

Some of the research by authors were supported by KAKENHI (grant numbers 20K06590 and 20H00405) and to M.K. and M.N., respectively.

LinkOut - more resources