Deciphering Melatonin-Stabilized Phase Separation in Phospholipid Bilayers

Abstract

Lipid bilayers are fundamental building blocks of cell membranes, which contain the machinery needed to perform a range of biological functions, including cell−cell recognition, signal transduction, receptor trafficking, viral budding, and cell fusion. Importantly, many of these functions are thought to take place in the laterally phase-separated regions of the membrane, commonly known as lipid rafts.Here, we provide experimental evidence for the "stabilizing" effect of melatonin, a naturally occurring hormone produced by the brain's pineal gland, on phase-separated model membranes mimicking the outer leaflet of plasma membranes. Specifically, we show that melatonin stabilizes the liquidordered/liquid-disordered phase coexistence over an extended range of temperatures. The melatonin-mediated stabilization effect is observed in both nanometer-and micrometer-sized liposomes using small angle neutron scattering (SANS), confocal fluorescence microscopy, and differential scanning calorimetry. To experimentally detect nanoscopic domains in 50 nm diameter phospholipid vesicles, we developed a model using the Landau−Brazovskii approach that may serve as a platform for detecting the existence of nanoscopic lateral heterogeneities in soft matter and biological materials with spherical and planar geometries.

The Release Kinetics of Melatonin from Innovative Dosage Forms: The Role of the Fractal Geometry of the “Vehicle”

“…For example, melatonin stabilizes the liquid-ordered/liquid-disordered phase coexistence over an extended range of temperatures. Melatonin appeared to induce re-ordering effects in liposome and Langmuir monolayers [20].…”

“…In Figure 2, we can also observe that melatonin is located in the interface between head groups and lipid tails, while cholesterol is located parallel to lipid chains [18]. The "stabilizing" effect of melatonin, a naturally occurring hormone produced by the brain's pineal gland, on phase-separated model membranes mimicking the outer leaflet of plasma membranes was also investigated [20]. For example, melatonin stabilizes the liquid-ordered/liquid-disordered phase coexistence over an extended range of temperatures.…”

Melatonin: Regulation of Biomolecular Condensates in Neurodegenerative Disorders

“…Lipid peroxidation also prevents the formation of lipid rafts at room temperature by enhancing phase separation that favors significant increases in the fraction of the non-raft L d phase [ 349 ]. Interestingly, melatonin was observed to stabilize lipid L o –L d phase separation over a range of temperatures and domain sizes, effectively preventing the formation of a non-raft L d phase, possibly by reducing line tension or acting as a surfactant at L o –L d interfaces [ 350 ]. ATP is possibly a surfactant [ 30 , 31 ] capable of reducing the interfacial free energy penalty during the formation of smaller-sized multiple coexisting MLOs, whereas larger droplets may form as a result of lower surfactant ratios [ 351 ].…”

Lateral heterogeneity and domain formation in cellular membranes

“…When the lipids phase separate, an SLD contrast is developed and the neutrons scatter from the compositional variations, directly probing our order parameter ϕ ( x ). (b) Neutron scattering data from lipid vesicles (points) and fits to the microemulsion theory reviewed here (dashed lines), taken from Bolmatov et al ( Bolmatov et al, 2019 ). (c) Neutron scattering data fit to a more detailed, microscopic model of lipid domain configurations, taken from Heberle et al ( Heberle et al, 2013 ).…”

“…Such a phenomenological approach was used successfully to interpret scattering data of lipid vesicles in the presence of melatonin ( Bolmatov et al, 2019 ) – although a true microemulsion phase could not be established as the scattering data was also consistent with ℓ 0 = 0 (a regular phase-separated phase). Fits using the microemulsion theory are shown in Fig.…”