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Membrane Organization and Ionization Behavior of the Minor but Crucial Lipid Ceramide-1-Phosphate

Edgar E. Kooijman ^*, Jesús Sot , L.-Ruth Montes , Alicia Alonso , Arne Gericke , Ben de Kruijff , Satyendra Kumar ^* ¶ and Felix M. Goñi 

^* Physics Department, Kent State University, Kent, Ohio; Unidad de Biofísica (CSIC-UPV/EHU), and Department of Biochemistry and Molecular Biology, University of the Basque Country, Bilbao, Spain; Chemistry Department, Kent State University, Kent, Ohio; Department of Chemical Biology, Institute of Biomembranes, Bijvoet Center, Utrecht University, Utrecht, The Netherlands; and ^¶ Division of Materials Research, National Science Foundations, Arlington, Virginia

Correspondence: Address reprint requests to Edgar E. Kooijman, E-mail: e.e.kooijman{at}gmail.com.

Ceramide-1-phosphate (Cer-1-P), one of the simplest of all sphingophospholipids, occurs in minor amounts in biological membranes. Yet recent evidence suggests important roles of this lipid as a novel second messenger with crucial tasks in cell survival and inflammatory responses. We present a detailed description of the physical chemistry of this hitherto little explored membrane lipid. At full hydration Cer-1-P forms a highly organized subgel (crystalline) bilayer phase (L_c) at low temperature, which transforms into a regular gel phase (L_β) at 45°C, with the gel to fluid phase transition (L_β–L) occurring at 65°C. When incorporated at 5 mol % in a phosphatidylcholine bilayer, the pK_a2 of Cer-1-P, 7.39 ± 0.03, lies within the physiological pH range. Inclusion of phosphatidylethanolamine in the phosphatidylcholine bilayer, at equimolar ratio, dramatically reduces the pK_a2 to 6.64 ± 0.03. We explain these results in light of the novel electrostatic/hydrogen bond switch model described recently for phosphatidic acid. In mixtures with dielaidoylphosphatidylethanolamine, small concentrations of Cer-1-P cause a large reduction of the lamellar-to-inverted hexagonal phase transition temperature, suggesting that Cer-1-P induces, like phosphatidic acid, negative membrane curvature in these types of lipid mixtures. These properties place Cer-1-P in a class more akin to certain glycerophospholipids (phosphatidylethanolamine, phosphatidic acid) than to any other sphingolipid. In particular, the similarities and differences between ceramide and Cer-1-P may be relevant in explaining some of their physiological roles.