Cell surface receptors in lysophospholipid signaling
Introduction
Lysophospholipids (LPs) are not only metabolites in membrane phospholipid synthesis, but also omnipresent bioactive molecules influencing a broad variety of biological processes by binding to cognate G protein-coupled receptors (GPCRs). The best characterized representatives of signaling LPs are lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P). Although their signaling role has been recognized for decades, the identification of high-affinity receptors for LPA and S1P in the last several years dramatically improved our comprehension of LP signaling. The widespread expression of cell surface LP receptors and coupling to several classes of G proteins allow regulation of various cellular processes with particular impact on neurogenesis, vascular development, wound healing, immunity, and cancer.
Section snippets
Metabolism of LPA and S1P
LPA is a simple lipid molecule made up of a glycerol backbone with a hydroxyl group, a phosphate group, and a long saturated or unsaturated fatty acid chain (Fig. 1). Several pathways for LPA synthesis and degradation have been implicated [1]. Extracellular LPA is likely to be generated by the phospholipases (PL) A1 and A2 mediating deacylation of phosphatidic acid and, additionally, by lysophospholipase D (lysoPLD) that hydrolyzes lysophosphatidylcholine to LPA [1]. Recently, lysoPLD from
Identification of LPA and S1P receptors
The first LP receptor was identified in 1996, during a search for genes with predominant expression in the ventricular zone (VZ) of the cerebral cortex. This led to the identification of ventricular zone gene 1 (VZG-1), that was shown to encode a high-affinity GPCR for LPA [27], [28]. Subsequently, sequence similarities allowed rapid identification of further cognate LPA and S1P receptors [29], [30]. In mammals, four high-affinity cell surface receptors for LPA have been described so far. Three
Expression of LPA and S1P receptors
LP receptors have been investigated based on mRNA expression of the respective receptors in different tissues of rodents and human (Table 1). In adult mice, LPA1 is widely expressed with high mRNA levels in testis, brain, lung, heart, spleen and intestine, and moderate levels in kidney, thymus, stomach and muscle [27], [29], [47]. No LPA1 expression was detected in liver of adult mice [27], [29], [47]. LPA1 is similarly expressed in adult human organs showing high mRNA expression in brain,
General aspects of LP signaling
Essentially, all cells in mammals respond in one way or another to LPA and S1P. The most common cellular responses are proliferation, cell survival, cell motility and differentiation. These effects are mediated by coupling of LP receptors to G proteins that regulate the activity of intracellular messenger molecules (Fig. 2). LP receptors couple to members of three major G protein families, the Gi (Gi1, Gi2, Gi3, Go1, Go2, Gz, Gt, Ggus), Gq (Gq, G11, G14, G15/16), and G12 (G12, G13) family. LPA1
LP signaling in mouse embryonic fibroblasts
Probably one of the best characterized primary cell type in terms of LP signaling are mouse embryonic fibroblasts (MEFs). In particular the analysis of MEFs derived from different LP receptor-null mice allowed clarification of the signaling pathways elicited by different LPA and S1P receptors (Fig. 3). MEFs express LPA1, LPA2, S1P1, S1P2 and S1P3 receptors [52], [61], [72], [73]. Stimulation with LPA in wild-type MEFs induce activation of PLC resulting in inositol 1,4,5-triphosphate (IP3) and
Phenotypes of LP receptor-null mice
A significant step towards unraveling the physiological relevance of LP signaling is the analysis of consequences arising from single or combined genetic deletions of LP receptors in mice. So far, LPA1(−/−), LPA2(−/−), LPA1(−/−) LPA2(−/−), S1P1(−/−), S1P2(−/−), S1P3(−/−), and S1P2(−/−) S1P3(−/−) mice have been described [52], [61], [72], [73], [74], [75], [76]. In the following section, macro- and microscopic phenotypes of these mice will be outlined.
LPA1(−/−) mice revealed semi-lethality with
Concluding remarks
The identification of high-affinity surface receptors for LPA and S1P has allowed rapid progress in understanding LP signaling mechanisms, clearly demarcating receptor-dependent from receptor-independent functions. A particularly valuable tool in this regard for studying the significance of LP receptor-mediated signaling has been single or combined targeted deletions of LP receptors in mouse. Analyses of LP receptor-null mice have revealed important insights into single cell signaling, allowing
Acknowledgements
We thank Drs. Joerg Birkenfeld and Florian Toepert for critically reading the manuscript and for help with ChemDraw. This work was supported by the National Institute of Mental Health and The Helen L. Dorris Institute for the Study of Neurological and Psychiatric Disorders of Children and Adolescents (J.C.), and by a fellowship for prospective researchers from the Swiss National Science Foundation (B.A.).
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