Review
Lysophospholipids and their receptors in the central nervous system

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Abstract

Lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P), two of the best-studied lysophospholipids, are known to influence diverse biological events, including organismal development as well as function and pathogenesis within multiple organ systems. These functional roles are due to a family of at least 11 G protein-coupled receptors (GPCRs), named LPA1–6 and S1P1–5, which are widely distributed throughout the body and that activate multiple effector pathways initiated by a range of heterotrimeric G proteins including Gi/o, G12/13, Gq and Gs, with actual activation dependent on receptor subtypes. In the central nervous system (CNS), a major locus for these signaling pathways, LPA and S1P have been shown to influence myriad responses in neurons and glial cell types through their cognate receptors. These receptor-mediated activities can contribute to disease pathogenesis and have therapeutic relevance to human CNS disorders as demonstrated for multiple sclerosis (MS) and possibly others that include congenital hydrocephalus, ischemic stroke, neurotrauma, neuropsychiatric disorders, developmental disorders, seizures, hearing loss, and Sandhoff disease, based upon the experimental literature. In particular, FTY720 (fingolimod, Gilenya, Novartis Pharma, AG) that becomes an analog of S1P upon phosphorylation, was approved by the FDA in 2010 as a first oral treatment for MS, validating this class of receptors as medicinal targets. This review will provide an overview and update on the biological functions of LPA and S1P signaling in the CNS, with a focus on results from studies using genetic null mutants for LPA and S1P receptors. This article is part of a Special Issue entitled Advances in Lysophospholipid Research.

Highlights

► This is a review on CNS aspects of lysophospholipids (LPs) and their receptors. ► LPs are bioactive lipids originating from the cell membrane and include LPA and S1P. ► Cognate GPCRs account for LP biology, pathology and new therapeutics.

Introduction

Lysophospholipids (LPs) are phospholipid derivatives originating from cell membranes and two of the best-studied LPs are lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P). These two LPs were previously known as biosynthetic metabolites of cell membrane phospholipids, but they are now regarded as important regulators for diverse biological functions through activation of their specific cognate receptors. At present, there is a family of 11 bona fide G protein-coupled receptors (LPA1–6; S1P1–5) that link into multiple downstream effector pathways (Fig. 1). LPA and S1P receptors are present in various organ systems, which accounts for their diverse biological roles [1], [2], [3], [4]. Important LPA and S1P-mediated biological functions were discovered by studies utilizing genetic null mutants for LPA and S1P receptors [1], [4], [5]. Currently, there are 10 published receptor‐null mice for the following LPA or S1P receptors: LPA1, LPA2, LPA3, LPA4, LPA5, S1P1, S1P2, S1P3, S1P4, and S1P5, all of which have been used to uncover valuable receptor-mediated biological functions (summarized in Table 1).

The CNS is one of the biological systems markedly affected by LPA and S1P signaling. Many subtypes of LPA and S1P receptors are expressed in one or more CNS cell types, and their ligands are also enriched there [1], [6], [7]. Consequently, LPA and S1P signaling affects CNS cell types such as neuroblasts, neurons, astrocytes, and oligodendrocytes to influence cell survival, proliferation, migration, differentiation, and morphological changes (reviewed in [1], [3], [8], [9], [10], [11]). To date, LPA and/or S1P receptors have been identified as important factors in CNS development, as well as having roles in diseases, including MS [12], [13], fetal hypoxia and hydrocephalus [14], [15], [16], neuropathic pain [17], [18], [19], brain ischemic stroke [20], [21], neurotrauma [22], developmental disorders like schizophrenia, as well as hearing loss [23], [24], [25], seizures [26], [27], [28], and Sandhoff disease [29].

In this review, we will focus on the biological roles of LPA and S1P receptors in different CNS cell types, including neurons, astrocytes, and oligodendrocytes, and discuss their involvement in CNS diseases. Specifically, we discuss in vivo and in vitro data that were obtained from studies using LPA or S1P receptor null mutants. Involved cell types affected in the CNS include not only CNS lineages but also non-CNS lineages such as resident cell types like microglia, which will also be considered.

Section snippets

LPA and S1P receptor expression in the CNS

In the past decades, the biological activities of LPA and S1P were mechanistically unclear, with explanations ranging from detergent-like membrane perturbation, second messenger activities, to possible receptors. In 1996, the first LP receptor, LPA1, was identified in the ventricular zone of the embryonic brain [30], [31] with subsequent deorphanization based on sequence homology of both new LPA and S1P receptors [7], [32], [33], [34], [35], [36], [37], [38], [39], [40], [41]. Now, there is a

Biological functions of LPA and S1P receptors in CNS cell types

The discovery of the first LPA receptor, LPA1, and the role it plays in nervous system development, has served as a template for LP research in the CNS as well as other tissues. Since then, a variety of specific responses at cellular and tissue levels have been identified, including proliferation, morphological changes, cell migration, differentiation, and survival. This section will discuss biological functions of LPA and S1P receptors in CNS cell types, such as neuroblasts, neurons,

LPA and S1P receptors as promising therapeutic targets in CNS diseases

The biological functions of LPA and S1P signaling on CNS cell types have led to translational research to identify medically relevant roles for LP receptors. Genetic nulls, combined with pharmacological LP receptor modulators, have been utilized to validate therapeutic functions in CNS diseases. The clearest success of this research is FTY720, an S1P receptor modulator approved by the FDA in 2010 as a first oral MS therapy [12], [13]. This success has provided proof-of-concept for other

Conclusions

Since the discovery of the first LP receptor, LPA1, 11 receptors are now included in this family of 6 LPA and 5 S1P receptors. These bona fide GPCRs are widely and diversely expressed throughout the body and during development, to influence myriad biological as well as pathological processes. A growing number of studies using genetic null mutants for these LP receptor subtypes (LPA1, LPA2, LPA3, LPA4, LPA5, S1P1, S1P2, S1P3, S1P4, and S1P5) have clarified specific functions mediated by each,

Acknowledgements

We thank Danielle Letourneau for editorial assistance and Sook-Hyun Yoon for figure editing. We apologize for any oversights. This work was supported by the National Institutes of Health (NS048478 and DA019674) to JC, and the Korean National Research Foundation (2010‐0003058) and a Novartis Postdoctoral Fellowship (Novartis Pharma, AG) to JWC.

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    This article is part of a Special Issue entitled Advances in Lysophospholipid Research.

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