Lysophosphatidic acid (LPA) and its receptors

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Lysophosphatidic acid (LPA), a bioactive phospholipid, and its family of cognate G protein-coupled receptors have demonstrated roles in many biological functions in the nervous system. To date, five LPA receptors have been identified, and additional receptors may exist. Most of these receptors have been genetically deleted in mice toward identifying biological and medically relevant roles. In addition, small molecule agonists and antagonists have been reported. Here we review recent data on the nervous system functions of LPA signaling, and summarize data on reported agonists and antagonists of LPA receptors.

Introduction

Lysophosphatidic acid (LPA; 1- or 2-acyl-sn-glycerol-3-phosphate) is a bioactive phospholipid with diverse biological functions on many cell types. LPA is detected in serum, plasma, other biological fluids, and tissues including brain [1].

LPA is generated by the action of a number of different enzymes including phospholipase A1 or A2, monoacylglycerol kinase, glycerol-3-phosphate acyltransferase, and autotaxin (ATX), a lysophospholipase D (lysoPLD) [2]. LPA is catabolized by a number of different pathways that include the actions of lipid phosphate phosphatases or LPA acyltransferase, thus terminating its signaling actions [2].

LPA elicits its functions through receptors on plasma membranes. So far, there are five G protein-coupled receptors (GPCRs) identified as specific receptors for LPA that are referred to as LPA1, LPA2, LPA3, LPA4, and LPA5 [3, 4, 5, 6, 7, 8]. In addition, recent reports have suggested that three additional GPCRs, GPR87, P2Y5, and P2Y10, may be responsive to LPA [9•, 10•, 11•], although further study is required to validate these observations. Analyses of gene knockout mice for most of the five bona fide receptors have revealed physiological and pathological roles of LPA signaling including brain development [12, 13, 14, 15], neuropathic pain [16], and female and male reproduction [17, 18], to name a few (see below).

This review focuses on the functions of LPA signaling in the nervous system and briefly introduces LPA agonists/antagonists (Figure 1, Figure 2 and Table 2). Because of space limitations, additional characteristics of known LPA receptors are merely summarized in Table 1.

Section snippets

Neural progenitor cells (NPCs)

The processes that mediate central nervous system (CNS) development include proliferation, differentiation, migration, and apoptosis. NPCs proliferate in the ventricular zone (VZ) to expand progenitor pools, and sequentially exit the cell cycle to differentiate into multiple cell types including neurons, astrocytes, and oligodendrocytes (Figure 1). During these processes, the cells change their morphology drastically and migrate out from the VZ toward their final destinations. The restricted

Knockout mice

LPA1-null mice have approximately 50% neonatal lethality, and exhibit craniofacial dysmorphism (shorter snouts and more widely spread eyes) and reduced body mass in survivors [12]. These mice are also characterized by the defects in normal suckling behavior, presumably because of a lack of olfactant detection and/or processing, which accounts for increased neonatal death and decreased postnatal growth. However, no obvious abnormalities in olfactory/vomeronasal epithelia, olfactory bulb, or

LPA signaling in pain

Intraplantar injection of LPA into the mouse hind limb induces peripheral nociception, which is markedly reduced by PTX-pretreatment or substance P receptor antagonist-pretreatment, and partially blocked by LPA1 antisense oligodeoxynucleotide administration [78, 79]. Taken together with a finding that LPA1 mRNA is detected in DRG [79], it appears that LPA induces peripheral nociception through LPA1 and Gi/o by releasing substance P from nociceptor endings.

Intrathecal injection of LPA into mice

LPA receptor agonists/antagonists

In recent years, several groups have reported the generation of agonist and antagonist compounds for LPA receptors that vary in specificities and apparent affinities (Table 2). Several have been reportedly used as study compounds in a number of in vitro applications. Notably, Ki16425 is commercially available and acts as an LPA1/LPA3-specific antagonist [83]. It has been used in cell culture experiments to inhibit such LPA-mediated processes as Ca2+ mobilization, migration, and neurite

Conclusions

LPA signaling is remarkably complex and heterogeneous and has been shown to influence all neural cell types. The developmental, physiological, and pathological significance of these responses in vivo is only beginning to be appreciated, due largely to the studies that have recently been performed on LPA receptor knockout mice. These studies have revealed that LPA influences such processes as the development of the CNS, the function of neurons and glia, and the onset of neuropathic pain.

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

Acknowledgements

We thank Danielle Letourneau for critical reading of the manuscript. This work was supported by the National Institute of Mental Health (grant no. MH051699 (JC)), the National Institute of Neurological Disorders and Stroke (grant no. NS048478 (JC)), and the National Institute of Child Health and Human Development (grant no. HD050685 (JC)).

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