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International Union of Pharmacology. XXXIV. Lysophospholipid Receptor Nomenclature

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International Union of Pharmacology. XXXIV. Lysophospholipid Receptor Nomenclature 0031-6997/02/5402-265–269$7.00 PHARMACOLOGICAL REVIEWS Vol. 54, No. 2 Copyright © 2002 by The American Society for Pharmacology and Experimental Therapeutics 20204/989285 Pharmacol Rev 54:265–269, 2002 Printed in U.S.A International Union of Pharmacology. XXXIV. Lysophospholipid Receptor Nomenclature JEROLD CHUN, EDWARD J. GOETZL, TIMOTHY HLA, YASUYUKI IGARASHI, KEVIN R. LYNCH, WOUTER MOOLENAAR, SUSAN PYNE, AND GABOR TIGYI Merck Research Laboratories, La Jolla, California (J.C.); Department of Medicine, University of California, San Francisco, California (E.J.G.); Department of Physiology, University of Connecticut, Farmington, Connecticut (T.L.H.); Department of Biomembrane and Biofunctional Chemisty, Hokkaido University, Sapporo, Japan (Y.I.); Department of Pharmacology, University of Virginia, Charlottesville, Virginia (K.R.L.); Division of Cellular Biochemistry, Netherlands Cancer Institute, Amsterdam, The Netherlands (W.M.); Department of Physiology and Pharmacology, University of Strathclyde, Glasgow, Scotland (S.P.); and Department of Physiology, University of Tennessee, Memphis, Tennessee (G.T.) This paper is available online at http://pharmrev.aspetjournals.org Abstract ............................................................................... 265 I. Introduction............................................................................ 265 II. Discovery of lysophospholipid receptors ................................................... 266 III. Receptor nomenclature .................................................................. 266 IV. Nonhuman lysophospholipid receptors .................................................... 267 Downloaded from V. Lysophospholipid receptor ligands ........................................................ 267 VI. Lysophospholipid receptor gene knockouts................................................. 267 VII. Lysophospholipid receptor expression ..................................................... 268 VIII. Conclusion ............................................................................. 268 References ............................................................................. 268 by guest on September 27, 2021 Abstract——The lysophospholipids, lysophospha- eight G protein-coupled receptors. Five of these are tidic acid (LPA) and sphingosine 1-phosphate (S1P), S1P-prefering while the remaining three are LPA re- are now recognized as important extracellular signal- ceptors. These receptors are expressed widely and in ing molecules. These lipid mediators are pleiotropic; aggregate signal through a variety of heterotrimeric G among the most common cellular responses are mito- proteins. The lysophospholipid receptor family is re- genesis, cell survival (anti-apoptosis), inhibition of ad- ferred to commonly as the “Edg” group (e.g., Edg-1, enylyl cyclase and calcium mobilization. Physiologic Edg-2, etc.). Herein, the molecular pharmacology of events associated with these mediators include plate- the lysophospholipid receptors is reviewed briefly, let aggregation, vasopressor activity, wound healing, and a rational nomenclature for LPA and S1P recep- immune modulation, and angiogenesis. Many of the tors that is consistent with the International Union of actions of LPA and S1P are mediated through a set of Pharmacology guidelines is proposed. I. Introduction tracellular signaling molecules. The first report of lyso- phosphatidic acid-evoked responses from tissue de- Lysophosphatidic acid (LPA1) and sphingosine scribed its activity as a vasopressor (Tokumura et al., 1-phosphate (S1P) are now known to be pleiotropic ex- 1978). Subsequently, LPA was found to be proliferative for cultured cells (van Corven et al., 1989)—an observa- Address correspondence to: Dr. Kevin R. Lynch, Subcommittee Chair, Pharmacology Box 800735, University of Virginia Health Center for Vascular Biology, Department of Physiology, University of System, 1300 Jefferson Park Avenue, Charlottesville, VA 22908. Connecticut, 263 Farmington Ave., Farmington, CT 06030; Yasuyuki 1 Abbreviations: LPA, lysophosphatidic acid; S1P, sphingosine Igarashi, Department of Biomembrane and Biofunctional Chemis- 1-phosphate; LPL, lysophospholipid; GPCR, G protein-coupled recep- try, Hokkaido University, Nishi 6, Kita 12, Kita-ku, Sapporo 060- tor; Edg, endothelial differentiation gene; NC-IUPHAR, Interna- 0812, Japan; Kevin R. Lynch (Chair), Department of Pharmacology, tional Union of Pharmacology Committee on Receptor Nomenclature Box 800735, University of Virginia, 1300 Jefferson Park Ave., Char- and Drug Classification; SPC, sphingosylphosphorylcholine; LPC, lottesville, VA 22908-0735; Wouter H. Moolenaar, Division of Cellu- lysophosphatidylcholine. lar Biochemistry, Netherlands Cancer Institute, Plesmanlaan 121, Composition of the NC-IUPHAR Subcommittee on Lysophospho- 1066 CX Amsterdam, The Netherlands; Susan Pyne, Department of lipid Receptors: Jerold Chun, Merck Research Laboratories, Physiology and Pharmacology, University of Strathclyde, 27 Taylor 505 Coast Boulevard South, La Jolla, CA 92037; Edward J. Goetzl, St., Glasgow G4 ONR, Scotland; and Gabor Tigyi, Department of Department of Medicine, University of California, U88B Box 0711, Physiology, University of Tennessee, 894 Union Ave., Memphis, TN 533 Parnassus Ave., San Francisco, CA 94143-0711; Timothy Hla, 38163. 265 266 CHUN ET AL. tion that spurred much subsequent investigation. S1P has also been shown to be proliferative for cultured cells (Zhang et al., 1991). Investigations into numerous as- pects of lysophospholipid (LPL) signaling led to the re- alization that many LPL-evoked events are mediated by heterotrimeric G proteins, thus predicting the existence of LPL G protein-coupled receptors (GPCRs). II. Discovery of Lysophospholipid Receptors The receptor cluster that contains the eight LPL re- ceptors has the colloquial name “Edg” (an acronym for endothelial differentiation gene). The name Edg (or EDG) was coined in 1990 by Hla and Maciag to describe a set of immediate early response gene products cloned from human umbilical vein endothelial cells; Edg-1 was found to be a rhodopsin family GPCR (Hla and Maciag, 1990). A GPCR that was 50% identical was reported in 1993 (“AGR16”; Okazaki et al., 1993) and independently the following year (“H218”; MacLennan et al., 1994). The Edg name appeared again in 1995 (Edg-2) to describe a third, more distantly related, GPCR (Masana et al., 1995). The orthologous (species homolog) mouse GPCR was then described (“rec1.3”; Macrae et al., 1996). The FIG 1. The single maximum parsimony tree of the human LPL recep- tor amino acid sequences and the human platelet-activating factor recep- other five members of the cluster were named in order of tor sequence. This unrooted tree was built with PROTPARS (available at their appearance as Edg-3, Edg-4, Edg-6, Edg-7, and www.evolution.genetics.washington.edu) in PHYLIP package (5 runs, 10–23 jumbles per run). Edg-8 and eventually AGR16/H218 became commonly known as Edg-5. A seminal event in the LPL field occurred when Chun and thus is a possible source of confusion (Hla et al., and colleagues discovered that mouse Edg-2 (they called 1997). A rational, alternate nomenclature has been pro- it “vzg-1”) is an LPA receptor (Hecht et al., 1996). This posed (Chun et al., 1999), but this scheme has not been was followed quickly by three reports that Edg-3 and embraced, and it is not consistent with IUPHAR guide- Edg-1 are S1P-preferring receptors (An et al., 1997; Lee lines (Humphrey et al., 2000; Ruffolo et al., 2000). Ac- et al., 1998; Zondag et al., 1998). Within several years, cording to those guidelines, a receptor is to be named reports from a number of groups established that there with the abbreviation for the natural agonist with the are eight Edg receptor genes in the human genome. Five highest potency, followed by a subscripted arabic num- of these encode S1P receptors (Edg-1, -3, -5, -6, and -8) ber. Because the NC-IUPHAR Subcommittee on Lyso- whereas the remaining three encode LPA receptors phospholipid Receptors recommends that sphingosine (Edg-2, -4, and -7). The S1P receptors share about 50% 1-phosphate be abbreviated S1P (rather than SPP or identical amino acids whereas the LPA receptors have Sph-P), Edg-1 becomes S1P1 and Edg-2 becomes LPA1. about 55% sequence identity. The subclusters are about The subcommittee decided further that the order of 35% identical. A maximum parsimony tree showing numbering is to reflect the chronology of the publication graphically the relationship among the LPL receptors of receptor sequence (regardless of whether the ligand and the distantly related platelet-activating factor re- was known at that time), thus Edg-5/H218/AGR16 be- ceptor is shown as the Fig. 1. Different aspects of LPL comes S1P2, etc. Table 1 lists recommended LPL recep- biochemistry, physiology, and cell biology are discussed tor names, the IUPHAR Receptor Code (Humphrey et in a variety of recent review articles (Hla, 2001; Tigyi, al., 2000), and previous LPL receptor names. LPL recep- 2002) (also for review, see Chun et al., 1999; Moolenaar, 1999; Pyne and Pyne, 2000; Fukushima et al., 2001; Hla TABLE 1 LPL receptors et al., 2001). Agonist IUPHAR Ligand Nomenclature Receptor Code Edg Name Previous Names III. Receptor Nomenclature LPA LPA1 2.1:LPL:2:LPA1: Edg-2 IpA1, vzg-1, rec1.3 LPA LPA2 2.1:LPL:4:LPA2: Edg-4 IpA2 Although the Edg acronym proved prescient for Edg-1 LPA LPA3 2.1:LPL:7:LPA3: Edg-7 IpA3 (Hla et al., 2001), this name has little relevance to the S1P S1P1
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