The actions and metabolism of lysophosphatidylinositol, an endogenous agonist for GPR55

doi:10.1016/j.prostaglandins.2013.05.004

Prostaglandins & Other Lipid Mediators

Volume 107, December 2013, Pages 103-116

https://doi.org/10.1016/j.prostaglandins.2013.05.004 Get rights and content

Highlights

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The bio-actions of lysophosphatidylinositol (LPI) are proposed.
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We identified another cannabinoid receptor GPR55 as a LPI receptor.
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We propose one of the synthesizing enzymes of 2-arachidonoyl LPI.
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We discuss physiological and pathophysiological processes involving LPI and GPR55.

Abstract

Lysophosphatidylinositol (LPI) is a subspecies of lysophospholipid and is assumed to be not only a degradation product of phosphatidylinositol (PI), but also a bioactive lysophospholipid mediator. However, not much attention has been directed toward LPI compared to lysophosphatidic acid (LPA), since the receptor for LPI has not been identified. During screening for an agonist for the orphan G protein coupled receptor GPR55, we identified LPI, 2-arachidonoyl LPI in particular, as an agonist for GPR55. Our efforts to identify an LPI receptor facilitated research on LPI as a lipid messenger. In addition, we also found that DDHD1, previously identified as phosphatidic acid-preferring phospholipase A1, was one of the synthesizing enzymes of 2-arachidonoyl LPI. Here, we summarized the background for discovering the LPI receptor, and the actions/metabolism of LPI. We also referred to the biosynthesis of PI, a 1-stearoyl-2-arachidonoyl species, since the molecule is the precursor of 2-arachidonoyl LPI. Furthermore, we discussed physiological and/or pathophysiological processes involving LPI and GPR55, including the relevance of LPI-GPR55 and cannabinoids, since GPR55 was previously postulated to be another cannabinoid receptor. Although there is no doubt that GPR55 is the LPI receptor, we should re-consider whether or not GPR55 is in fact another cannabinoid receptor.

Section snippets

Cannabinoid receptors, CB1 and CB2, and their endogenous agonists

Cannabinoids are bioactive constituents of the marijuana plant Cannabis sativa, and Δ⁹-tetrahydrocannabinol (Δ⁹-THC) is one of the major active substances of marijuana (Fig. 1). Synthetic compounds with cannabinoid-like activity and those that interact with specific receptors, in addition to phytochemicals, have been included as cannabinoids [1], [2], [3], [4].

Most of the pharmacological actions of cannabinoids have been shown to be mediated by two types of G-protein-coupled receptors (GPCRs),

LPI as a bioactive lipid messenger

LPI is a subspecies of lysophospholipid with inositol in its head group. The structures of 1-acyl and 2-acyl LPI are depicted in Fig. 1. Not much attention has been directed toward LPI; information concerning LPI as a bioactive lipid is more limited than that of LPA. The first evidence showing a possible physiological role for LPI concerned its effect on Ca²⁺ mobilization; LPI elicited an increase in intracellular Ca²⁺. Metz found that LPI could promote insulin release from the pancreatic

Molecular species of phosphatidylinositol

The fatty acid composition of phosphatidylinositol (PI) in mammalian cells and tissues has a characteristic feature over those of other phospholipids [70], [71]. The predominant molecular species of PI is the 1-stearoyl-2-arachidonoyl species (18:0–20:4), which represents 40% and 58% of PI in rabbit alveolar macrophages and the rat liver, respectively. We postulated that 1-stearoyl-2-arachidonoyl PI is the precursor of 2-arachidonoyl LPI and 1-stearoyl LPI, the most active and abundant species

Phospholipase A1

PLA1 is an enzyme that hydrolyzes fatty acids at the sn-1 position of phospholipids. PLA1s produce 2-acyl lysophospholipids and fatty acids (Fig. 4) [80]. Lower numbers of PLA1 have been cloned than those of PLA2 and their properties and physiological roles have not yet been fully established. PLA1 family members can also be classified according to their distribution (extracellular versus intracellular). In mammals, extracellular or secretory PLA1s include phosphatidylserine (PS)-specific PLA1

Export of LPI

The export system of LPI should be essential for the action of LPI on the cell surface receptor GPR55. We found that approximately 45% of LPI produced by DDHD1 was released into the medium, although the mechanism by which these cells released LPI was unknown. Piñeiro recently showed that the export of LPI was mediated by the ATP-binding cassette transporter ABCC1/MRP1 in PC-3 cancer cells [64]. The authors suggested an autocrine loop that regulates cell proliferation, especially in cancer

Conclusion and future directions

The biological actions of LPI have been reported previously [36], [37], [38], [39], [40], [41]; however, details of the action of LPI remained unsolved because the receptor had not been identified. The first identification of the LPI receptor came from the search for an endogenous agonist for the novel cannabinoid receptor GPR55 [49], [50], [51]. We screened various candidates by monitoring the intracellular signaling of GPR55-expressing HEK293 cells, and identified LPI, 2-arachidonoyl LPI in

Acknowledgements

We thank Mr. Makoto Ito for preparing the phylogenetic tree for GPCR and phospholipases. This study was supported in part by a Grant-in-Aid for Scientific Research (21590075, 24590095) from the Ministry of Education, Culture, Sports, Sciences, and Technology of Japan.

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ReviewThe actions and metabolism of lysophosphatidylinositol, an endogenous agonist for GPR55

Highlights

Abstract

Section snippets

Cannabinoid receptors, CB1 and CB2, and their endogenous agonists

LPI as a bioactive lipid messenger

Molecular species of phosphatidylinositol

Phospholipase A1

Export of LPI

Conclusion and future directions

Acknowledgements

Curr Opin Pharmacol

Biochim Biophys Acta

Biochem Biophys Res Commun

Biochem Biophys Res Commun

Biochem Biophys Res Commun

J Biol Chem

FEBS Lett

Biochem Pharmacol

J Biol Chem

Prog Lipid Res

Cell

J Biol Chem

J Biol Chem

FEBS Lett

J Biol Chem

Biochem Biophys Res Commun

Biochim Biophys Acta

Prostaglandins Other Lipid Mediat

Biochem Biophys Res Commun

Biochem Biophys Res Commun

Biochim Biophys Acta

Brain Res Mol Brain Res

Biochem Biophys Res Commun

Anal Biochem

Methods Enzymol

J Biol Chem

J Biol Chem

J Biol Chem

Pain

J Biol Chem

J Biol Chem

J Lipid Res

Biochimie

J Biol Chem

J Biol Chem

J Biol Chem

J Biol Chem

J Biol Chem

J Biol Chem

J Biol Chem

Am J Hum Genet

Am J Hum Genet

Biochim Biophys Acta

Prog Lipid Res

J Biol Chem

J Biol Chem

Biochim Biophys Acta

J Lipid Res

J Biol Chem

Life Sci

Review
The actions and metabolism of lysophosphatidylinositol, an endogenous agonist for GPR55