br Conflict of interest statement br Acknowledgements
Conflict of interest statement
Acknowledgements RF is supported by Pancreatic Cancer Research Fund (grant to MF); MF is supported by Prostate Cancer UK (PG12-23 and PG13-029).
Molecular species and the biosynthesis of phosphatidylinositol, the precursor of LPI
Biosynthesis of lysophosphatidylinositol
Export and degradation of LPI
Conclusion and future directions The biological actions of LPI have been reported previously , , , , , ; 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 , , . We screened various candidates by monitoring the intracellular signaling of GPR55-expressing HEK293 cells, and identified LPI, 2-arachidonoyl LPI in particular, as an agonist for GPR55. Our efforts to identify the LPI receptor facilitated research on LPI as lipid messengers. Based on our pioneering research, much evidence has been accumulated to show that LPI is involved in physiological and/or pathophysiological processes in a GPR55-dependent manner , , , . Our previous studies focused on the LPI-GPR55 axis in navitoclax bcl-w functions , , . The reasons for this were: (1) GPR55 was identified as another cannabinoid receptor and was present in brain tissue , , , , . (2) Considerable amounts of LPI, an agonist for GPR55, were present in brain tissue . (3) The LPI-synthesizing enzyme DDHD1 was also found in the brain and neuroblastoma cells . Therefore, the brain has the components necessary for LPI synthesis and signaling via the GPR55 receptor. We suggest that DDHD1/LPI/GPR55 signaling may be involved in brain functions such as neuronal transmission because LPI was synthesized in a stimulus-dependent manner. The involvement of LPI-GPR55 in neuropathic pain has also been reported , as have the protective roles of LPI against glutamate-induced neuronal cell death and cerebral ischemia . Further studies are needed to establish the relevance of DDHD1/LPI/GPR55 and such brain functions. The identification of LPI-synthesizing enzymes is very important because these enzymes initiate LPI signaling. We identified DDHD1 as a candidate for LPI-synthesizing enzymes (Fig. 5) . Other researchers have also suggested that cPLA2α is involved in the formation of LPI in cancer cells . It is noteworthy that these enzymes are activated by extracellular stimuli. In addition, we believe that other lipases may be involved in the formation of LPI. DDHD2/KIA0725 was also shown to have PLA1 activity for PI, although other phospholipids also served as substrates . Further studies are needed to further identify LPI-synthesizing enzymes. Based on structure–activity relationships, we identified 2-arachidonoyl LPI as the most potent agonist for GPR55 . The results showed that 2-arachidonoyl LPI is very important for the biosynthesis of the parent molecule, the 1-stearyl-2-arachidonoyl PI species. 1-Acyl LPI or 2-acyl LPI acyltransferases (LPIAT1/MBOAT7 or AGPAT8/ALCAT1) are involved in the incorporation of arachidonic or stearic acids into PI, respectively (Fig. 3). However, the regulation of these acyltransferases has not yet been established. In addition, we focused on the reverse reactions of these acyltransferase activities. The roles of the reverse reactions of these acyltransferases are now being investigated in our laboratory. Further studies are needed to elucidate the regulation and connection between acyltransferases and the generation of LPI species. The degradation pathways of LPI are also important, since degradation is involved in the shutdown of LPI signaling. In addition, lysoPI-PLC activity is able to convert 2-arachidonoyl LPI (an agonist for GPR55) to 2-arachidonoylglycerol (2-AG, an agonist for CB1 and CB2). lysoPLD activity is also able to convert 2-arachidonoyl LPI (an agonist for GPR55) to 2-arachidonoyl LPA (an agonist for LPA receptors and GPR35). Further studies are needed to elucidate the physiological roles of the conversion of these ligands (Fig. 6).