Lysophosphatidic acid (LPA) is a small, ubiquitous phospholipid that acts as an extracellular signaling molecule by binding to and activating at least five known G protein-coupled receptors (GPCRs): LPA(1)-LPA(5). They are encoded by distinct genes named LPAR1-LPAR5 in humans and Lpar1-Lpar5 in mice. The biological roles of LPA are diverse and include developmental, physiological, and pathophysiological effects. This diversity is mediated by broad and overlapping expression patterns and multiple downstream signaling pathways activated by cognate LPA receptors. Studies using cloned receptors and genetic knockout mice have been instrumental in uncovering the significance of this signaling system, notably involving basic cellular processes as well as multiple organ systems such as the nervous system. This has further provided valuable proof-of-concept data to support LPA receptors and LPA metabolic enzymes as targets for the treatment of medically important diseases that include neuropsychiatric disorders, neuropathic pain, infertility, cardiovascular disease, inflammation, fibrosis, and cancer.
Sphingosine 1-phosphate (S1P), a lysophospholipid, has gained relevance to multiple sclerosis through the discovery of FTY720 (fingolimod), recently approved as an oral treatment for relapsing forms of multiple sclerosis. Its mechanism of action is thought to be immunological through an active phosphorylated metabolite, FTY720-P, that resembles S1P and alters lymphocyte trafficking through receptor subtype S1P 1 . However, previously reported expression and in vitro studies of S1P receptors suggested that direct CNS effects of FTY720 might theoretically occur through receptor modulation on neurons and glia. To identify CNS cells functionally contributing to FTY720 activity, genetic approaches were combined with cellular and molecular analyses. These studies relied on the functional assessment, based on clinical score, of conditional null mouse mutants lacking S1P 1 in CNS cell lineages and challenged by experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. All conditional null mutants displayed WT lymphocyte trafficking that responded normally to FTY720. In marked contrast, EAE was attenuated and FTY720 efficacy was lost in CNS mutants lacking S1P 1 on GFAP-expressing astrocytes but not on neurons. In situ hybridization studies confirmed that astrocyte loss of S1P 1 was the key alteration in functionally affected mutants. Reductions in EAE clinical scores were paralleled by reductions in demyelination, axonal loss, and astrogliosis. Receptor rescue and pharmacological experiments supported the loss of S1P 1 on astrocytes through functional antagonism by FTY720-P as a primary FTY720 mechanism. These data identify nonimmunological CNS mechanisms of FTY720 efficacy and implicate S1P signaling pathways within the CNS as targets for multiple sclerosis therapies.ultiple sclerosis is an autoimmune disorder characterized by CNS demyelination, inflammation, and neurodegeneration (1). Current Food and Drug Administration (FDA)-approved therapies predominantly target immunological pathways through injectable agents. FTY720 (known clinically as fingolimod) is an oral drug that has shown efficacy in human multiple sclerosis clinical trials (2, 3), and in September 2010, received FDA approval as an oral therapy for relapsing forms of multiple sclerosis. The actions of FTY720 seem to involve at least two, paradoxically, opposite sphingosine 1-phosphate (S1P) receptor mechanisms operating in the immune system: agonism and functional antagonism. FTY720 is phosphorylated in vivo to produce the active metabolite FTY720-P, which is a nonselective S1P receptor agonist for four of the five known S1P receptors (4-6), and can function as an agonist in vivo (7). However, FTY720-P can also act as a functional antagonist, where bound S1P receptors are irreversibly internalized and degraded rather than recycled back to the cell surface as occurs with S1P ligands (8, 9); additionally, FTY720-P signaling may persist even after receptor internalization (10). The biological locus responsible for FTY720 efficac...
Lysophosphatidic acid (LPA) is a bioactive lipid mediator with diverse physiological and pathological actions on many types of cells. LPA has been widely considered to elicit its biological functions through three types of G protein-coupled receptors, Edg-2 (endothelial cell differentiation gene-2)/LPA 1 /vzg-1 (ventricular zone gene-1), Edg-4/LPA 2 , and Edg-7/LPA 3 . We identified an orphan G protein-coupled receptor, p2y 9 /GPR23, as the fourth LPA receptor (LPA 4 ). Membrane fractions of RH7777 cells transiently expressing p2y 9 /GPR23 displayed a specific binding for 1-oleoyl-LPA with a K d value of around 45 nM. Competition binding and reporter gene assays showed that p2y 9 /GPR23 preferred structural analogs of LPA with a rank order of 1-oleoyl-> 1-stearoyl-> 1-palmitoyl-> 1-myristoyl-> 1-alkyl-> 1-alkenyl-LPA. In Chinese hamster ovary cells expressing p2y 9 /GPR23, 1-oleoyl-LPA induced an increase in intracellular Ca 2؉ concentration and stimulated adenylyl cyclase activity. Quantitative real-time PCR demonstrated that mRNA of p2y 9 /GPR23 was significantly abundant in ovary compared with other tissues. Interestingly, p2y 9 /GPR23 shares only 20 -24% amino acid identities with Edg-2/LPA 1 , Edg-4/LPA 2 , and Edg-7/LPA 3 , and phylogenetic analysis also shows that p2y 9 /GPR23 is far distant from the Edg family. These facts suggest that p2y 9 /GPR23 has evolved from different ancestor sequences from the Edg family.
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