Lysophospholipids and their receptors in the central nervous system

Abstract

Lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P), two of the best-studied lysophospholipids, are known to influence diverse biological events, including organismal development as well as function and pathogenesis within multiple organ systems. These functional roles are due to a family of at least 11 G protein-coupled receptors (GPCRs), named LPA1–6 and S1P1–5, which are widely distributed throughout the body and that activate multiple effector pathways initiated by a range of heterotrimeric G proteins including Gi/o, G12/13, Gq and Gs, with actual activation dependent on receptor subtypes. In the central nervous system (CNS), a major locus for these signaling pathways, LPA and S1P have been shown to influence myriad responses in neurons and glial cell types through their cognate receptors. These receptor-mediated activities can contribute to disease pathogenesis and have therapeutic relevance to human CNS disorders as demonstrated for multiple sclerosis (MS) and possibly others that include congenital hydrocephalus, ischemic stroke, neurotrauma, neuropsychiatric disorders, developmental disorders, seizures, hearing loss, and Sandhoff disease, based upon the experimental literature. In particular, FTY720 (fingolimod, Gilenya, Novartis Pharma, AG) that becomes an analog of S1P upon phosphorylation, was approved by the FDA in 2010 as a first oral treatment for MS, validating this class of receptors as medicinal targets. This review will provide an overview and update on the biological functions of LPA and S1P signaling in the CNS, with a focus on results from studies using genetic null mutants for LPA and S1P receptors. This article is part of a Special Issue entitled Advances in Lysophospholipid Research.

Rapid and profound rewiring of brain lipid signaling networks by acute diacylglycerol lipase inhibition

“…More recently, lipids have become recognized as a distinct type of chemical messenger in the nervous system that appear to be generated at the time of their intended action rather than amassed in vesicles (2)(3)(4)(5). This "on-demand" model for production implicates lipid biosynthetic enzymes as major regulators of chemical signaling in the central nervous system (CNS).…”

Modulatory Effects of Fingolimod (FTY720) on the Expression of Sphingolipid Metabolism-Related Genes in an Animal Model of Alzheimer’s Disease

“…The influence of sphingolipids may be largely mediated through their role in plasma membrane microdomains called lipid rafts [17], which display extensive links with AβPP metabolism, Aβ production, and aggregation [18,19]. Moreover, S1PRs modulate neuronmicroglia interactions, microglial activation, and secretion of neurotoxic compounds and seem to influence the fine balance between the restorative and destructive outcomes of astrogliosis [20,21].…”

The Polybasic Insertion in Autotaxin α Confers Specific Binding to Heparin and Cell Surface Heparan Sulfate Proteoglycans

“…LPA, a major serum constituent, signals through specific G protein-coupled receptors to influence numerous cellular processes including cell migration, proliferation and differentiation (3,4). ATX and LPA signaling play a vital role in embryonic development (5)(6)(7) and are implicated in a wide variety of physiological and pathological processes, as diverse as lymphocyte homing (8,9), neurogenesis (10,11), tumor progression (12)(13)(14), and fibrosis (15).…”