Lysophosphatidic Acid Signalling in Nervous System Development and Function
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REVIEW PAPER
Lysophosphatidic Acid Signalling in Nervous System Development and Function Eric Birgbauer1 Received: 12 August 2020 / Accepted: 30 October 2020 © Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract One class of molecules that are now coming to be recognized as essential for our understanding of the nervous system are the lysophospholipids. One of the major signaling lysophospholipids is lysophosphatidic acid, also known as LPA. LPA activates a variety of G protein-coupled receptors (GPCRs) leading to a multitude of physiological responses. In this review, I describe our current understanding of the role of LPA and LPA receptor signaling in the development and function of the nervous system, especially the central nervous system (CNS). In addition, I highlight how aberrant LPA receptor signaling may underlie neuropathological conditions, with important clinical application. Keywords LPA receptors · Autotaxin · Cortical development · Axon guidance · Neuropathic pain · Lysophospholipid
Introduction The human brain is an incredibly complex organ, with almost 100 billion neurons making a 100 trillion connections and an almost equal number of glial cells (Azevedo et al. 2009). Furthermore, the brain is not a static organ, but is undergoing cellular remodeling and synaptic modulation, which is the basis of our complex learning and memory. Even more amazing is that the brain develops de novo in every organism, ultimately from a single cell, the fertilized egg. The process of brain development and function requires the complex role of a large molecular repertoire. However, one signaling molecule that we are just beginning to learn its role, and which our understanding of that role is rapidly expanding, is the bioactive lipid lysophosphatidic acid (LPA). Lysophosphatidic acid (LPA), also known as monoacyl-sn-glycerol-3-phosphate, is a lysophospholipid that has a phosphoglycerol head group with a single fatty acid moiety. It is not a single chemical entity but represents a class of biological molecules with different fatty acid chain length and degrees of saturation. A variety of these different molecules are expressed biologically at different levels in * Eric Birgbauer [email protected] 1
Department of Biology, Winthrop University, Rock Hill, SC, USA
different tissues, including brain (Sugiura et al. 1999; Yung et al. 2014), but one of the most abundant species is 18:1 oleoyl-LPA (1-acyl-2-hydroxy-sn-glycero-3-phosphate), which is also the primary species in laboratory use. The highest levels of LPA are produced by platelets during clotting (Eichholtz et al. 1993), which can reach 10–15 µM in serum (Yung et al. 2014). However, levels in plasma are lower, generally less than 1 µM, and even lower in cerebrospinal fluid (CSF); furthermore, tissue levels of LPA under normal physiological conditions are generally quite low, in the nanomolar to tens or low hundreds nanomolar range (Yung et al. 2014). LPA is produced enzymatically primarily by two pathways, although there may b
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