Lysophosphatidic Acid (LPA) Receptor Signaling

Mirendil, Hope; Lin, Mu‐En; Chun, Jerold

doi:10.1002/9781118531426.ch1

Cited by 4 publications

(4 citation statements)

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“…In view of the broad neurobiological influences of LPA signaling, its dysregulation may lead to diverse neuropathologies (Bandoh et al, 2000; Houben and Moolenaar, 2011; Yung et al, 2011; Ueda et al, 2013). LPs and their relevance to non-nervous system tissues have been reviewed elsewhere (Choi et al, 2010; Mirendil et al, 2013). …”

Section: Introductionmentioning

confidence: 99%

Lysophosphatidic Acid Signaling in the Nervous System

Yung

Stoddard

Mirendil

et al. 2015

Neuron

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226

177

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Summary The brain is composed of many lipids with varied forms that serve not only as structural components but also as essential signaling molecules. Lysophosphatidic acid (LPA) is an important bioactive lipid species that is part of the lysophospholipid (LP) family. LPA is primarily derived from membrane phospholipids and signals through six cognate G protein-coupled receptors (GPCRs), LPA1-6. These receptors are expressed on most cell types within central and peripheral nervous tissues and have been functionally linked to many neural processes and pathways. This review covers a current understanding of LPA signaling in the nervous system, with particular focus on the relevance of LPA to both physiological and diseased states.

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Section: Introductionmentioning

confidence: 99%

Lysophosphatidic Acid Signaling in the Nervous System

Yung

Stoddard

Mirendil

et al. 2015

Neuron

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226

177

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“…LPA is present in nearly all cells, tissues and fluids of the body (Mirendil et al, 2013) and its effects are mediated by cognate cell-surface G protein-coupled receptors (GPCRs) consisting of six family members designated LPA 1 -LPA 6 (Kihara et al, 2014) that couple to heterotrimeric G protein complexes to activate downstream signaling pathways. Targeted deletion of the LPA receptors has revealed physiological effects on every organ system examined thus far, with receptor dysregulation linked to a range of disease indications including hydrocephalus (Yung et al, 2011), infertility (Ye et al, 2005), fibrosis (Tager et al, 2008), pain (Inoue et al, 2004) and cancer (Mills and Moolenaar, 2003).…”

Section: Introductionmentioning

confidence: 99%

Crystal Structure of Antagonist Bound Human Lysophosphatidic Acid Receptor 1

Chrencik¹,

Roth²,

Terakado

et al. 2015

Cell

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181

175

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Summary Lipid biology continues to emerge as an area of significant therapeutic interest, particularly as the result of an enhanced understanding of the wealth of signaling molecules with diverse physiological properties. This growth in knowledge is epitomized by lysophosphatidic acid (LPA), which functions through interactions with six cognate G protein-coupled receptors. Herein we present three crystal structures of LPA1 in complex with antagonist tool compounds selected and designed through structural and stability analysis. Structural analysis combined with molecular dynamics identified a basis for ligand access to the LPA1 binding pocket from the extracellular space contrasting with the proposed access for the sphingosine 1-phosphate receptor. Characteristics of the LPA1 binding pocket raise the possibility of promiscuous ligand recognition of phosphorylated endocannabinoids. Cell-based assays confirmed this hypothesis, linking the distinct receptor systems through metabolically related ligands with potential functional and therapeutic implications for treatment of disease.

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“… 66 , 67 , 68 , 69 Disturbances in neural precursor cell migration, proliferation and cortical layer formation are strongly linked to several environmental and genetic risk factors, and LPA receptor modulation is known to be capable of disrupting these neurodevelopmental processes. 15 Alterations in LPA receptor signaling could represent a shared, proximal modulator of these molecular and cellular events; specifically those events initiated by hemorrhage or related environmental risk factors for schizophrenia. Notably, gene expression analyses identified a significant overlap with a highly validated schizophrenia-related gene set in both serum- and, especially, LPA exposure models.…”

Section: Discussionmentioning

confidence: 99%

“…LPA acts through at least six currently identified cell surface G protein-coupled receptors, LPA 1 –LPA 6 . 15 These receptors are widely expressed in the developing brain, and LPA signaling affects a range of important neurodevelopmental processes, including cell proliferation, migration, process outgrowth and apoptosis. 16 LPA is present in the blood and can reach concentrations in serum of up to 20 μ M , 17 which is on the order of 20 000-fold over apparent LPA receptor K D s. 16 LPA can also induce production of interleukin-6, tumor necrosis factor alpha/beta and other cytokines during immune activation or prenatal cerebral bleeding, 18 , 19 providing a link between LPA signaling and previously identified prenatal environmental risk factors relevant to schizophrenia.…”

Section: Introductionmentioning

confidence: 99%

LPA signaling initiates schizophrenia-like brain and behavioral changes in a mouse model of prenatal brain hemorrhage

et al. 2015

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Genetic, environmental and neurodevelopmental factors are thought to underlie the onset of neuropsychiatric disorders such as schizophrenia. How these risk factors collectively contribute to pathology is unclear. Here, we present a mouse model of prenatal intracerebral hemorrhage—an identified risk factor for schizophrenia—using a serum-exposure paradigm. This model exhibits behavioral, neurochemical and schizophrenia-related gene expression alterations in adult females. Behavioral alterations in amphetamine-induced locomotion, prepulse inhibition, thigmotaxis and social interaction—in addition to increases in tyrosine hydroxylase-positive dopaminergic cells in the substantia nigra and ventral tegmental area and decreases in parvalbumin-positive cells in the prefrontal cortex—were induced upon prenatal serum exposure. Lysophosphatidic acid (LPA), a lipid component of serum, was identified as a key molecular initiator of schizophrenia-like sequelae induced by serum. Prenatal exposure to LPA alone phenocopied many of the schizophrenia-like alterations seen in the serum model, whereas pretreatment with an antagonist against the LPA receptor subtype LPA1 prevented many of the behavioral and neurochemical alterations. In addition, both prenatal serum and LPA exposure altered the expression of many genes and pathways related to schizophrenia, including the expression of Grin2b, Slc17a7 and Grid1. These findings demonstrate that aberrant LPA receptor signaling associated with fetal brain hemorrhage may contribute to the development of some neuropsychiatric disorders.

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Lysophosphatidic Acid (LPA) Receptor Signaling

Cited by 4 publications

References 253 publications

Lysophosphatidic Acid Signaling in the Nervous System

Lysophosphatidic Acid Signaling in the Nervous System

Crystal Structure of Antagonist Bound Human Lysophosphatidic Acid Receptor 1

LPA signaling initiates schizophrenia-like brain and behavioral changes in a mouse model of prenatal brain hemorrhage

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