Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0030193 (pain)
 261,466 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recently, we reported that lysophosphatidic acid (LPA) induces long-lasting mechanical allodynia and thermal hyperalgesia as well as demyelination and upregulation of pain-related proteins through one of its cognate receptors, LPA1. In addition, mice lacking the LPA1 receptor gene (lpa1-/- mice) lost these nerve injury-induced neuropathic pain behaviors and phenomena. However, since lpa1-/- mice did not exhibit any effects on the basal nociceptive threshold, it is possible that nerve injury-induced neuropathic pain and its machineries are initiated by LPA via defined biosynthetic pathways that involve multiple enzymes. Here, we attempted to clarify the involvement of a single synthetic enzyme of LPA known as autotaxin (ATX) in nerve injury-induced neuropathic pain. Wild-type mice with partial sciatic nerve injury showed robust mechanical allodynia starting from day 3 after the nerve injury and persisting for at least 14 days, along with thermal hyperalgesia. On the other hand, heterozygous mutant mice for the autotaxin gene (atx+/-), which have 50% ATX protein and 50% lysophospholipase D activity compared with wild-type mice, showed approximately 50% recovery of nerve injury-induced neuropathic pain. In addition, hypersensitization of myelinated Abeta or Adelta-fiber function following nerve injury was observed in electrical stimuli-induced paw withdrawal tests using a Neurometer. The hyperalgesia was completely abolished in lpa1-/- mice, and reduced by 50% in atx+/- mice. Taken together, these findings suggest that LPA biosynthesis through ATX is the source of LPA for LPA1 receptor-mediated neuropathic pain. Therefore, targeted inhibition of ATX-mediated LPA biosynthesis as well as LPA1 receptor and its downstream pathways may represent a novel way to prevent nerve injury-induced neuropathic pain.
Mol Pain 2008 Feb 08
PMID:Autotaxin, a synthetic enzyme of lysophosphatidic acid (LPA), mediates the induction of nerve-injured neuropathic pain. 1826 Dec 10

Lysophosphatidic acid receptor (LPA(1)) signaling initiates neuropathic pain and several pathological events in a partial sciatic nerve injury model. Recently, we reported that lysophosphatidic acid (LPA) induces neuropathic pain as well as demyelination and pain-related protein expression changes via LPA(1) receptor signaling. Lysophosphatidylcholine (LPC), also known as lysolecithin, which is hydrolyzed by autotaxin/ATX into LPA, induces similar plastic changes. Here, we attempted to clarify whether ATX and LPA(1) receptor signaling is involved in the LPC-induced neuropathic pain. In wild-type mice, a single intrathecal (i.t.) injection of LPC induced mechanical allodynia and thermal hyperalgesia 2 days after injection; this persisted for 7 days at least. On the other hand, LPC-induced mechanical allodynia and thermal hyperalgesia were completely abolished in mice lacking an LPA(1) receptor gene. Furthermore, the LPC-induced response was also significantly, but partially reduced in heterozygous mutant mice for the ATX gene. These findings suggest that intrathecally-injected LPC is converted to LPA by ATX, and this LPA activates the LPA(1) receptor to initiate neuropathic pain.
 ...
PMID:Lysophosphatidylcholine induces neuropathic pain through an action of autotaxin to generate lysophosphatidic acid. 1828 50

Lysophosphatidic acid (LPA, 1- or 2-acyl-sn-glycerol 3-phosphate) is a simple phospholipid but displays an intriguing cell biology that is mediated via interactions with G protein-coupled seven transmembrane receptors (GPCRs). So far, five GPCRs, designated LPA1-5, and, more recently, two additional GPCRs, GPR87 and P2Y5, have been identified as receptors for LPA. These LPA receptors can be classified into two families, the EDG and P2Y families, depending on their primary structures. Recent studies on gene targeting mice and family diseases of these receptors revealed that LPA is involved in both pathological and physiological states including brain development (LPA1), neuropathy pain (LPA1), lung fibrosis (LPA1), renal fibrosis (LPA1) protection against radiation-induced intestinal injury (LPA2), implantation (LPA3) and hair growth (P2Y5). LPA is produced both in cells and biological fluids, where multiple synthetic reactions occur. There are at least two pathways for LPA production. In serum or plasma, LPA is predominantly produced by a plasma enzyme called autotaxin (ATX). ATX is a multifunctional ectoenzyme and is involved in many patho-physiological conditions such as cancer, neuropathy pain, lymphocyte tracking in lymph nodes, obesity, diabetes and embryonic blood vessel formation. LPA is also produced from phosphatidic acid (PA) by its deacylation catalyzed by phospholipase A (PLA)-type enzymes. However, the physiological roles of this pathway as well as the enzymes involved remained to be solved. A number of phospholipase A1 and A2 isozymes could be involved in this pathway. One PA-selective PLA1 called mPA-PLA1alpha/LIPH is specifically expressed in hair follicles, where it has a critical role in hair growth by producing LPA through a novel LPA receptor called P2Y5.
 ...
PMID:Two pathways for lysophosphatidic acid production. 1862 Nov 44

Lysophosphatidic acids (LPAs) are structurally simple lipid phosphate esters with a widely appreciated role as extracellular signaling molecules. LPA binds to selective cell surface receptors to promote cell growth, survival, motility and differentiation. Studies using LPA receptor knockout mice and experimental therapeutics targeting these receptors identify roles for LPA signaling in processes that include cardiovascular disease and function, angiogenesis, reproduction, cancer progression and neuropathic pain. These studies identify considerable functional redundancy between these receptors and raise the possibility that additional lysophosphatidic acid receptors remain to be identified. LPA is present in the blood and other biological fluids at physiologically relevant concentrations and can likely be rapidly generated and degraded in different locations, for example at sites of inflammation, vascular injury and thrombosis or in the tumor micro environment. Recent work identifies a secreted enzyme, autotaxin (ATX), as the key component of an extracellular pathway for generation of lysophosphatidic acid by lysophospholipase D catalyzed hydrolysis of lysophospholipid substrates. In contrast to the apparently redundant functions of LPA receptors, studies using ATX knock out and transgenic mice indicate that this enzyme is uniquely required for LPA signaling during early development and serves as the primary determinant of circulating LPA levels in adult animals. Accordingly, pharmacological inhibition of ATX may be a viable and potentially effective way to interfere with LPA signaling in the cardiovascular system and possibly other settings such as tumor metastasis for therapeutic benefit. In this review we provide an update on recent advances in defining roles for LPA signaling in major disease processes and discuss recent progress in understanding the regulation and function of autotaxin focusing on strategies for the identification and initial evaluation of small molecule autotaxin inhibitors.
 ...
PMID:Therapeutic potential of autotaxin/lysophospholipase d inhibitors. 1869 Oct 16

Lysophosphatidic acid (LPA, 1- or 2-acyl-sn-glycerol 3-phosphate) is a simple phospholipid but displays an intriguing cell biology that is mediated via interactions with both G-protein-coupled seven transmembrane receptors (GPCRs) and nuclear hormone receptors. So far, seven GPCRs (LPA(1-5) and recently reported GPR87/LPA(6) and P2Y5/LPA(7)) and a nuclear hormone receptor, PPARgamma, have been identified. LPA is predominantly produced in blood and a plasma enzyme, autotaxin, is involved in its production. Recent gene manipulating studies of these proteins have shown that LPA is involved in both pathological and physiological states including brain development, neuropathy pain, implantation, protection against radiation-induced intestinal injury and blood vessel formation. In addition, lipids similar to LPA, such as sphingosine 1-phosphate (S1P) and 2-arachidonylglycerol (2-AG), share common cellular signaling pathways with LPA and are now considered as promising targets of human therapy including immunosuppressant and anti-obesity drugs. Thus, LPA is now one of the most attractive targets for prevention and treatment of various diseases. Receptor-selective antagonists and agonists as well as inhibitors of LPA producing enzymes are undoubtedly useful. Recognition of the ligand, LPA, by each receptor seems to be quite different, as LPA species with various fatty acids at either the sn-1 or sn-2 position of the hydroxy residue activate each receptor quite differently. In the last decade a series of LPA analogs in which the sn-1 or sn-2 hydroxy, acyl chain, glycerol and phosphate group are modified have been created and evaluated by several laboratories. Here we review recent advances in the development of LPA-receptor targeted compounds (agonists and antagonists) and anti-autotaxin inhibitors.
 ...
PMID:LPA and its analogs-attractive tools for elucidation of LPA biology and drug development. 1878 39

We previously reported that nerve injury-induced neuropathic pain and its underlying mechanisms are initiated by lysophosphatidic acid. In the present study, by measuring cell-rounding in a biological assay using lysophosphatidic acid 1 receptor-expressing B103 cells, we evaluated the molecular mechanism underlying lysophosphatidic acid biosynthesis following intense stimulation of primary afferents. Lysophosphatidic acid production was induced by treatment of spinal cord slices with capsaicin (10 microM), an intense stimulator of primary afferents, in the presence of recombinant autotaxin, but not in its absence. Lysophosphatidic acid was also induced by combination treatment of slices with high doses (10 and 30 microM) of substance P and NMDA, but not by other combinations of substance P, NMDA, calcitonin gene-related peptide and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (30 microM each) in the presence of recombinant autotaxin. We also found that following neurokinin 1 and NMDA receptor activation, activation of both cytosolic phospholipase A(2) and calcium-independent intracellular phospholipase A(2) signalling pathways through protein kinase C and mitogen-activated protein/extracellular signal-regulated kinase activation and intracellular calcium elevation were required for lysophosphatidic acid production. These findings suggest that simultaneous intense stimulation of neurokinin 1 and NMDA receptors in the spinal dorsal horn triggers lysophosphatidic acid production from lysophosphatidylcholine through extracellular autotaxin.
 ...
PMID:Simultaneous stimulation of spinal NK1 and NMDA receptors produces LPC which undergoes ATX-mediated conversion to LPA, an initiator of neuropathic pain. 1901 89

Autotaxin (ATX) catalyzes the hydrolysis of lysophosphatidylcholine (LPC) to form the bioactive lipid lysophosphatidic acid (LPA). LPA stimulates cell proliferation, cell survival, and cell migration and is involved in obesity, rheumatoid arthritis, neuropathic pain, atherosclerosis and various cancers, suggesting that ATX inhibitors have broad therapeutic potential. Product feedback inhibition of ATX by LPA has stimulated structure-activity studies focused on LPA analogs. However, LPA displays mixed mode inhibition, indicating that it can bind to both the enzyme and the enzyme-substrate complex. This suggests that LPA may not interact solely with the catalytic site. In this report we have prepared LPC analogs to help map out substrate structure-activity relationships. The structural variances include length and unsaturation of the fatty tail, choline and polar linker presence, acyl versus ether linkage of the hydrocarbon chain, and methylene and nitrogen replacement of the choline oxygen. All LPC analogs were assayed in competition with the synthetic substrate, FS-3, to show the preference ATX has for each alteration. Choline presence and methylene replacement of the choline oxygen were detrimental to ATX recognition. These findings provide insights into the structure of the enzyme in the vicinity of the catalytic site as well as suggesting that ATX produces rate enhancement, at least in part, by substrate destabilization.
 ...
PMID:Autotaxin structure-activity relationships revealed through lysophosphatidylcholine analogs. 1934 87

Autotaxin (ATX) is a member of the ecto-nucleotide pyrophosphatase/phosphodiesterase (NPP) family and is a lysophospholipase D that cleaves the choline headgroup from lysophosphatidylcholine to generate the bioactive lipid lysophosphatidic acid (LPA). Enhanced expression of ATX and specific receptors for LPA in numerous cancer cell types has created an interest in studying ATX as a potential chemotherapeutic target. Likewise, ATX has been linked to several additional human diseases including multiple sclerosis, diabetes, obesity, neuropathic pain, and Alzheimer's disease. ATX inhibitors reported to date consist of metal ion chelators, lipid-like product analogs, and non-lipid small molecules. In the current research, we examined the pharmacology of the best of our previously reported non-lipid small molecule inhibitors. Here, these six inhibitors were studied utilizing the synthetic fluorescent lysophospholipid substrate FS-3, the nucleotide substrate pNP-TMP and the endogenous substrate LPC (16:0). All six compounds inhibited FS-3 hydrolysis >or=50%, whereas only three inhibited the hydrolysis of pNP-TMP to this degree. None of the six compounds blocked LPC 16:0 hydrolysis within the desired 50% inhibition range. The most potent analog (5, H2L 7905958) displayed an IC(50) of 1.6microM (K(i)=1.9microM, competitive inhibition) with respect to ATX-mediated FS-3 hydrolysis and an IC(50) of 1.2microM (K(i)=K(i)(')=6.5microM, non-competitive inhibition) against ATX-mediated pNP-TMP hydrolysis. All six inhibitors were specific for ATX as they were without affect on two additional lipid preferring NPP isoforms.
 ...
PMID:Characterization of non-lipid autotaxin inhibitors. 2000 24

We previously reported that lysophosphatidic acid (LPA) initiates nerve injury-induced neuropathic pain and its underlying mechanisms. In addition, we recently demonstrated that intrathecal injection of LPA induces de novo LPA production through the action of autotaxin (ATX), which converts lysophosphatidylcholine to LPA. Here, we examined nerve injury-induced de novo LPA production by using a highly sensitive biological titration assay with B103 cells expressing LPA1 receptors. Nerve injury caused high levels of LPA production in the ipsilateral sides of the spinal dorsal horn and dorsal roots, but not in the dorsal root ganglion, spinal nerve, or sciatic nerve. Nerve injury-induced LPA production reached its maximum at 3 h after injury, followed by a rapid decline by 6 h. The LPA production was significantly attenuated in ATX heterozygous mutant mice, whereas the concentration and activity of ATX in cerebrospinal fluid were not affected by nerve injury. On the other hand, the activities of cytosolic phospholipase A2 (cPLA2) and calcium-independent phospholipase A2 (iPLA2) were enhanced, with peaks at 1 h after injury. Both de novo LPA production and neuropathic pain-like behaviors were substantially abolished by intrathecal injection of arachidonyl trifluoromethyl ketone, a mixed inhibitor of cPLA2 and iPLA2, or bromoenol lactone, an iPLA2 inhibitor, at 1 h after injury. However, administration of these inhibitors at 6 h after injury had no significant effect on neuropathic pain. These findings provide evidence that PLA2- and ATX-mediated de novo LPA production in the early phase is involved in nerve injury-induced neuropathic pain.
 ...
PMID:Evidence for de novo synthesis of lysophosphatidic acid in the spinal cord through phospholipase A2 and autotaxin in nerve injury-induced neuropathic pain. 2012 31

Lysophosphatidic acid (LPA) exhibits a wide variety of biological functions as a bio-active lysophospholipid through G-protein-coupled receptors specific to LPA. Currently at least six LPA receptors are identified, named LPA(1) to LPA(6), while the existence of other LPA receptors has been suggested. From studies on knockout mice and hereditary diseases of these LPA receptors, it is now clear that LPA is involved in various biological processes including brain development and embryo implantation, as well as patho-physiological conditions including neuropathic pain and pulmonary and renal fibrosis. Unlike sphingosine 1-phosphate, a structurally similar bio-active lysophospholipid to LPA and produced intracellularly, LPA is produced by multiple extracellular degradative routes. A plasma enzyme called autotaxin (ATX) is responsible for the most of LPA production in our bodies. ATX converts lysophospholipids such as lysophosphatidylcholine to LPA by its lysophospholipase D activity. Recent studies on ATX have revealed new aspects of LPA. In this review, we highlight recent advances in our understanding of LPA functions and several aspects of ATX, including its activity, expression, structure, biochemical properties, the mechanism by which it stimulates cell motility and its pahto-physiological function through LPA production.
 ...
PMID:Biological roles of lysophosphatidic acid signaling through its production by autotaxin. 2041 46


1 2 3 4 Next >>