title: Targeted deletion of LPA5 identifies novel roles for lysophosphatidic acid signaling in development of neuropathic pain.
abstract: Lysophosphatidic acid (LPA) is a bioactive lipid that serves as an extracellular signaling molecule acting through cognate G protein-coupled receptors designated LPA(1-6) that mediate a wide range of both normal and pathological effects. Previously, LPA(1), a G(αi)-coupled receptor (which also couples to other G(α) proteins) to reduce cAMP, was shown to be essential for the initiation of neuropathic pain in the partial sciatic nerve ligation (PSNL) mouse model. Subsequent gene expression studies identified LPA(5), a G(α12/13)- and G(q)-coupled receptor that increases cAMP, in a subset of dorsal root ganglion neurons and also within neurons of the spinal cord dorsal horn in a pattern complementing, yet distinct from LPA(1), suggesting its possible involvement in neuropathic pain. We therefore generated an Lpar5 null mutant by targeted deletion followed by PSNL challenge. Homozygous null mutants did not show obvious base-line phenotypic defects. However, following PSNL, LPA(5)-deficient mice were protected from developing neuropathic pain. They also showed reduced phosphorylated cAMP response element-binding protein expression within neurons of the dorsal horn despite continued up-regulation of the characteristic pain-related markers Caα(2)δ(1) and glial fibrillary acidic protein, results that were distinct from those previously observed for LPA(1) deletion. These data expand the influences of LPA signaling in neuropathic pain through a second LPA receptor subtype, LPA(5), involving a mechanistically distinct downstream signaling pathway compared with LPA(1).
authors.affiliation: Scripps Research Institute, Molecular Biology Department, Dorris Neuroscience Center, La Jolla, California 92037; Biomedical Sciences Graduate Program, University of California San Diego, La Jolla, California 92093.
authors.forename: Mu-En
authors.initials: ME
authors.lastname: Lin
authors.affiliation: Scripps Research Institute, Molecular Biology Department, Dorris Neuroscience Center, La Jolla, California 92037.
authors.forename: Richard R
authors.initials: RR
authors.lastname: Rivera
authors.affiliation: Scripps Research Institute, Molecular Biology Department, Dorris Neuroscience Center, La Jolla, California 92037. Electronic address: jchun@scripps.edu.
authors.forename: Jerold
authors.initials: J
authors.lastname: Chun
mesh_terms: D000818:Animals; D000242:Cyclic AMP / Q000235:genetics / Q000378:metabolism; D044365:GTP-Binding Protein alpha Subunits, G12-G13 / Q000235:genetics / Q000378:metabolism; D005727:Ganglia, Spinal / Q000378:metabolism* / Q000473:pathology; D017353:Gene Deletion; D008246:Lysophospholipids / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009437:Neuralgia / Q000235:genetics / Q000378:metabolism*; D049368:Receptors, Lysophosphatidic Acid / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements / Q000235:genetics; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D008246:Lysophospholipids; D009419:Nerve Tissue Proteins; D049368:Receptors, Lysophosphatidic Acid; D014157:Transcription Factors; D000242:Cyclic AMP; D044365:GTP-Binding Protein alpha Subunits, G12-G13; C032881:lysophosphatidic acid