LPA(4)/GPR23 is a lysophosphatidic acid (LPA) receptor utilizing G(s)-, G(q)/G(i)-mediated calcium signaling and G(12/13)-mediated Rho activation.
Lysophosphatidic acid (LPA) is a bioactive lysophospholipid that signals through G protein-coupled receptors (GPCRs) to produce a range of biological responses. A recently reported fourth receptor, LPA(4)/GPR23, was notable for its low homology to the previously identified receptors LPA(1-3) and for its ability to increase intracellular concentrations of cAMP and calcium. However, the signaling pathways leading to LPA(4)-mediated induction of cAMP and calcium levels have not been reported. Using epitope-tagged LPA(4), pharmacological intervention, and G protein mini-genes, we provide independent confirmatory evidence that supports LPA(4) as a fourth LPA receptor, including LPA concentration-dependent responses and specific membrane binding. Importantly, we further demonstrate new LPA-dependent activities of LPA(4) that include the following: receptor internalization; G(12/13)- and Rho-mediated neurite retraction and stress fiber formation; G(q) protein and pertussis toxin-sensitive calcium mobilization and activation of a nonselective cation conductance; and cAMP increases mediated by G(s). The receptor is broadly expressed in embryonic tissues, including brain, as determined by Northern blot and reverse transcription-PCR analysis. Adult tissues have increased expression in skin, heart, and to a lesser extent, thymus. These data confirm the identification and extend the functionality of LPA(4) as an LPA receptor, bringing the number of independently verified LPA receptors to five, with both overlapping and distinct signaling properties and tissue expression.
Lee
Chang-Wook
CW
Department of Molecular Biology, Helen L. Dorris Institute for Neurological and Psychiatric Disorders, The Scripps Research Institute, La Jolla, California 92037.
Rivera
Richard
R
Department of Molecular Biology, Helen L. Dorris Institute for Neurological and Psychiatric Disorders, The Scripps Research Institute, La Jolla, California 92037.
Dubin
Adrienne E
AE
Department of Molecular Biology, Helen L. Dorris Institute for Neurological and Psychiatric Disorders, The Scripps Research Institute, La Jolla, California 92037.
Chun
Jerold
J
Department of Molecular Biology, Helen L. Dorris Institute for Neurological and Psychiatric Disorders, The Scripps Research Institute, La Jolla, California 92037. Electronic address: jchun@scripps.edu.
D000328:Adult; D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D045744:Cell Line, Tumor; D000242:Cyclic AMP / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian / Q000378:metabolism; D004789:Enzyme Activation; D044365:GTP-Binding Protein alpha Subunits, G12-G13 / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000235:genetics / Q000378:metabolism; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000235:genetics / Q000378:metabolism; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D008246:Lysophospholipids / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D016501:Neurites / Q000378:metabolism; D009928:Organ Specificity / Q000502:physiology; D049368:Receptors, Lysophosphatidic Acid / Q000235:genetics / Q000378:metabolism*; D018048:Receptors, Purinergic P2 / Q000235:genetics / Q000378:metabolism*; D022502:Stress Fibers / Q000235:genetics / Q000378:metabolism*; D020741:rho GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism
C082320:LPAR4 protein, human; D008246:Lysophospholipids; D049368:Receptors, Lysophosphatidic Acid; D018048:Receptors, Purinergic P2; D000242:Cyclic AMP; D019204:GTP-Binding Proteins; D044365:GTP-Binding Protein alpha Subunits, G12-G13; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D019205:GTP-Binding Protein alpha Subunits, Gs; D020741:rho GTP-Binding Proteins