title: Protean agonism of the lysophosphatidic acid receptor-1 with Ki16425 reduces nerve growth factor-induced neurite outgrowth in pheochromocytoma 12 cells.
abstract: We report here a novel role for the constitutively active lysophosphatidic acid receptor-1 (LPA(1)) receptor in providing Gbetagamma subunits for use by the Trk A receptor. This enhances the ability of nerve growth factor (NGF) to promote signalling and cell response. These conclusions were based on three lines of evidence. Firstly, the LPA(1) receptor was co-immunoprecipitated with the Trk A receptor from lysates, suggesting that these proteins form a complex. Secondly, Ki16425, a selective protean agonist of the LPA(1) receptor, decreased constitutive basal and LPA-induced LPA(1) receptor-stimulated GTPgammaS binding. Ki16425 reduced the LPA-induced activation of p42/p44 mitogen activated protein kinase (MAPK), while acting as a weak stimulator of p42/p44 MAPK on its own, properties typical of a protean agonist. Significantly, Ki16425 also reduced the NGF-induced stimulation of p42/p44 MAPK and inhibited NGF-stimulated neurite outgrowth. Thirdly, the over-expression of the C-terminal GRK-2 peptide, which sequesters Gbetagamma subunits, reduced the NGF-induced activation of p42/p44 MAPK. In contrast, the stimulation of PC12 cells with LPA leads to a predominant G(i)alpha2-mediated Trk A-independent activation of p42/p44 MAPK, where Gbetagamma subunits play a diminished role. These findings suggest a novel role for the constitutively active LPA(1) receptor in regulating NGF-induced neuronal differentiation.
authors.affiliation: Department of Physiology and Pharmacology, Strathclyde Institute for Biomedical Sciences, University of Strathclyde, Glasgow, UK.
authors.forename: Noreen A
authors.initials: NA
authors.lastname: Moughal
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Waters
authors.forename: William J
authors.initials: WJ
authors.lastname: Valentine
authors.forename: Michelle
authors.initials: M
authors.lastname: Connell
authors.forename: Jill C
authors.initials: JC
authors.lastname: Richardson
authors.forename: Gabor
authors.initials: G
authors.lastname: Tigyi
authors.forename: Susan
authors.initials: S
authors.lastname: Pyne
authors.forename: Nigel J
authors.initials: NJ
authors.lastname: Pyne
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000502:physiology; D044387:GTP-Binding Protein beta Subunits / Q000502:physiology; D044388:GTP-Binding Protein gamma Subunits / Q000502:physiology; D007555:Isoxazoles / Q000494:pharmacology*; D020932:Nerve Growth Factor / Q000494:pharmacology*; D016501:Neurites / Q000187:drug effects* / Q000502:physiology*; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D016716:PC12 Cells; D011422:Propionates / Q000494:pharmacology*; D051381:Rats; D020917:Receptor, trkA / Q000378:metabolism; D049368:Receptors, Lysophosphatidic Acid / Q000819:agonists* / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C477898:3-(4-(4-((1-(2-chlorophenyl)ethoxy)carbonyl amino)-3-methyl-5-isoxazolyl) benzylsulfanyl) propanoic acid; D044387:GTP-Binding Protein beta Subunits; D044388:GTP-Binding Protein gamma Subunits; D007555:Isoxazoles; D011422:Propionates; D049368:Receptors, Lysophosphatidic Acid; D020932:Nerve Growth Factor; D020917:Receptor, trkA; D019206:GTP-Binding Protein alpha Subunits, Gi-Go