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- Title
Protean agonism of the lysophosphatidic acid receptor-1 with Ki16425 reduces nerve growth factor-induced neurite outgrowth in pheochromocytoma 12 cells.
- Authors
Moughal, Noreen A; Waters, Catherine M; Valentine, William J; Connell, Michelle; Richardson, Jill C; Tigyi, Gabor; Pyne, Susan; Pyne, Nigel J
- 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.
- Publication
Journal of neurochemistry, 2006, Vol 98, Issue 6, p1920
- ISSN
0022-3042
- Publication type
Journal Article
- DOI
10.1111/j.1471-4159.2006.04009.x