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Strathprints serves world leading Open Access research by the University of Strathclyde, including research by the Strathclyde Institute of Pharmacy and Biomedical Sciences (SIPBS), where research centres such as the Industrial Biotechnology Innovation Centre (IBioIC), the Cancer Research UK Formulation Unit, SeaBioTech and the Centre for Biophotonics are based.

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Protean agonism of the lysophosphatidic acid receptor-1 with Ki16425 reduces nerve growth factor-induced neurite outgrowth in pheochromocytoma 12 cells

Moughal, Noreen A and Waters, Catherine M and Valentine, William J and Connell, Michelle and Richardson, Jill C and Tigyi, Gabor and Pyne, Susan and Pyne, Nigel J (2006) Protean agonism of the lysophosphatidic acid receptor-1 with Ki16425 reduces nerve growth factor-induced neurite outgrowth in pheochromocytoma 12 cells. Journal of Neurochemistry, 98 (6). pp. 1920-1929. ISSN 0022-3042

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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.