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Signals from the AT₂ (Angiotensin Type 2) Receptor of Angiotensin II Inhibit p21^ras and Activate MAPK (Mitogen-Activated Protein Kinase) to Induce Morphological Neuronal Differentiation in NG108–15 Cells

Service of Endocrinology (L.G., L.L., N.G-P.) Department of Anatomy and Cell Biology (L.G., L.L., N.R., C.A., N.G-P.) Department of Physiology and Biophysics (M.D.P, N.G-P.) Faculty of Medicine University of Sherbrooke Sherbrooke J1H 5N4, Quebec, Canada

In a previous study, we had shown that activation of the AT₂ (angiotensin type 2) receptor of angiotensin II (Ang II) induced morphological differentiation of the neuronal cell line NG108–15. In the present study, we investigated the nature of the possible intracellular mediators involved in the AT₂ effect. We found that stimulation of AT₂ receptors in NG108–15 cells resulted in time-dependent modulation of tyrosine phosphorylation of a number of cytoplasmic proteins. Stimulation of NG108–15 cells with Ang II induced a decrease in GTP-bound p21^ras but a sustained increase in the activity of p42^mapk and p44^mapk as well as neurite outgrowth. Similarly, neurite elongation, increased polymerized tubulin levels, and increased mitogen-activated protein kinase (MAPK) activity were also observed in a stably transfected NG108–15 cell line expressing the dominant-negative mutant of p21^ras, RasN17. These results support the observation that inhibition of p21^ras did not impair the effect of Ang II on its ability to stimulate MAPK activity. While 10 µM of the MEK inhibitor, PD98059, only moderately affected elongation, 50 µM PD98059 completely blocked the Ang II- and the RasN17-mediated induction of neurite outgrowth. These results demonstrate that some of the events associated with the AT₂ receptor-induced neuronal morphological differentiation of NG108–15 cells not only include inhibition of p21^ras but an increase in MAPK activity as well, which is essential for neurite outgrowth.

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