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Involvement of Protein Kinase C (PKC) in the Early Action of Angiotensin II Type 2 (AT₂) Effects on Neurite Outgrowth in NG108–15 Cells: AT₂-Receptor Inhibits PKC and p21^ras Activity

Service of Endocrinology (H.B., L.G., M.-O.G., N.G.-P.) and Department of Physiology and Biophysics (L.G., M.-D.P.), Faculty of Medicine, Université de Sherbrooke, Sherbrooke, Quebec, Canada J1H 5N4

Address all correspondence and requests for reprints to: Nicole Gallo-Payet, Service d’endocrinologie, Faculté de Médecine et des Sciences de la Santé, Université de Sherbrooke, Sherbrooke, Québec, Canada J1H 5N4. E-mail: nicole.gallo-payet{at}usherbrooke.ca.

The aim of the present study was to investigate whether protein kinase C (PKC) isoforms may be among the putative candidates implicated in the primary effects of the Ang II type 2 (AT₂) receptor. Western blot analyses revealed the presence of PKC,, , and in NG108–15 cells. After a 3-d treatment with 3 nM Gö6976, a specific inhibitor of classical PKC isoforms, cells were characterized by the presence of one elongated process similar to that observed after treatment with Ang II or with CGP42112, a selective AT₂ receptor agonist. Similar findings were observed in cells expressing a dominant-negative mutant of PKC (K368A). Inhibition of PKC in NG108–15 cells also decreased cell number and proliferation. In conditions of acute stimulation, Ang II induced a time-dependent and transient inhibition of PKC activity, as well as a decrease in PKC levels associated with the membrane. Treatment of cells with Gö6976 was also found to inhibit p21^ras (between 1–10 min) but stimulated Rap1 activity (1–5 min) in a time-course similar to that of Ang II. Incubation of NG108–15 cells with Gö6976 (3 nM) inhibited basal p42/p44^mapk phosphorylation, but failed to interfere with its activation by the AT₂ receptor, indicating that inhibition of PKC is not directly involved in the Rap1-MEK-p42/p44^mapk cascade. Taken together, these results indicate that PKC is a primary target of the AT₂ receptor. Inhibition of PKC leads to a decrease in both p21^ras activity and cell proliferation, which may facilitate AT₂ receptor signaling through p42/p44^mapk, thereby leading to neurite outgrowth.

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				B. Plouffe, M.-O. Guimond, H. Beaudry, and N. Gallo-Payet Role of Tyrosine Kinase Receptors in Angiotensin II AT2 Receptor Signaling: Involvement in Neurite Outgrowth and in p42/p44mapk Activation in NG108-15 Cells Endocrinology, October 1, 2006; 147(10): 4646 - 4654. [Abstract] [Full Text] [PDF]