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Raf-1 Kinase Activation by Angiotensin II in Adrenal Glomerulosa Cells: Roles of G_i, Phosphatidylinositol 3-Kinase, and Ca²⁺ Influx

Endocrinology and Reproduction Research Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892-4510; and Molecular Radiology Section, Virginia Commonwealth University (P.D.), Richmond, Virginia 23298-0058

Address all correspondence and requests for reprints to: Dr. K. J. Catt, ERRB, NICHD, National Institutes of Health, Building 49, Room 6A-36, 49 Convent Drive, Bethesda, Maryland 20892-4510. E-mail: catt{at}helix.nih.gov

Little is known of the mechanisms leading to mitogen-activated protein kinase (MAPK) activation via G_q-coupled receptors. We therefore examined the pathways by which angiotensin II (Ang II) activates Raf-1 kinase, an upstream intermediate in the pathway to MAPK, via the G_q-coupled AT₁ angiotensin receptor in bovine adrenal glomerulosa (BAG) cells. Ang II caused a rapid and transient activation of Raf-1 that reached a peak at 5–10 min. Ang II was a potent stimulus of Raf-1 activation with an ED₅₀ of 10 pM and a maximal response at 1 nM, although higher Ang II concentrations elicited a submaximal response. Ang II-stimulated Raf-1 activity was unaffected by down-regulation of protein kinase C and intracellular Ca²⁺ chelation (using BAPTA) but was partially inhibited by pertussis toxin, and was abolished by manumycin A. Removal of extracellular Ca²⁺ (by EGTA) or blockade of L type Ca²⁺ channels (by nifedipine), as well as inhibition of MEK-1 kinase (by PD98059), enhanced Raf-1 activity, whereas wortmannin (100 nM) inhibited approximately one half of Ang II-stimulated Raf-1 activity. Hence, Raf-1 kinase activation by Ang II in BAG cells is dependent on Ras, is mediated in part via G_i and phosphatidylinositol 3-kinase, and is negatively regulated via Ca²⁺ influx and a downstream signaling element(s).

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