title: Protein kinase C and Src family kinases mediate angiotensin II-induced protein kinase D activation and acute aldosterone production.
abstract: Recent evidence has shown a role for the serine/threonine protein kinase D (PKD) in the regulation of acute aldosterone secretion upon angiotensin II (AngII) stimulation. However, the mechanism by which AngII activates PKD remains unclear. In this study, using both pharmacological and molecular approaches, we demonstrate that AngII-induced PKD activation is mediated by protein kinase C (PKC) and Src family kinases in primary bovine adrenal glomerulosa cells and leads to increased aldosterone production. The pan PKC inhibitor Ro 31-8220 and the Src family kinase inhibitors PP2 and Src-1 inhibited both PKD activation and acute aldosterone production. Additionally, like the dominant-negative serine-738/742-to-alanine PKD mutant that cannot be phosphorylated by PKC, the dominant-negative tyrosine-463-to-phenylalanine PKD mutant, which is not phosphorylatable by the Src/Abl pathway, inhibited acute AngII-induced aldosterone production. Taken together, our results demonstrate that AngII activates PKD via a mechanism involving Src family kinases and PKC, to underlie increased aldosterone production.
authors.affiliation: Charlie Norwood VA Medical Center, Augusta, GA 30904, United States; Department of Physiology, Medical College of Georgia at Georgia Regents University, Augusta, GA 30912, United States.
authors.forename: Lawrence O
authors.initials: LO
authors.lastname: Olala
authors.affiliation: Institute of Molecular Medicine and Genetics, Medical College of Georgia at Georgia Regents University, Augusta, GA 30912, United States.
authors.forename: Brian A
authors.initials: BA
authors.lastname: Shapiro
authors.affiliation: Department of Surgery, Medical College of Georgia at Georgia Regents University, Augusta, GA 30912, United States.
authors.forename: Todd C
authors.initials: TC
authors.lastname: Merchen
authors.affiliation: Department of Surgery, Medical College of Georgia at Georgia Regents University, Augusta, GA 30912, United States.
authors.forename: James J
authors.initials: JJ
authors.lastname: Wynn
authors.affiliation: Charlie Norwood VA Medical Center, Augusta, GA 30904, United States; Department of Physiology, Medical College of Georgia at Georgia Regents University, Augusta, GA 30912, United States; Departments of Cell Biology and Anatomy, Medicine and Orthopaedic Surgery, Medical College of Georgia at Georgia Regents University, Augusta, GA 30912, United States. Electronic address: WB@gru.edu.
authors.forename: Wendy B
authors.initials: WB
authors.lastname: Bollag
mesh_terms: D000328:Adult; D000450:Aldosterone / Q000096:biosynthesis*; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D002417:Cattle; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D007211:Indoles; D050505:Mutant Proteins / Q000378:metabolism; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D015383:Zona Fasciculata / Q000201:enzymology; D015384:Zona Glomerulosa / Q000201:enzymology; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: C412373:AG 1879; D007211:Indoles; D050505:Mutant Proteins; D011743:Pyrimidines; D000804:Angiotensin II; D019000:Phosphotyrosine; D000450:Aldosterone; C089212:protein kinase D; D019061:src-Family Kinases; D011493:Protein Kinase C; C064758:Ro 31-8220
keywords: Adrenal glomerulosa; Aldosterone; Angiotensin II (AngII); Protein kinase C (PKC); Protein kinase D (PKD); Src family kinases