title: Losartan-sensitive AII receptors linked to depolarization-dependent cortisol secretion through a novel signaling pathway.
abstract: In bovine adrenal zona fasciculata (AZF) cells, angiotensin II (AII) may stimulate depolarization-dependent Ca2+ entry and cortisol secretion through inhibition of a novel potassium channel (IAC), which appears to set the resting potential of these cells. Aspects of the signaling pathway, which couples AII receptors to membrane depolarization and secretion, were characterized in patch clamp and membrane potential recordings and in secretion studies. AII-mediated inhibition of IAC, membrane depolarization, and cortisol secretion were all blocked by the AII type I (AT1) receptor antagonist losartan. These responses were unaffected by the AT2 antagonist PD123319. Inhibition of IAC by AII was prevented by intracellular application of guanosine 5'-O-2-(thio)-diphosphate but was not affected by pre-incubation of cells with pertussis toxin. Although mediated through an AT1 receptor, several lines of evidence indicated that AII inhibition of IAC occurred through an unusual phospholipase C (PLC)-independent pathway. Acetylcholine, which activates PLC in AZF cells, did not inhibit IAC. Neither the PLC antagonist neomycin nor PLC-generated second messengers prevented IAC expression or mimicked the inhibition of this current by AII. IAC expression and inhibition by AII were insensitive to variations in intracellular or extracellular Ca2+ concentration. AII-mediated inhibition of IAC was markedly reduced by the non-hydrolyzable ATP analog adenosine 5'-(beta, gamma-imino)triphosphate and by the non-selective protein kinase inhibitor staurosporine. The protein phosphatase antagonist okadaic acid reversibly inhibited IAC in whole cell recordings. These findings indicate that AII-stimulated effects on IAC current, membrane voltage, and cortisol secretion are linked through a common AT1 receptor. Inhibition of IAC in AZF cells appears to occur through a novel signaling pathway, which may include a losartan-sensitive AT1 receptor coupled through a pertussis-insensitive G protein to a staurosporine-sensitive protein kinase. Apparently, the mechanism linking AT1 receptors to IAC inhibition and Ca2+ influx in adrenocortical cells is separate from that involving inositol trisphosphate-stimulated Ca2+ release from intracellular stores. AII-stimulated cortisol secretion may occur through distinct parallel signaling pathways.
authors.affiliation: Department of Pharmacology, Ohio State University, College of Medicine, Columbus 43210-1239, USA.
authors.forename: B
authors.initials: B
authors.lastname: Mlinar
authors.forename: B A
authors.initials: BA
authors.lastname: Biagi
authors.forename: J J
authors.initials: JJ
authors.lastname: Enyeart
mesh_terms: D000311:Adrenal Glands / Q000378:metabolism* / Q000502:physiology; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology*; D002417:Cattle; D004789:Enzyme Activation; D019204:GTP-Binding Proteins / Q000378:metabolism; D006150:Guanine Nucleotides / Q000378:metabolism; D006854:Hydrocortisone / Q000378:metabolism*; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D015640:Ion Channel Gating; D019808:Losartan; D008564:Membrane Potentials; D010740:Phospholipases / Q000378:metabolism; D010766:Phosphorylation; D026902:Potassium Channel Blockers; D011494:Protein Kinases / Q000378:metabolism; D011945:Receptors, Angiotensin / Q000187:drug effects / Q000378:metabolism*; D015398:Signal Transduction; D013777:Tetrazoles / Q000494:pharmacology*
chemical_list: D001713:Biphenyl Compounds; D006150:Guanine Nucleotides; D007093:Imidazoles; D026902:Potassium Channel Blockers; D011945:Receptors, Angiotensin; D013777:Tetrazoles; D000804:Angiotensin II; D011494:Protein Kinases; D010740:Phospholipases; D019204:GTP-Binding Proteins; D019808:Losartan; D006854:Hydrocortisone