title: Hormonal regulation of angiotensin II type 1 receptor expression and AT1-R mRNA levels in human adrenocortical cells.
abstract: Human adrenocortical H295R cells express AII receptors which are predominantly of the AT1 but not AT2 subclass. These receptors are functionally coupled to phosphoinositidase C in a manner similar to that seen in fetal human, sheep and bovine adrenocortical cells. Treatment of H295R cells with forskolin or dbcAMP to activate the protein kinase A pathway caused a rapid (maximal by 3 h) and sustained decrease in AT1-R mRNA levels which in turn preceded a time-dependent (maximal by 12 h) and dose-dependent loss of [125I]AII binding and phosphoinositidase C activation on subsequent AII challenge. Thus, both decreased AT1-R mRNA levels and functional receptor expression appear to parallel each other in response to activation of protein kinase A. Activation of the Ca2+/protein kinase C pathways by treatment with AII also caused a rapid (maximal by 3 h) and dose-dependent loss in AT1-R mRNA, but mRNA levels subsequently rose again, approaching control levels by 36 h. Treatment with AII for 48 h had little effect on either [125I]AII binding or the subsequent phosphoinositidase C response. The effect of AII, but not forskolin, was blocked by the presence of cycloheximide. The action of AII on AT1-R mRNA was probably mediated through both protein kinase C and Ca(2+)-sensitive protein kinases as the effect at 4 h was not completely reproduced by phorbol ester alone, but was fully reproduced by a combination of phorbol ester and Ca2+ ionophore. However, increased Ca2+ influx alone, due to treatment with BAYK8644 or elevated extracellular K+, also resulted in a decrease in AT1-R mRNA levels. Thus in the H295R cell, control of AT1-R expression appears to be complex, being achieved at least in part through control of the level of AT1-R mRNA by multiple independent signaling pathways including protein kinase A, protein kinase C and Ca2+.
authors.affiliation: Dept Ob/Gyn, Univ. Texas Southwestern Medical Center, Dallas 75235, USA.
authors.forename: I M
authors.initials: IM
authors.lastname: Bird
authors.forename: J I
authors.initials: JI
authors.lastname: Mason
authors.forename: W E
authors.initials: WE
authors.lastname: Rainey
mesh_terms: D000262:Adenylyl Cyclases / Q000187:drug effects; D000302:Adrenal Cortex / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology; D002417:Cattle; D004789:Enzyme Activation; D006728:Hormones / Q000502:physiology*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D019808:Losartan; D010727:Phosphoric Diester Hydrolases / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism*; D011945:Receptors, Angiotensin / Q000096:biosynthesis / Q000187:drug effects* / Q000235:genetics; D012756:Sheep; D013777:Tetrazoles / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D001713:Biphenyl Compounds; D006728:Hormones; D007093:Imidazoles; D011725:Pyridines; D012333:RNA, Messenger; D011945:Receptors, Angiotensin; D013777:Tetrazoles; D000804:Angiotensin II; C073402:PD 123319; D010727:Phosphoric Diester Hydrolases; C021491:glycerophosphoinositol glycerophosphodiesterase; D000262:Adenylyl Cyclases; D019808:Losartan