title: Type 1 angiotensin receptor (AT1-R)-mediated decrease in type 2 angiotensin receptor mRNA level is dependent on Gq and extracellular signal-regulated kinase 1//2 in AT1-R-transfected PC12 cells.
abstract: Angiotensin II (Ang II) functions through two major Ang II receptor subtypes, type 1 (AT1-R) and type 2 (AT2-R), both of which are classified to be G protein-coupled receptors. AT2-R is highly expressed at the fetal stage, and in heart remodelling and brain ischaemia; therefore, it is important to clarify the regulatory mechanisms of AT2-R expression. Although AT1-R is generally believed to modulate AT2-R expression in some tissues or cells, the exact mechanism remains to be clarified. In the present study, we examined the effect of AT1-R stimulation on expression of endogenous rat AT2-R (rAT2-R) in AT1-R-transfected PC12 cells. rAT2-R mRNA and protein expression were decreased by Ang II in PC12 cells transfected with rAT1A-R in a time-dependent manner, mediated through a decline in mRNA stability. The C-terminus of G protein-coupled receptor (GPCR) is important for GPCR-mediated signal transduction. Therefore, we used C-terminus-deleted human AT1-R (hAT1-327STOP), which is thought to be a nondesensitised mutant of hAT1-R. As a result, Ang II decreased rAT2-R mRNA expression to a greater extent in cells transfected with hAT1-327STOP than with wild-type hAT1-R. The decrease was completely reversed by AT1-R antagonist candesartan, G(q) inhibitor YM254980, and mitogen-activated protein kinase (MAPK) kinase 1/2 inhibitor U0126, but not by pertussis toxin, which uncouples the receptor with G(i), or p38 MAPK inhibitor SB203580. We suggest, possibly for the first time, that the hAT1-R/G(q)/extracellular signal-regulated kinase 1/2 pathway is involved in the down-regulation of AT2-R using PC12 cells transfected with AT1-R.
authors.affiliation: Department of Cellular Signalling, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Saito
authors.forename: Y
authors.initials: Y
authors.lastname: Shinohara
authors.forename: H
authors.initials: H
authors.lastname: Sasaki
authors.forename: Y
authors.initials: Y
authors.lastname: Netsu
authors.forename: M
authors.initials: M
authors.lastname: Yoshida
authors.forename: N
authors.initials: N
authors.lastname: Nakahata
mesh_terms: D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D015536:Down-Regulation; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D019950:Mitogen-Activated Protein Kinase 1 / Q000502:physiology*; D048052:Mitogen-Activated Protein Kinase 3 / Q000502:physiology*; D016716:PC12 Cells; D017434:Protein Structure, Tertiary / Q000502:physiology; D020871:RNA Stability / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D044140:Receptor, Angiotensin, Type 1 / Q000737:chemistry / Q000235:genetics* / Q000502:physiology*; D044139:Receptor, Angiotensin, Type 2 / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D014162:Transfection
chemical_list: D012333:RNA, Messenger; D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D000804:Angiotensin II; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D043802:GTP-Binding Protein alpha Subunits, Gq-G11