Involvement of MAP kinase in angiotensin II-induced phosphorylation and intracellular targeting of neuronal AT1 receptors.
MAP kinase stimulation is a key signaling event in the AT1 receptor (AT1R)-mediated chronic stimulation of tyrosine hydroxylase and norepinephrine transporter in brain neurons by angiotensin II (Ang II). In this study, we investigated the involvement of MAP kinase in AT1R phosphorylation to further our understanding of these persistent neuromodulatory actions of Ang II. Ang II caused a time-dependent phosphorylation of neuronal AT1R. This phosphorylation was associated with internalization and translocation of AT1R into the nucleus. MAP kinase also stimulated phosphorylation of neuronal AT1R. The conclusion that MAP kinase participates in neuronal AT1R phosphorylation and its targeting into the nucleus is supported further by the following. (1) MAP kinase-mediated phosphorylation of AT1R was blocked by the AT1R antagonist losartan; (2) AT1R co-immunoprecipitated with MAP kinase; (3) MAP kinase-kinase inhibitor PD98059 attenuated Ang II-induced phosphorylation of AT1R; and (4) PD98059 blocked Ang II-induced nuclear translocation of AT1Rs. In summary, these observations demonstrate that Ang II-induced phosphorylation of AT1R is mediated by its activation of MAP kinase. A possible role of AT1R translocation into the nucleus on persistent neuromodulatory actions of Ang II has been discussed.
Yang
H
H
Department of Physiology, College of Medicine, University of Florida, Gainesville, Florida 32610, USA.
Lu
D
D
Vinson
G P
GP
Raizada
M K
MK
D015059:1-Sarcosine-8-Isoleucine Angiotensin II / Q000494:pharmacology; D000804:Angiotensin II / Q000494:pharmacology*; D000818:Animals; D001692:Biological Transport; D001713:Biphenyl Compounds / Q000494:pharmacology; D001933:Brain Stem / Q000166:cytology / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000502:physiology*; D002467:Cell Nucleus / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D007031:Hypothalamus / Q000166:cytology / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D019808:Losartan; D009419:Nerve Tissue Proteins / Q000502:physiology*; D009474:Neurons / Q000378:metabolism* / Q000648:ultrastructure; D009687:Nuclear Proteins / Q000187:drug effects / Q000502:physiology*; D010766:Phosphorylation / Q000187:drug effects; D010940:Plant Proteins; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D051381:Rats; D011921:Rats, Inbred WKY; D015398:Signal Transduction / Q000502:physiology*; D013777:Tetrazoles / Q000494:pharmacology
C076980:AT-1 protein, Pisum sativum; D001713:Biphenyl Compounds; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D005419:Flavonoids; D007093:Imidazoles; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010940:Plant Proteins; D013777:Tetrazoles; D000804:Angiotensin II; D015059:1-Sarcosine-8-Isoleucine Angiotensin II; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019808:Losartan; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one