D. Lu et al., ANGIOTENSIN-II-INDUCED NUCLEAR TARGETING OF THE ANGIOTENSIN TYPE-1 (AT(1)) RECEPTOR IN BRAIN NEURONS, Endocrinology, 139(1), 1998, pp. 365-375
Angiotensin II (Ang II) interaction with the neuronal AT(1) receptor r
esults in a chronic stimulation of neuromodulation that involves the e
xpression of norepinephrine transporter (NET) and tyrosine hydroxylase
(TH). In view of this unique property and the presence of putative nu
clear localization signal (NLS) consensus sequence in the AT(1) recept
or, this study was conducted to investigate the hypothesis that Ang II
would induce nuclear sequestration of this G protein-coupled receptor
and that the sequestration may have implications on Ang II-induced ex
pression of NET and TH genes. Incubation of neuronal cultures with Ang
Il caused a time-and dose-dependent increase in the levels of AT(1) r
eceptor immunoreactivity in the nucleus. A 6.7-fold increase was obser
ved with 100 nM Ang II, in 15 min, that was blocked by losartan, an AT
(1) receptor-specific antagonist. Ang II-induced nuclear sequestration
was specific for AT(1) receptor, because Ang II failed to produce a s
imilar effect on neuronal AT(1) receptors. The presence of the putativ
e NLS sequence in the cytoplasmic tail of the AT(1) receptor seems to
be the key in nuclear targeting because: 1) nuclear targeting was atte
nuated by a peptide of the AT(1) receptor that contained the putative
NLS sequence; and 2) Ang II failed to cause nuclear translocation of t
he AT(2) receptor, which does not contain the putative NLS. Ang II als
o caused a time- and dose-dependent stimulation of P62 phosphorylation
, a glycoprotein of the nuclear pore complex. A 6-fold stimulation of
phosphorylation was observed with 100 nM Ang II, in 15 min, that was c
ompletely blocked by losartan and not by PD123,319, an AT(2) receptor
specific antagonist. Preloading of neurons with p62-pep (a peptide con
taining consenses of mitogen-activated protein kinase in p62) resulted
in a loss of Ang II-induced p62 phosphorylation and stimulation of NE
T and TH messenger RNA levels. In conclusion, these data demonstrate t
hat Ang II induces nuclear sequestration of AT(1) receptor involving N
LS in the AT(1) receptor and p62 of the nuclear pore complex in brain
neurons. A possible role of such a nuclear targeting of the AT(1) rece
ptor on chronic neuromodulatory actions of Ang II has been discussed.