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Departments of Physiology (D.L., H.Y., M.K.R.) and Neuroscience (G.S.), University of Florida, College of Medicine, Gainesville, Florida 32610
Address all correspondence and requests for reprints to: Mohan K. Raizada, Ph.D., Department of Physiology, P.O. Box 100274, Univer-sity of Florida, Gainesville, Florida 32610. E-mail: mraizada{at}phys.med.ufl.edu
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Abstract |
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Ang II also 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 completely blocked by losartan and not by PD123,319, an AT2 receptor specific antagonist. Preloading of neurons with p62-pep (a peptide containing consenses of mitogen-activated protein kinase in p62) resulted in a loss of Ang II-induced p62 phosphorylation and stimulation of NET and TH messenger RNA levels.
In conclusion, these data demonstrate that Ang II induces nuclear sequestration of AT1 receptor involving NLS in the AT1 receptor and p62 of the nuclear pore complex in brain neurons. A possible role of such a nuclear targeting of the AT1 receptor on chronic neuromodulatory actions of Ang II has been discussed.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We have focused our efforts to elucidate the signal transduction pathways involved in the chronic Ang II-induced neuromodulation. Our studies have established that the interaction of Ang II with the neuronal AT1 receptor initiates a cascade of signaling events involving the activation of Ras, Raf-1, and MAP kinase (9). Activation of MAP kinase leads to increased activities of serum response element and AP1-binding elements that result in the increased transcription of NET, dopamine ß hydroxylase, and TH genes (12). Thus, it is evident, from the above discussion, that the neuronal AT1 receptor is a unique GPCR: 1) it is linked to Ras, Raf-1, and MAP kinase signal transduction pathways involved in the chronic neuromodulatory actions of Ang II; and 2) desensitization and down-regulation of AT1 receptor, induced by Ang II, does not seem to have an effect on chronic stimulation of neuromodulation (13). This is, in contrast to other GPCRs, where agonist-induced cellular responses are immediately followed by desensitization and down-regulation of the receptor (14). Thus, we hypothesized that a distinct Ang II-induced intracellular targeting of the neuronal AT1 receptor could account for the uniqueness. This view is supported by the sequence analysis of the AT1 receptor, which indicates the presence of a sequence of basic amino acids in the cytoplasmic tail (KKFKK, amino acids307–311), which could possibly form a nuclear localization signal (NLS) sequence. NLS sequences are involved in the nuclear transport of various signaling proteins that exert transcriptional control by their sequestration into the nucleus (15, 16). Thus, our objective in this investigation was to test the hypothesis that Ang II induces translocation of AT1 receptor into the nuclear compartment in the neurons and to determine the involvement of NLS in this targeting. The data demonstrate that, indeed, the AT1 receptor is targeted to the nucleus, and we present evidence that the putative NLS sequence and phosphorylation of p62, a protein of the nuclear pore complex (NPC), are important in this targeting.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Preparation of neuronal cells in primary culture
Neuronal cells in primary culture were established essentially
as described previously (26, 27). Briefly, areas containing
hypothalamus and brain stem of 1-day-old Wistar Kyoto normotensive rat
brains were dissected, brain cells dissociated by trypsin, and plated
in poly L-lysine precoated tissue culture dishes in DMEM
containing 10% PDHS (26, 27). Culture dishes of 35-mm diameter (3
x 106 cells) or 100-mm diameter (2 x 107
cells) were prepared for experiments. After 48 h, cultures were
treated with 1% cytosine arabinoside for 3 days, followed by
establishment of culture for an additional 10 days, before their use in
experiments. These cultures contain 90–95% neuronal cells and 5–10%
astroglial cells (4, 26, 27).
Immunofluorescent staining of neurons for AT1 and
AT2 receptors
Neuronal cells were fixed in 1% buffered-formalin. In certain
experiments, nuclei from neuronal cells were isolated (see below),
fixed onto glass slides in 1% buffered-formalin. Cells or nuclei were
treated with methanol for 5 min at -10 C and preincubated with 10%
FBS for 1 h at 37 C. This was followed by incubation with mouse
monoclonal anti-AT1 receptor antibody at 1 µg/ml in PBS
containing 0.5% BSA for 16 h at 4 C. Rhodamine-conjugated
antimouse IgG was used as the second antibody, followed by
counterstaining with 4'-6-diamidine-2-phenylindole-dihydrochloride
(DAPI) to identify nuclear DNA and nuclei, as described previously (12, 13). Appropriate controls, in which either primary antibody was
replaced by growth medium, without AT1 receptor antibody or
without secondary antibody, were run in parallel to determine
nonspecific staining. Use of polyclonal AT1 receptor
antibody provided a similar staining pattern, although the monoclonal
antibody provided a picture with lower background. The cells were
processed for confocal microscopy, as described previously (1).
Distribution of AT2 receptor immunoreactivity was
determined as described above for the AT1 receptor, except
that a polyclonal AT2 receptor-specific antibody and
rhodamine-conjugated antirabbit second antibody were used. The
specificity of this antibody has previously been established (25).
Isolation of nuclei and immunoblotting of AT1 receptors
from neuronal cells
Neuronal cells, grown in 100-mm-diameter tissue culture dishes,
were used to separate nuclear fraction from the rest of the cell
fraction, as described by us elsewhere (12, 13). This protocol yields
highly pure nuclear fraction that was minimally contaminated by
cytoplasmic marker proteins (12, 13). Purified nuclei were lysed in the
nuclear lysis buffer (25 mM Tris-HCl, pH 7.4, 25
mM NaCl, 1% Triton x 100, 1% deoxycholic acid,
0.1% SDS, 1 mM sodium orthovanadate, 1 mM
phenylemethylsulfonyl fluoride, 10 µg/ml aprotinin, and 0.8
µg/ml leupeptin). Lysate was centrifuged at 12,000 x
g for 5 min at 4 C, and the supernatant was saved as nuclear
extract for AT1 receptor immunoblotting.
Extract containing 400 µg protein was mixed with 1 µg rabbit
anti-AT1 receptor polyclonal antibody overnight at 4 C.
Immunoprecipitates were collected on protein A/G agarose and subjected
to SDS-PAGE, followed by immunoblotting with the use of AT1
receptor monoclonal antibody, as described elsewhere (13). Although
both antibodies, on their own, provided similar results, this
combination use of polyclonal (for immunoprecipitation) and monoclonal
(for immunoblotting) AT1 receptor antibodies provided
highly specific AT1 receptor bands with very little
background. Protein-bound antibody was detected by HRP-labeled second
antibody and enhanced by a chemiluminescence assay reagent. Bands
corresponding to the AT1 receptor (
49 kDa protein) were
visualized by exposure to x-ray film. X-ray films were scanned by using
a UVP Imagestore 5000 System (UV Product, San Gabriel, CA). Data were
analyzed using a SW 5000 Gel Analysis program and presented as observed
density in the AT1 receptor band that was normalized for
equal loading by total protein, as described previously (9, 12). In
certain experiments, neuronal cells and nuclear extracts were subjected
to SDS-PAGE, proteins transferred to membrane that was subjected to
Western blotting with the use of either polyclonal or monoclonal
AT1 receptor antibody, essentially as described previously
(28).
Osmotic loading of synthetic peptides into neurons
A peptide corresponding to the AT1 receptor
tail [amino acids295–315, LNPLFYGFLGKKFKKYFLALL
(AT1-pep)] and its mutant, in which lysine residues at
amino acids305,306,308,309 were replaced by alanine
(AT1-mut), were synthesized. The rationale for selecting
this sequence was based on the identification of a putative NLS
sequence (amino acids307–311) in this region of the
receptor. Another peptide corresponding to amino
acids189–198 of p62 [GSPFTPATLA (p62-pep)] and its
mutant, in which Thr193 was replaced by Ala (p62-mut), were
synthesized. All peptides were synthesized by Genemed Biotechnologies
Inc. This region contained the consensus recognition sequence for MAP
kinase phosphorylation (29). The reason for selecting this region of
the p62 was based on our previous observation that Ang II stimulates
MAP kinase and that MAP kinase is involved in chronic neuromodulatory
actions of Ang II (9, 12). Osmotic loading of these peptides was
carried out essentially as described previously (30). In brief,
neuronal cells were rinsed in PBS, pH 7.4, incubated for 10 min with
loading solution (0.5 M sucrose, 10% polyethylene glycol
1000, 10% FBS, and 200 µg/ml AT1-pep or p62pep or their
mutants in DMEM, buffered with 25 mM HEPES, pH 6.8),
followed by rapidly rinsing the cells with a hypotonic solution [6.5
vol H2O: 3.5 vol DMEM, buffered with 25 mM
HEPES, pH 6.8 (30)]. After this treatment, cells were incubated with
DMEM, containing 10% PDHS, and immediately used for experiments.
Effect of Ang II on phosphorylation of neuronal p62 protein
Neuronal cells were grown in 100-mm-diameter tissue culture
dishes. They were rinsed in phosphate-free DMEM and were incubated with
20 mCi [32P]-orthophosphate in phosphate-free DMEM for
2 h at 37 C. After incubation with 100 nM Ang II at 37
C, cells were rinsed six times with ice-cold PBS, pH 7.4, and lysed for
20 min on ice in the lysis buffer (25 mM Tris-HCl, pH 7.4,
25 mM NaCl, 1% Triton X-100, 1% deoxycholic acid, 1
mM sodium orthovanadate, 10 mM sodium fluoride,
10 mM sodium pyrophosphate, 0.5 mM EGTA, 1
mM phenylmethylsulfonyl fluoride, 10 µg/ml aprotinin, and
0.8 µg/ml leupeptin). Samples were centrifuged at 12,000 g
for 5 min at 4 C, and supernatants containing 200 µg protein were
used for immunoprecipitation by anti-p62 (5 µg) specific antibody.
Immune complexes were collected on agarose beads, conjugated with
protein A+G (Santa Cruz Biotechnology), suspended in Laemmli’s sample
buffer, boiled for 3 min, and subjected to SDS/PAGE, followed by
autoradiography (9, 12). The radiolabeled band corresponding to a
62,000 MW protein was quantitated essentially as described previously
(12, 13).
Quantitation of NET and TH messenger RNAs (mRNAs) by RT-PCR
Neuronal cells were osmotically loaded with p62-pep or p62-mut
and stimulated with Ang II for 4 h. Total RNA was isolated, and
NET and TH mRNA levels were quantitated by a semiquantitative RT-PCR,
essentially as described previously (1, 2).
Experimental groups and data analysis
Each data point for the measurement of nuclear AT1
receptor immunoreactivity, p62 phosphorylation, and NET and TH mRNAs
was collected from three culture dishes. Each culture dish contained
cells generated by pooling of dissociated brain cells from 8–10 rats.
Each data point was repeated at least 3 times. Comparisons between data
points were made by using one-way ANOVA and Dunnett’s test, using
Statistica Software (Tulsa, OK). All immunofluorescence experiments
were repeated at least 6 times. One hundred to 250 cells were examined,
and representative images were collected.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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49 kDa) and a minor (60 kDa) protein bands (Fig. 1
). Western blot analysis of control
neurons and nuclear extracts of Ang II-treated neurons, with the use of
monoclonal antibody, provided identical results (Fig. 1). This
indicated that both monoclonal and polyclonal antibodies, raised
against AT1 receptor, recognize protein of approximately 49
kDa as a major AT1 receptor protein in neuronal cells.
Specificity of these antibodies was further confirmed in control
Western blotting, in which PBS or normal rabbit serum were substituted
for primary antibodies. No protein band of approximately 49 kDa was
observed in these controls. Neuronal cell extract or nuclear extract
from Ang II-treated cells was subjected to immunoprecipitation with
polyclonal AT1 receptor antibody, followed by
immunoblotting with monoclonal antibody, essentially as described in
Materials and Methods. This protocol also provided a
predominant protein band of approximately 49 kDa, with a minor band of
approximately 60 kDa, similar to that seen with the individual
antibodies on Western blots (Fig. 1C). These data showed that both
antibodies recognize the same AT1 receptor protein in
neuronal cells and in the nuclear fraction of Ang II-treated neurons.
These data are consistent with, at least, the observations reported
with the monoclonal AT1 receptor antibody. They show that
this antibody recognizes AT1 receptor protein of varying
size (44–70 kDa), indicating that the SDS-PAGE mobility of the
receptor may be tissue specific (17, 18, 19, 20, 21, 22, 23).
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shows that the distribution of
AT1 receptor immunoreactivity in neuronal cells was
comparable with both polyclonal (Fig. 2B) and monoclonal (Fig. 2D)
antibodies. AT1 receptor immunoreactivity was predominantly
localized in the plasma membrane; however, some staining was detected
in the intracellular compartment. Although the staining pattern was
comparable with both antibodies, the monoclonal antibody provided
significantly lower background. No significant staining was observed
when primary antibodies were replaced with normal rabbit serum for
polyclonal (Fig. 2A), or PBS for monoclonal, antibody (Fig. 2C). In
addition, no staining was seen when fluorescently-labeled secondary
antibodies were deleted from the staining protocol. Finally, both
antibodies provided little descrete staining for AT1
receptor immunoreactivity in PC12 cells (Fig. 2, E and F). This is
consistent with other observations indicating that these cells
predominantly express AT2, and not AT1,
receptor subtypes (31, 32). Thus, monoclonal antibody was used for all
subsequent immunofluorescent experiments, and a combination of
polyclonal for immunoprecipitation, followed by immunoblotting by
monoclonal antibodies, was used in quantitation of an AT1
receptor band of approximately 49 kDa.
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). Confocal imaging also indicated that
a significant AT1 receptor immunoreactivity was present in
the cytoplasmic compartment of the neuronal cells (Fig. 3A). In
contrast, no detectable level of the receptor immunoreactivity was
observed in the nuclear compartment. A dramatic redistribution of
AT1 receptors was observed when neurons were incubated with
100 nM Ang II for 15 min. Ang II-treated neurons revealed
receptor immunoreactivity, apparently in the nuclei (Fig. 3A). The
nuclear sequestration was time- and dose-dependent and reached maximal
levels in 15–30 min with 100 nM Ang II. It was blocked by
coincubation of neurons with Ang II and 10 µM losartan,
an AT1 receptor subtype-specific antagonist and not by 10
µM PD123319, an AT2 receptor-specific
antagonist (Fig. 3A). Nuclear fractions from the control and Ang
II-treated neurons were prepared according to previously established
protocol (12, 13). They were analyzed by immunoblotting to confirm the
nuclear sequestration of AT1 receptor immunoreactivity
detected by immunofluorescence technique. Nuclear fractions from
control, untreated neurons showed low, but significant, levels of
AT1 receptor immunoreactivity (Fig. 3B). Ang II caused a
6.7-fold increase in the levels of AT1 receptor
immunoreactivity in the nuclear fraction that was blocked by losartan
and not by PD123319 (Fig. 3B). This indicated that the occupancy of
AT1 receptor by Ang II is important in its nuclear
targeting. Ang II caused a time-dependent increase in the nuclear
sequestration of this immunoreactivity. It was 3-fold in 5 min and
reached optimal levels (6-fold) in 15 min, followed by a 15% decrease
in 30 min (Fig. 4). Increases in
AT1 receptor immunoreactivity in the nuclear fraction were
associated with its parallel decrease in the rest of the cell fractions
(Fig. 4). Nuclear sequestration of AT1 receptor
immunoreactivity also was Ang II concentration-dependent. Ang II as low
as 10 nM showed a 3-fold increase, whereas 100
nM caused a maximal (4-fold) increase in nuclear
immunoreactivity (Fig. 5).
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shows that
AT2 receptor immunoreactivity was primarily localized on
neuronal plasma membrane. No significant amount of immunoreactivity was
visible in either the cytoplasmic or the nuclear compartments.
Incubation with 100 nM Ang II for 30 min caused no
significant redistribution of AT2 receptor immunoreactivity
on the plasma membrane. In addition, no nuclear translocation and
sequestration of the AT2 receptor immunoreactivity was
observed.
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shows that preincubation of neurons
with the AT1-pep caused an 85% decrease in the
AT1 receptor immunoreactivity in the nuclear fraction.
AT1-mut had no effect on this nuclear targeting. Figure 7B
confirms these observations with the use of confocal microscopy of
nuclear preparations. Ang II-induced nuclear sequestration (Fig. 7B)
was attenuated by AT1-pep and not by AT1-mut.
Nuclei from control neurons or neurons treated with AT1-pep
or with AT1-mut showed very little AT1 receptor
immunoreactivity.
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Figure 8 shows that Ang II caused a
time-dependent increase in the incorporation of
[32P]-orthophosphate into p62. A 2-fold increase in the
phosphorylation, observed as early as 5 min, reached a maximal level of
6-fold in 15 min, followed by a slight decline in 30 min.
Interestingly, the time course of p62 phosphorylation was similar to
that observed for nuclear sequestration of the AT1
receptor. Figure 9 shows that Ang
II-induced p62 phosphorylation was blocked by losartan and not by
PD123319, indicating the involvement of the AT1 receptor in
this process.
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shows that the nuclei isolated from
neurons preloaded with p62-pep before Ang II treatment, had little
AT1 receptor immunoreactivity. In contrast, nuclei from
neurons preloaded with p62-mut showed levels of AT1
receptor immunoreactivity comparable with the Ang II-treated neurons.
This indicated that Ang II stimulates phosphorylation of p62 and that
inhibition of p62 phosphorylation causes attenuation of Ang II-induced
nuclear translocation of AT1 receptors. Figure 10B provides
confocal microscopic evidence of this observation. Preloading of
p62-pep resulted in a significant decrease in AT1 receptor
immunofluorescence in the nuclei of Ang II-treated neurons. p62-mut
showed no such inhibitory action.
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, indeed, illustrate
this point. Preloading of p62-pep, after Ang II stimulation, resulted
in a 70% decrease in Ang II stimulation of NET and TH mRNA levels.
p62-mut had no such inhibitory effect. It is pertinent to point out
that the experimental conditions also inhibit Ang II-induced nuclear
sequestration of Stat3 and AT1 receptors.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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This study raises a number of issues concerning the functional relevance of the nuclear targeting of the AT1 receptor in the neurons. These issues are worthy of discussion that will help provide future direction in this field of investigation. First, what are the cellular and physiological consequences of the nuclear targeting of the AT1 receptor in neurons? We suggest that it may be involved in the chronic neuromodulatory actions of Ang II. This idea is supported by the observation that both nuclear targeting for the AT1 receptor and the Ang II stimulation of mRNAs for NET and TH are blocked by the inhibition of p62 phosphorylation. Thus, nuclear AT1 receptors may interact with the DNA, or a specific nuclear protein, to regulate the transcription of NET, TH, or other genes relevant to the neuromodulatory actions of Ang II. There is no evidence in support of this view, because this report is the first example of nuclear targeting of a GPCR. However, analogous situations are well established for steroid hormone receptors. Steroid hormone receptors contain NLS sequences that play an important role in their nuclear translocation. Nuclear targeting is accompanied by specific DNA binding and transcriptional control of various steroid-hormone-responsive genes (44, 45). Second, AT1 receptors are present, both on the neuronal plasma membrane and in the cytoplasmic compartment, and presently, which compartment contributes to the nuclear AT1 receptors remains an open question. Binding of Ang II to the plasma membrane AT1 receptor activates the Ras-MAP kinase signal transduction pathway (9). Activation of MAP kinase results not only in the stimulation of downstream signaling leading to neuromodulation (12) but also in the phosphorylation of the AT1 receptor (13). The phosphorylated receptors are internalized (13). This would suggest that the plasma membrane receptors are translocated into the nucleus. This view is further supported by the observation that both the phosphorylated AT1 receptor and the nuclear AT1 receptor lack Ang II binding activity (13). However, this does not preclude other possibilities of nuclear targeting of cytosolic receptors. Finally, it remains to be determined whether nuclear targeting is specific for the AT1 receptor or it could be a general phenomenon for other GPCR. It would be surprising that AT1 receptor was unique in exhibiting agonist-induced nuclear translocation. Indeed, examination of amino acid sequences of other G protein-coupled receptors reveals that several others have sequences in the C-terminal cytoplasmic loop that conform to the consensus expected for the NLS sequence. For example, human M1, M3, and M5A muscarinic acetylcholine receptors contain sequences KRRWRK, KKKRRK, and RWKKKV, respectively (46, 47, 48). Similarly, the human platelet activating factor receptor contains the sequence KKFRKH, which also might have NLS activity (49). It remains to be seen whether these receptors, like AT1 receptor, also translocate to the nucleus after agonist stimulation.
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Acknowledgments |
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Footnotes |
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Received February 7, 1997.
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K. L. O'Malley, Y.-J. I. Jong, Y. Gonchar, A. Burkhalter, and C. Romano Activation of Metabotropic Glutamate Receptor mGlu5 on Nuclear Membranes Mediates Intranuclear Ca2+ Changes in Heterologous Cell Types and Neurons J. Biol. Chem., July 18, 2003; 278(30): 28210 - 28219. [Abstract] [Full Text] [PDF]
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J. Vazquez, C. Sun, J. Du, L. Fuentes, C. Sumners, and M. K. Raizada Transduction of a Functional Domain of the AT1 Receptor in Neurons by HIV-Tat PTD Hypertension, March 1, 2003; 41(3): 751 - 756. [Abstract] [Full Text] [PDF]
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A. M. Marrache, F. Gobeil Jr., S. G. Bernier, J. Stankova, M. Rola-Pleszczynski, S. Choufani, G. Bkaily, A. Bourdeau, M. G. Sirois, A. Vazquez-Tello, et al. Proinflammatory Gene Induction by Platelet-Activating Factor Mediated Via Its Cognate Nuclear Receptor J. Immunol., December 1, 2002; 169(11): 6474 - 6481. [Abstract] [Full Text] [PDF]
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P. S. Subramaniam and H. M. Johnson Lipid Microdomains Are Required Sites for the Selective Endocytosis and Nuclear Translocation of IFN-{gamma}, Its Receptor Chain IFN-{gamma} Receptor-1, and the Phosphorylation and Nuclear Translocation of STAT1{alpha} J. Immunol., August 15, 2002; 169(4): 1959 - 1969. [Abstract] [Full Text] [PDF]
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 J. F. Reilly and P. A. Maher Importin {beta}-mediated Nuclear Import of Fibroblast Growth Factor Receptor: Role in Cell Proliferation J. Cell Biol., March 19, 2001; 152(6): 1307 - 1312. [Abstract] [Full Text] [PDF]
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R. Chen, Y. V. Mukhin, M. N. Garnovskaya, T. E. Thielen, Y. Iijima, C. Huang, J. R. Raymond, M. E. Ullian, and R. V. Paul A functional angiotensin II receptor-GFP fusion protein: evidence for agonist-dependent nuclear translocation Am J Physiol Renal Physiol, September 1, 2000; 279(3): F440 - F448. [Abstract] [Full Text] [PDF]
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 H. Wang, M. J. Katovich, C. H. Gelband, P. Y. Reaves, M. I. Phillips, and M. K. Raizada Sustained Inhibition of Angiotensin I-Converting Enzyme (ACE) Expression and Long-Term Antihypertensive Action by Virally Mediated Delivery of ACE Antisense cDNA Circ. Res., October 1, 1999; 85(7): 614 - 622. [Abstract] [Full Text] [PDF]
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P. Sarret, D. Nouel, C. Dal Farra, J.-P. Vincent, A. Beaudet, and J. Mazella Receptor-mediated Internalization Is Critical for the Inhibition of the Expression of Growth Hormone by Somatostatin in the Pituitary Cell Line AtT-20 J. Biol. Chem., July 2, 1999; 274(27): 19294 - 19300. [Abstract] [Full Text] [PDF]
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M. Bhattacharya, K. Peri, A. Ribeiro-da-Silva, G. Almazan, H. Shichi, X. Hou, D. R. Varma, and S. Chemtob Localization of Functional Prostaglandin E2 Receptors EP3 and EP4 in the Nuclear Envelope J. Biol. Chem., May 28, 1999; 274(22): 15719 - 15724. [Abstract] [Full Text] [PDF]
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E. G. Ignatova, M. M. Belcheva, L. M. Bohn, M. C. Neuman, and C. J. Coscia Requirement of Receptor Internalization for Opioid Stimulation of Mitogen-Activated Protein Kinase: Biochemical and Immunofluorescence Confocal Microscopic Evidence J. Neurosci., January 1, 1999; 19(1): 56 - 63. [Abstract] [Full Text] [PDF]
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 M. Bhattacharya, K. G. Peri, G. Almazan, A. Ribeiro-da-Silva, H. Shichi, Y. Durocher, M. Abramovitz, X. Hou, D. R. Varma, and S. Chemtob Nuclear localization of prostaglandin E2 receptors PNAS, December 22, 1998; 95(26): 15792 - 15797. [Abstract] [Full Text] [PDF]
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 B. C. Yang, M. I. Phillips, D. Mohuczy, H. Meng, L. Shen, P. Mehta, and J. L. Mehta Increased Angiotensin II Type 1 Receptor Expression in Hypercholesterolemic Atherosclerosis in Rabbits Arterioscler. Thromb. Vasc. Biol., September 1, 1998; 18(9): 1433 - 1439. [Abstract] [Full Text] [PDF]
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N. O. Dulin, P. Pratt, C. Tiruppathi, J. Niu, T. Voyno-Yasenetskaya, and M. J. Dunn Regulator of G Protein Signaling RGS3T Is Localized to the Nucleus and Induces Apoptosis J. Biol. Chem., July 7, 2000; 275(28): 21317 - 21323. [Abstract] [Full Text] [PDF]
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J. L. Cook, Z. Zhang, and R. N. Re In Vitro Evidence for an Intracellular Site of Angiotensin Action Circ. Res., December 7, 2001; 89(12): 1138 - 1146. [Abstract] [Full Text] [PDF]
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