ACCELERATED PUBLICATION
Cyclic AMP-independent Activation of Protein Kinase A by
Vasoactive Peptides*
Nickolai O.
Dulin
,
Jiaxin
Niu,
Darren D.
Browning,
Richard D.
Ye, and
Tatyana
Voyno-Yasenetskaya
From the Department of Pharmacology, University of Illinois at
Chicago College of Medicine, Chicago, Illinois 60612
Received for publication, April 16, 2001, and in revised form, April 25, 2001
 |
ABSTRACT |
Protein kinase A (PKA) is an important
effector enzyme commonly activated by cAMP. The present study focuses
on our finding that the vasoactive peptide endothelin-1 (ET1), whose
signaling is not coupled to cAMP production, stimulates PKA in two
independent cellular models. Using an in vivo assay for PKA
activity, we found that ET1 stimulated PKA in HeLa cells overexpressing
ET1 receptors and in aortic smooth muscle cells expressing endogenous
levels of ET1 receptors. In these cell models, ET1 did not stimulate cAMP production, indicating a novel mechanism for PKA activation. The
ET1-induced activation of PKA was found to be dependent on the
degradation of inhibitor of
B, which was previously reported to bind and inhibit PKA. ET1 potently stimulated the nuclear
factor-
B pathway, and this effect was inhibited by overexpression of
the inhibitor of
B dominant negative mutant (I
B
m) and by
treatment with the proteasome inhibitor MG-132. Importantly, I
B
m
and MG-132 had similar inhibitory effects on ET1-induced activation of
PKA without affecting Gs-mediated activation of PKA or
ET1-induced phosphorylation of mitogen-activated protein kinase.
Finally, another vasoactive peptide, angiotensin II, also stimulated
PKA in a cAMP-independent manner in aortic smooth muscle cells. These findings suggest that cAMP-independent activation of PKA might be a
general response to vasoactive peptides.
 |
INTRODUCTION |
Endothelin-1 (ET1)1 is a
vasoactive peptide implicated in embryonic development and in
pathophysiology of cardiovascular, renal, and respiratory systems (1,
2). Two types of ET1 receptors, namely ETA and
ETB, have been cloned and identified as typical G
protein-coupled receptors (3, 4). ETA receptors are coupled to Gq/11, G12/13, and Gi
heterotrimeric G proteins, leading to stimulation of phospholipase C,
small GTPase RhoA, and inhibition of adenylyl cyclase, respectively
(5-8). The coupling of ET1 receptors to Gs is
controversial. A modest cAMP response to ET1 was reported by some
investigators (9-11), whereas no response or inhibition of cAMP levels
was shown by others (5, 7, 12-15). Moreover, there was no convincing
evidence that the main target of cAMP, the protein kinase A (PKA),
could be activated by ET1.
The PKA holoenzyme is a tetrameric complex consisting of two catalytic
subunits (PKAc) bound to a homodimer of two regulatory subunits (PKAr).
The established mechanism of PKA activation in response to various
hormones involves stimulatory G proteins, Gs, which
activate adenylyl cyclase resulting in production of cAMP. Binding of
cAMP to PKAr leads to a release and activation of PKAc (16, 17).
Recently, a novel mechanism for PKA activation by lipopolysaccharide
(LPS) has been described that is related to the nuclear factor-
B
(NF
B) pathway (18). NF
B is a transcription factor that is
commonly activated during immune and inflammatory responses (19, 20).
Under basal conditions, NF
B exists in an inactive state bound to its
natural inhibitor I
B. Activation of NF
B occurs as a result of
agonist-induced phosphorylation and degradation of I
B followed by a
release of free NF
B. Apparently, a certain pool of PKAc also exists
in a complex with I
B (18). Under basal conditions, I
B retains
PKAc in the inactive state, presumably by masking its ATP binding site.
LPS-induced phosphorylation and degradation of I
B results in a
release and activation of PKAc (18). However, except for bacterially
derived LPS, there was no evidence that other physiological agonists
are able to activate PKA by this mechanism. The present study
demonstrates for the first time that ET1 stimulates PKA activity by a
cAMP-independent mechanism involving degradation of I
B. Moreover,
our data suggest that this is most likely a general phenomenon common
for vasoactive peptides.
 |
MATERIALS AND METHODS |
Reagents--
The cDNA for ETA receptor
was kindly provided by Dr. Masashi Yanagisawa (University of
Texas, South Western Medical Center, Dallas, TX). The cDNA for
FLAG-tagged vasodilator-stimulated phosphoprotein (VASP) was a
gift from Dr. Michael Uhler (University of Michigan, Ann Arbor,
MI). The cDNA for the dominant negative mutant of PKA (
R1
) was a gift from Dr. Stanley McKnight (University of
Washington, Seattle, WA). The cDNA for the
phosphorylation-deficient S32A,S36A mutant of mouse I
B
(I
B
m) was a gift from Dr. Inder Verma (The Salk Institute, La
Jolla, CA). The phosphorylation-deficient S19A,S23A mutant of mouse
I
B
(I
B
m) was generated by polymerase chain reaction, and
its identity was confirmed by sequencing. The NF
B-driven luciferase
reporter plasmid was described previously (21). Endothelin-1, isoproterenol, tumor necrosis factor
, and MG-132 were from
Calbiochem. Angiotensin II was from Peninsula Laboratories. Monoclonal
anti-FLAG antibodies were from Sigma. Polyclonal anti-phospho-MAP
kinase antibodies were from New England Biolabs.
Cell Culture and DNA Transfection--
The HeLa cells (ATCC)
were maintained in Dulbecco's modified Eagle's medium (DMEM)
supplemented with 2 mM glutamine, 100 units/ml streptomycin, 100 units/ml penicillin, and 10% fetal bovine serum (FBS). The primary culture of rat aortic smooth muscle cells (RASMC) from Wistar-Kyoto rats was kindly provided by Dr. Sergei Orlov (University of Montreal, Montreal, Canada). The RASMC were cultured for
up to 10 passages in DMEM supplemented with 10% FBS, 2 mM glutamine, 100 units/ml streptomycin, and 100 units/ml penicillin as
described elsewhere (22). For transient overexpression of proteins, the
HeLa cells or RASMC were transfected with desired DNA in the presence
of serum, using LipofectAMINE-2000 or LipofectAMINE-Plus reagents (Life
Technologies, Inc.), respectively, following the manufacturer's
protocol. The cells were serum-starved in 0.2% FBS for 24 h
before the experiment.
PKA Activity in Intact Cells--
Phosphorylation-induced
electrophoretic mobility shift of the VASP is a highly sensitive
functional assay for the activity of cyclic
nucleotide-dependent protein kinases in intact cells (23,
24) and was used in this study. The specificity of PKA-mediated phosphorylation of VASP was confirmed by overexpression of the dominant
negative mutant of PKA,
R1
, which abolished VASP phosphorylation induced by isoproterenol (see Fig. 1C) or by 8-bromo-cAMP
(25) but not by 8-bromo-cGMP (25). The assay involved transient
transfection of cells with FLAG-tagged VASP cDNA, stimulation of
quiescent cells with desired agonists, cell lysis followed by
immunoblotting of cell lysates with FLAG antibodies (see below), and
monitoring the phosphorylation-dependent electrophoretic
mobility shift of VASP, as described previously (25).
Immunoblotting--
After stimulation of quiescent cells with
desired agonists, the cells were lysed in the buffer containing 25 mM HEPES (pH 7.5), 150 mM NaCl, 1% Triton
X-100, 0.1% SDS, 5 mM EDTA, 1 mM NaF, 200 µM sodium orthovanadate, and protease inhibitors (1 µg/ml leupeptin, 1 µg/ml aprotinin, 1 mM
phenylmethylsulfonyl fluoride). The lysates were cleared from insoluble
material by centrifugation at 20,000 × g for 10 min,
subjected to polyacrylamide gel electrophoresis, transferred to
nitrocellulose, and analyzed by Western blotting with 0.5 µg/ml
primary antibodies followed by 0.3 µg/ml horseradish peroxidase-conjugated secondary antibodies and developed by ECL (Amersham Pharmacia Biotech).
Cyclic AMP Assay--
Cyclic AMP accumulation was determined as
described previously (26). Briefly, cells were serum-starved and
labeled with 3 µCi/ml [3H]adenine for 24 h, washed
twice with serum-free DMEM, and stimulated with desired agonists for
various times at 37 °C. Reactions were terminated by aspiration of
medium followed by addition of ice-cold 5% trichloroacetic
acid. Acid-soluble nucleotides were separated on ion-exchange columns
and subjected to scintillation spectroscopy. The radioactivity of
cAMP-containing fractions was normalized on the total (cAMP + ATP)
radioactivity in each sample and finally expressed as -fold increase
over control (zero time point).
 |
RESULTS |
ET1-induced Activation of PKA--
Fig.
1 shows a time course of PKA activation
in response to ET1 (Fig. 1A) and
2-adrenergic
receptor agonist isoproterenol (ISO) (Fig. 1B) after
transient transfection of HeLa cells with ETA and
2-adrenergic receptor, respectively, as measured by gel retardation of the PKA substrate VASP (see "Materials and
Methods"). ET1 induced a transient phosphorylation of VASP with a
maximum at 5 min. In contrast, ISO-induced phosphorylation of VASP was much stronger and persisted for at least 1 h (Fig. 1B).
To confirm that phosphorylation of VASP is mediated by PKA, we employed
a cAMP-unresponsive dominant negative mutant of PKAr,
R1
. As
shown in Fig. 1C, phosphorylation of VASP, induced by ET1
and ISO, was abolished by overexpression of
R1
. Confirming the
specificity of
R1
, it had no effect on ET1-induced MAP kinase
phosphorylation (Fig. 1D) or on cGMP-mediated
phosphorylation of VASP (25).

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Fig. 1.
Activation of PKA by ET1 and ISO in
transiently transfected HeLa cells. A and B,
time course of VASP phosphorylation in response to ET1 and ISO.
HeLa cells grown on 12-well plates were transfected with 100 ng of
FLAG-tagged VASP cDNA, 400 ng of ETA (A), or
400 ng of 2-adrenergic receptor (B2AR;
B) cDNAs and 1 µg of empty vector, serum-starved and
stimulated with 100 nM ET1 (A) or 10 µM ISO (B) for various times. The cells were
lysed, and the cell extracts were subjected to immunoblotting with
anti-FLAG antibodies. C and D, effect of
PKA-dominant negative mutant ( R1 ) on ET1-
and ISO-induced phosphorylation of VASP and MAP kinase. HeLa cells were
co-transfected with cDNAs for FLAG-tagged VASP, ETA, or
2-adrenergic receptor as in A and
B, together with 1 µg of empty vector or cDNA for
R1 , as indicated. After stimulation with 100 nM ET1
or 10 µM ISO for 5 min, the cells were lysed, and the
cell extracts were subjected to immunoblotting with anti-FLAG
antibodies (C) or anti-phospho-MAP kinase
(P-MAPK) antibodies (D). Shown are the
representative blots from at least two independent experiments with
similar results. P-VASP, phospho-VASP.
|
|
ET1-induced Activation of PKA Is Mediated by Degradation of
I
B--
Because two mechanisms of PKA activation have been
described, it was important first to examine whether the effect of ET1 on PKA activity was mediated by cAMP. As shown in Fig.
2, ET1 did not stimulate cAMP production
but rather reduced basal levels of cAMP in ETA-transfected
HeLa cells. By contrast, ISO (positive control) increased cAMP levels
by more than 8-fold in
2-adrenergic receptor-transfected
cells (Fig. 2). This suggests that ET1-induced activation of PKA is
cAMP-independent and confirms that in our cellular model, ET1 signaling
is not coupled to Gs and adenylyl cyclase.

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Fig. 2.
Effect of ET1 and ISO on cAMP levels in
transiently transfected HeLa cells. HeLa cells grown on 12-well
plates were transfected with 400 ng of ETA or 400 ng of
2-adrenergic receptor (B2AR) cDNAs,
serum-starved and stimulated with 100 nM ET1 or 10 µM ISO for various times as indicated. The intracellular
cAMP content was then measured as described under "Materials and
Methods" and expressed as -fold of control. Data represent mean ± S.D. from one of two independent experiments with similar results,
performed in triplicates.
|
|
We next addressed the possibility of a cAMP-independent mechanism of
ET1-induced PKA activity, described previously for LPS, wherein PKA
activation was mediated by proteasome-dependent degradation of I
B (18). ET1 stimulated NF
B activity in HeLa cells by
35.8 ± 4.4-fold, as measured by
B-dependent
expression of the luciferase gene (Fig.
3). This effect of ET1 was inhibited by
the proteasome inhibitor MG-132, as well as by overexpression of the
phosphorylation-deficient dominant negative mutant of I
B, I
B
m
(Fig. 3). These data indicate that ET1 stimulates NF
B via
phosphorylation and degradation of I
B.

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Fig. 3.
ET1-induced activation of
NF B. HeLa cells grown on 12-well plates
were transfected with 100 ng of B-driven luciferase reporter
plasmid, 100 ng of pcDNA3-LacZ, 400 ng of ETA cDNA,
and 400 ng of empty vector or the cDNA for I B dominant negative
mutant, I B m, as indicated. Quiescent cells were pretreated with
or without proteasome inhibitor MG-132 (50 µM) for 1 h as indicated, followed by stimulation with 100 nM ET1 for
6 h. Luciferase activity in cell lysates was then measured,
normalized on -galactosidase activity, and expressed as -fold
activation over control (mean ± S.D. from one of three
independent experiments with similar results, performed in
triplicates).
|
|
Preincubation of cells with increasing concentrations of MG-132
resulted in a dose-dependent inhibition of ET1-induced PKA activity, reaching maximum at 15 µM MG-132 (Fig.
4A). By contrast, up to 50 µM MG-132 had no significant effect on ET1-induced
phosphorylation of MAP kinase (Fig. 4B) or the ISO-induced
VASP shift (Fig. 4F). This suggests that ET1-induced
activation of PKA is mediated by proteasome-dependent
protein degradation. To examine whether this PKA activation is
dependent on the degradation of I
B, we employed phosphorylation-deficient dominant negative mutants of I
B. PKA was
previously shown to bind I
B
, as well as I
B
isoforms (18). Therefore, we examined the effects of I
B
-S32A,S36A (I
B
m)
and I
B
-S19A,S23A (I
B
m) overexpression on ET1-induced PKA
activity. Overexpression of increasing amounts of I
B
m resulted in
a dose-dependent inhibition of ET1-induced PKA activity
(Fig. 4C) without affecting MAP kinase phosphorylation (Fig.
4D) or the ISO-induced VASP shift (Fig. 4F). By
contrast, overexpression of I
B
m had no significant effect on
ET1-induced VASP phosphorylation (Fig. 4E). Taken together, these data suggest that proteasome-dependent degradation of
I
B
mediates ET1-stimulated PKA activity in HeLa cells.

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Fig. 4.
Effect of MG-132,
I B m, and
I B m on ET1- and
ISO-induced phosphorylation of VASP and MAP kinase. HeLa
cells grown on 12-well plates were transfected with 100 ng of FLAG-VASP
cDNA, 400 ng of ETA (A-E) or 400 ng of
2-adrenergic receptor (F) cDNAs, and 400 ng of empty vector or various amounts of cDNA for I B m
(C and D) or I B m (E), as
indicated. Quiescent cells were pretreated with or without various
concentrations of MG-132 for 1 h (A and B),
followed by stimulation with 100 nM ET1 (A-E)
or 10 µM ISO (F) for 5 min. The cells were
lysed, and the cell extracts were analyzed on VASP shift
(A, C, E, and F) and MAP
kinase phosphorylation (B and D) by
immunoblotting with anti-FLAG and anti-phospho-MAP kinase
(P-MAPK) antibodies, respectively. P-VASP,
phospho-VASP.
|
|
Activation of PKA by ET1 and Angiotensin II in Vascular Smooth
Muscle Cells--
It was important to confirm that cAMP-independent
activation of PKA by ET1 in HeLa cells was not an artifact of
ETA overexpression. Therefore, we next examined the ability
of ET1 to activate PKA in a primary culture of RASMC, which express
endogenous levels of ETA receptors. As shown in Fig.
5A, ET1 and ISO stimulated phosphorylation of VASP in these cells with a striking similarity to
their effects in the transiently transfected cellular model (compare
Fig. 5A and Fig. 1). Moreover, in RASMC, PKA was also stimulated by another vasoactive peptide, angiotensin II (AII) (Fig.
5A). Importantly, ET1 and AII failed to stimulate cAMP
production in RASMC, whereas ISO increased cAMP levels by more than
200-fold (Fig. 5B). This suggests that cAMP-independent
activation of PKA may be a general phenomenon, common for vasoactive
peptides.

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Fig. 5.
Activation of PKA by ET1, AII, and ISO in
vascular smooth muscle cells. Rat aortic smooth muscle cells were
transfected with 200 ng of FLAG-VASP cDNA, serum-starved and
stimulated with 100 nM ET1, 100 nM AII, or 10 µM ISO for various times as indicated. The cells were
lysed, and the cell extracts were analyzed on VASP shift
(A) or on cAMP levels (B; mean ± S.D. from
one representative experiment performed in triplicate). Note the
difference between A and B in stimulation time
points. Shown are the representative data from at least three
(A) or two (B) experiments. P-VASP,
phospho-VASP.
|
|
 |
DISCUSSION |
The present study describes for the first time cAMP-independent
activation of PKA by G protein-coupled receptor agonist endothelin-1 and provides the mechanism of this signaling event.
Cyclic AMP-independent Activation of PKA by Vasoactive
Peptides--
Employing two independent cellular models with
overexpressed or endogenous levels of ETA receptors, we
provide strong evidence for the ability of ET1 to stimulate PKA
activity in a cAMP-independent manner. Moreover, this may represent a
general phenomenon common for vasoactive peptides, because angiotensin
II elicited similar effect on PKA in RASMC. With the exception of one
study, which showed a modest, cAMP-dependent activation of
PKA by ET1 in pig coronary arteries (10), the stimulation of PKA by
either ET1 or AII has not been reported. In our experiments, ET1 failed
to stimulate cAMP production but rather reduced the basal levels of
cAMP. This is in accord with other investigators having shown that ET1
either had no effect or inhibited basal or agonist-induced cAMP
production, which is consistent with the coupling of ETA receptors to Gi proteins (5, 7, 13-15). However, one might still consider the possibility of compartment-specific changes in
cAMP-levels in response to ET1, which have not been detected in the
present study.
ET1-induced PKA Activity Is Dependent on I
B
Degradation--
The cAMP-independent mechanism of PKA activation,
which is mediated by LPS-induced degradation of I
B, has been
described previously by Zhong et al. (18). However, except
for bacterially derived LPS, no physiological ligand has been reported
to activate PKA by this mechanism. The present work demonstrates for
the first time that the physiologically relevant hormone ET1, which is
central to cardiovascular, renal, and pulmonary physiology, also
stimulates PKA in an I
B-dependent manner (Fig. 4). This
suggests that this mechanism for PKA activation is more widespread and
might also be relevant to other G protein-coupled receptors.
Several important questions are still to be resolved, such as the
signaling pathways, which link ETA receptors to the
degradation of I
B and activation of PKA, as well as the functional
significance of ET1-induced PKA activation. I
B degradation can be
mediated by a variety of mechanisms, including protein kinase C (27, 28), mitogen-activated protein kinase (29), or Akt/protein kinase
B (21). ETA receptors can activate all
above-mentioned molecules (30-32), suggesting several possibilities
for the signaling cascades leading to ET1-induced activation of PKA.
Regarding the functional significance of ET1-induced PKA activation,
stimulation of PKA by isoproterenol or forskolin was shown to inhibit
agonist-induced activation of phospholipase C (33),
Ca2+ mobilization (34), and Ca2+ entry (22), as
well as MAP kinase cascade (7, 35), the signaling pathways commonly
stimulated by G protein-coupled receptors including ETA.
Moreover, it is generally accepted that activation of PKA leads to cell
relaxation and regulation of cell growth (36, 37), which is opposite of
vasoconstrictive and proliferative effects of ET1. This suggests that
activation of PKA may serve as a regulatory mechanism in the function
of ET1. Future studies will address these issues.
 |
ACKNOWLEDGEMENTS |
We thank Dr. Masashi Yanagisawa
for providing ETA receptor cDNA, Dr. Michael Uhler
for providing FLAG-VASP cDNA, Dr. Stanley McKnight for providing
R1
cDNA, Dr. Inder Verma for providing I
B
m cDNA,
Dr. Sergei Orlov for providing primary culture of rat aortic smooth
muscle cells, and Dr. Tohru Kozasa for useful suggestions.
 |
FOOTNOTES |
*
This work was supported by National Institutes of Health
Grant GM56159 and a grant from American Heart Association (to
T. V. Y.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Dept. of Pharmacology
(M/C 868), Medical Sciences Bldg., Rm. E-407, 835 S. Wolcott Ave.,
University of Illinois at Chicago, Chicago, IL 60612. Tel.: 312-355-2568; Fax: 312-996-1225; E-mail: dulin@uic.edu.
Published, JBC Papers in Press, April 30, 2001, DOI 10.1074/jbc.C100195200
 |
ABBREVIATIONS |
The abbreviations used are:
ET1, endothelin-1;
I
B, inhibitor of
B;
ISO, isoproterenol;
LPS, lipopolysaccharide;
NF
B, nuclear factor
B;
PKA, protein kinase A;
RASMC, rat aortic smooth muscle cells;
VASP, vasodilator-stimulated
phosphoprotein;
MAP, mitogen-activated protein;
DMEM, Dulbecco's
modified Eagle's medium;
FBS, fetal bovine serum;
AII, angiotensin
II.
 |
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