From the Departments of Physiology,
Neuropharmacology, and Medicine, Yokohama City University School of
Medicine, Yokohama 236-0004, Japan, the
Departments of Clinical
Neuropathology and Anatomy and Embryology, Tokyo Metropolitan
Institute for Neuroscience, Tokyo 183-8526, Japan, and the
¶ Departments of Cell Biology and Molecular Medicine and Medicine,
New Jersey Medical School, Newark, New Jersey 07103
Received for publication, February 14, 2003, and in revised form, March 12, 2003
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ABSTRACT |
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Various neurotransmitters, such as dopamine,
stimulate adenylyl cyclase to produce cAMP, which regulates neuronal
functions. Genetic disruption of the type 5 adenylyl cyclase isoform
led to a major loss of adenylyl cyclase activity in a striatum-specific manner with a small increase in the expression of a few other adenylyl
cyclase isoforms. D1 dopaminergic agonist-stimulated adenylyl cyclase
activity was attenuated, and this was accompanied by a decrease in the
expression of the D1 dopaminergic receptor and
Gs The neurotransmitter dopamine acts through various dopaminergic
receptor subtypes that are associated with either stimulation or
inhibition of adenylyl cyclases
(ACs),1 leading to the
regulation of physiological functions such as the control of various
motor functions or psychomotor activity (1). This dopamine-sensitive AC
activity is highest in the striatum as well as in associated limbic
structures of the brain where their levels of activity exceed, by
orders of magnitude, those in other areas of the brain. Such
differences in striatal enzymatic activity may be attributed to the
amount and/or combination of the enzyme isoforms that are expressed
differentially in each brain region (2, 3). The brain expresses all
nine AC isoforms (AC1-AC9) that have distinct biochemical properties,
i.e. regulation by Gi, G The striatum is considered to be the center of sensorimotor integration
within the basal ganglia (9) and receives widespread excitatory input
from all regions of the cortex that converge with extensive
dopaminergic signals, both D1 and D2, afferent from the
midbrain. Concerted and balanced activity of these two dopaminergic
signals is believed to play a key role in regulating striatal motor
functions. In this study, we examined the role of their potential
target enzyme isoform, AC5, by the use of knockout mice in which the
AC5 gene was disrupted.
Generation of Knockout Mice--
We disrupted the AC5 gene by
the homologous recombination technique at the exon with the first
translation initiation site (Fig. 1A). The type 5 AC gene
has another translation initiation site with a reasonable Kozak
consensus sequence within the same exon (8) that was excised in the
final targeting vector. The integration of the knockout transgene was
confirmed by genomic Southern analysis (Fig. 1B). All mice
were 129/SvJ-C57BL/6 mixed background littermates from F1 heterozygote
crosses. All experiments were performed in 8-12-week-old homozygous
(AC5 RNase Protection Assay--
Partial fragments of mouse AC
cDNA clones for each isoform (types 1-9) and neuropeptides,
i.e. enkephalin, substance P, and dynorphin, were obtained
by PCR. A human 28 S ribosomal RNA probe was used as an internal
control. RNase protection assay was performed using the RPA III
kit (Ambion, Austin, TX).
AC Assay--
Striatal tissues were dissected from mice, and
membrane preparations were prepared for AC assays as described
previously (10, 11).
Radioligand Binding Assay--
D1 and D2 dopaminergic receptor
binding assays were performed using [3H]SCH23390 and
[3H]spiperone, respectively, as described previously (12,
13). Preliminary experiments demonstrated that the
Kd and Bmax values for D1 and
D2 dopaminergic receptors were similar to those reported previously
(12, 13).
Behavioral Tests--
Motor functions of mice were assessed by
Rotarod test (14), locomotor activity tests (14, 15), pole test (16),
and tail suspension test (17).
Impaired Motor Functions--
Given that AC is the major effector
enzyme of dopaminergic signals in the striatum, we conducted various
motor function tests to evaluate striatal function in an animal model
in which the AC5 gene was disrupted (AC5
Spontaneous activity was determined both horizontally (locomotion) and
vertically (rearings). Mice were placed in a cage, and their movements
were videotaped for analysis. WT and heterozygous mice revealed a
similar performance in open field locomotor activity, while
AC5 AC5 Expression and AC Activity in AC5
We also examined receptor agonist-stimulated AC activity (Fig.
3C). In general, in many tissues including the heart,
marked stimulation of AC is readily attainable with
Gs-coupled receptor agonists, although the inhibition of AC
with Gi-coupled receptor agonists may not always be easy.
In the striatum, however, SKF38393, a D1 dopaminergic receptor agonist,
modestly stimulated AC activity in WT (40.7 ± 2.6% increase over
that with 10 µM GTP). Quinpirole, a D2 agonist, inhibited
SKF38393-stimulated AC activity; the inhibition was significant but
small (13.5 ± 1.1% decrease). In AC5 Changes in Other Molecules Involved in Dopaminergic
Signaling--
The disruption of the major striatal AC isoform
may change the expression of other molecules involved in dopaminergic
signaling. D1 dopaminergic receptor binding sites were modestly
decreased in AC5
We then examined whether there was any increase in the expression of
other AC isoforms in AC5 Dopaminergic Agonists Improved Motor Function in
AC5 We have demonstrated that the disruption of the AC5 gene led to a
major deficit in AC activity in a striatal specific manner and an
abnormal coordination represented by impaired Rotarod performance as
well as other motor disorders that mimicked Parkinson's disease. Selective stimulation of D2 dopaminergic receptors by cabergoline restored coordination, suggesting that the attenuation of D2
dopaminergic signal underlied abnormal coordination in
AC5 The supersensitive response to D1 dopaminergic stimulation (Fig.
5A) mimicked the supersensitivity in Parkinson's disease. As in Parkinson's disease, AC5 The robust nature of our finding, however, suggests that the
neurotransmitter signal at the level of an effector isoform, i.e. the integration of multiple receptor subtype signals on
one effector isoform, may be as equally important as the
neurotransmitter signal at the level of their respective
receptor subtypes in regulating neuronal functions that has been more
widely recognized. Our findings also implicate that targeting an AC
isoform(s), such as AC5, in future pharmacotherapy may be an
effective way to treat motor dysfunction in human
diseases (26).
. D2 dopaminergic agonist-mediated
inhibition of adenylyl cyclase activity was also blunted. Type 5 adenylyl cyclase-null mice exhibited Parkinsonian-like motor
dysfunction, i.e. abnormal coordination and bradykinesia
detected by Rotarod and pole test, respectively, and to a lesser
extent locomotor impairment was detected by open field tests.
Selective D1 or D2 dopaminergic stimulation improved some of
these disorders in this mouse model, suggesting the partial
compensation of each dopaminergic receptor signal through the
stimulation of remnant adenylyl cyclase isoforms. These findings extend
our knowledge of the role of an effector enzyme isoform in
regulating receptor signaling and neuronal functions and imply that
this isoform provides a site of convergence of both D1 and D2
dopaminergic signals and balances various motor functions.
INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
, calcium, or
various kinases (4). Most, if not all, isoforms are enriched in
specific brain regions (2, 5) rather than diffusely distributed
throughout the brain. AC5, for example, is the dominant isoform in the
striatum as well as in the heart (6-8). However, the coupling of each
enzyme isoform to a specific neuronal function or functions and a
receptor signal remains unknown as does whether the function of an AC
isoform, unlike that of the receptors, can be substituted by another isoform.
EXPERIMENTAL PROCEDURES
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
/
) and wild-type (WT) littermates. This study was
approved by the Animal Care and Use Committee at the Yokohama City
University School of Medicine and New Jersey Medical School.
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Fig. 1.
Gene targeting strategy and characterization
of AC5 /
mice. The type 5 AC was disrupted by
homologous recombination technique at the 5'-end of the type 5 AC gene
containing the exon with the first translation initiation site. The
type 5 AC gene has an additional downstream translational start site
accompanied by a reasonable Kozak consensus sequence within the same
exon that was excised in the targeting vector (A). A
Southern blot of the targeted allele of tail DNA of F2 mice is shown in
B. KO, knockout; K, KpnI;
E, EcoRI; X, XhoI;
A, ApaI; P, PstI;
BS, BssHII; H, HindIII;
RV, EcoRV; N, NcoI;
B, BamHI.
RESULTS
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
/
). The most
dramatic change was found in coordinated movement, which was evaluated
by Rotarod performance. In this test, we measured the time that mice
could stay on an accelerating Rotarod without falling. In general,
there was a major impairment in AC5
/
and to a lesser
degree in the heterozygous mice relative to WT (Fig.
2A). AC5
/
could spend significantly less time on the Rotarod, and heterozygous mice could spend slightly less time than WT. When tests were repeated, their performance improved significantly after a few trials. However, AC5
/
performed very poorly even after several trials.
When the test was repeated on the following day, the results were
similar, disputing the possibility that AC5
/
required a
longer period to learn the performance (data not shown).
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Fig. 2.
Motor dysfunction in AC5 /
mice. A, Rotarod test. Each mouse was placed on a
3.5-cm-diameter rod covered with rubber to evaluate Rotarod performance
(14). Mice were left for 1 min on the rod for habituation. The rod
rotated gradually increasing from 4 to 40 rpm over the course of 5 min,
and the time that mice could stay on an accelerating Rotarod without
failing was recorded. Five trials were conducted for each individual
10-25 min apart within the dark phase of the light/dark cycle. Mice
that stayed on the Rotarod for >300 s were considered complete
responders, and their latencies were recorded as 300 s. *,
p < 0.05 relative to +/+; +, p < 0.05 relative to +/
; n = 17-20. B and
C, activity tests. The tests were performed as described
previously (14, 15). Mice were put in the darkened testing room for 60 min for habituation before testing. Locomotor activity (B)
was assessed using an activity monitor equipped with photocell beams
(Columbus Instruments, Columbus, OH). The number of photobeam
interruptions in each perpendicular axis was recorded and totaled for 5 min. The behavior of the mice was recorded simultaneously by video
camera for later analysis, and their rearing actions were counted
(C). *, p < 0.05 relative to +/+;
n = 15-20. D, pole test. To evaluate
bradykinesia, pole test was performed (16). In brief, mice were placed
head upward on the top of a rough surfaced pole (8 mm in diameter and
50 cm in height) that was wrapped with gauze to prevent slipping. The
time until the mouse turned completely downward (open
bars, Tturn) and the time until it climbed
down to the floor (closed bars, TLA)
were measured. *, p < 0.01 relative to +/+;
n = 14-17. Means ± S.E. are shown. Homozygous
(AC5
/
) (closed circles,
/
), heterozygous
(shaded circles, +/
), and WT (open circles,
+/+) are shown.
/
showed a small but significant degree of reduction
(Fig. 2, B and C). To evaluate bradykinesia, pole
test was performed. The time until they turned downward
(Tturn) and the time until they descended to the
floor were measured (TLA). We found that
AC5
/
had marked deficits in this test; they showed an
over 3-fold prolongation of both recording time indexes (Fig.
2D). It was also possible that striatal dysfunction led to
choleric or dystonic movements. Such abnormal movements may be
demonstrated most readily in mice as a clasping of the limbs that is
triggered by tail suspension test (17). However, we found no such
abnormal movements in both AC5
/
and WT (data not shown).
/
--
These
results indicated impairments of striatal functions in
AC5
/
presumably induced by the loss of AC5. While AC5
may be striatum-specific with regard to its distribution (18), it
remained unknown whether it was dominant for cAMP production in the
striatum. AC5 mRNA was expressed at least 10-20-fold more
abundantly in the striatum than in the other brain regions, such as the
cortex and the cerebellum, in WT (Fig.
3A); this was in agreement
with previous findings (18). In AC5
/
, AC5 mRNA
expression was negated, but histological examinations revealed no
changes such as neuronal loss and/or reactive gliosis at 8-12 weeks
old (data not shown). We found, however, that AC activity was greatly
decreased in striatal membrane preparations in AC5
/
(Fig. 3B). In contrast, AC activity was significantly, but
only to a small degree, decreased in the cortex where AC5 could be detected in WT and showed no difference in the cerebellum where AC5 was
scarcely detected in WT. For comparison, AC activity in the heart,
another tissue in which AC5 is dominantly expressed (8), was decreased
by only 30% (data not shown), indicating that the contribution of AC5
to cAMP production is greater in the striatum than in the heart.
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Fig. 3.
AC activity and its mRNA expression in
various brain regions. AC catalytic activity was compared as
described previously (15) using the membrane preparations from the
striatum, cortex, and cerebellum (A). AC assays were
conducted in the presence of 50 µM forskolin. Expression
of AC5 mRNA was quantitated by RNase protection assays with 28 S
rRNA as loading standard (B). A representative result is
shown. D1 or D2 receptor agonist-stimulated AC activity was also
examined (C). AC assays were conducted in the presence of 1 µM SKF38393 (SKF) or 1 µM
SKF38393 and 10 µM quinpirole (QPL) in a
reaction buffer containing 10 µM GTP. Each AC catalytic
activity was compared with that in the presence of 10 µM
GTP alone. Open bars, WT (+/+); closed bars,
AC5 /
(
/
). Means ± S.E. are shown. *,
p < 0.05; **, p < 0.01 relative to
+/+; n = 4. NS, not
significant.
/
, the
responses to D1 and D2 dopaminergic receptor agonists were markedly
diminished; the D1 dopaminergic agonist-mediated stimulation was very
small, and the D2 dopaminergic agonist-mediated inhibition in
AC5
/
was hardly detectable. It is tentative to
speculate that the loss of D2 agonist-mediated inhibition was due to
the loss of AC5, which is Gi-inhibitable, as proposed
recently in a similar model (19), while it is also possible that the AC
catalytic activity was too low to demonstrate inhibition by AC assays
with membrane preparations. Thus, in vitro AC assays may not
be sufficient in terms of sensitivity to study changes in selective
dopaminergic signal in AC5
/
. We did not understand,
however, why the response to D1 agonist stimulation as shown by percent
increase was also attenuated in AC5
/
because other
remnant AC isoforms must be able to respond to Gs, if not
Gi, stimulation. We also examined cAMP accumulation in
intact striatal neuronal cells from the fetus; however, the difference
in cAMP production was not as great as in the above AC assays using
membrane preparations from adults (data not shown).
/
, while D2 receptor binding sites were
similar to those in WT (Fig.
4A). The short, but not the
long, form of Gs protein expression was decreased in
AC5
/
(Fig. 4B) presumably due to the loss of
positive feed forward regulatory loop. Western blotting for various
molecules, using either the membrane preparation or whole tissue
homogenates, revealed that the protein expression of Golf,
Gi, Gq, G
, and PKA (the
catalytic
subunit) were not changed (data not shown). Changes in
neurotransmitters, such as dynorphin, substance P, and enkephalin, were
examined by RNase protection assays that may be linked to the activity
of D1 and D2 dopaminergic receptors. The expression of dynorphin, which
acts on presynaptic
-receptors to inhibit AC (20), was modestly
increased (Fig. 4C). In contrast, the expressions of
enkephalin and substance P were unchanged (Fig. 4C). The
expressions of glutamic acid decarboxylase and tyrosine hydroxylase,
which are involved in the synthesis of
-aminobutyric acid and
dopamine, respectively, were also unchanged as determined by
immunoblotting (data not shown). The above findings suggested that the
expression of some molecules, i.e. D1 dopaminergic
receptors, Gs, and dynorphin, was changed in such a way to
suppress the D1 dopaminergic pathway despite the disruption of the
major AC isoform.
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Fig. 4.
Expression of receptors, Gs,
neurotransmitters, and AC isoforms in the striatum. Dopaminergic
receptor subtype expression was quantitated by radioligand binding
assays as described previously using [3H]SCH23390
(left, for D1) and [3H]spiperone
(right, for D2) in striatal membrane preparations
(A). Relative changes in the Bmax
values are shown as percentages. Note that preliminary experiments
demonstrated that the Kd values of D1 and D2 were
similar to those reported previously. Open bars, WT (+/+);
closed bars, AC5 /
(
/
). Means ± S.E. are shown. *, p < 0.01; n = 5. Expression of Gs protein in the striatal membranes was
determined by immunoblotting (B). Top, a
representative immunoblotting of Gs protein
(long, the long Gs form; short, the
short Gs form). Bottom, comparison of the amount
of both Gs forms (Gs short and Gs
long) between WT and AC5
/
. Open bars,
WT (+/+); closed bars, AC5
/
(
/
).
Means ± S.E. are shown. *, p < 0.01;
n = 4-6. Expression of dynorphin (Dyn),
substance P (Sub-P), and enkephalin (Enk)
mRNA was compared by RNase protection assays (C). 28 S
rRNA was used for standardization. Relative values were compared
between WT (open bars, +/+) and AC5
/
(closed bars,
/
). Means ± S.E. are shown. *,
p < 0.05; n = 4-6. Comparative levels
of each AC isoform mRNA expression (AC1-AC9) were determined by
RNase protection assays (D). All AC isoforms except AC4 and
AC8 were detectable. 28 S rRNA was used for standardization. Open
bars, WT (+/+); closed bars, AC5
/
(
/
). Means ± S.E. are shown. *, p < 0.05;
n = 4-7.
/
. Since AC isoform antibodies
that can convincingly determine the level of protein expression are not
available, we quantitated the mRNA expression of the AC isoforms by
RNase protection assays (Fig. 4D). All AC isoforms except
AC4 and AC8 were detected. Among these isoforms, we found a modest
increase of AC6, the most relevant isoform to AC5, as well as AC2, AC7,
and AC9 but not AC1 and AC3 in AC5
/
. We thought,
however, that such small increases in the expression of AC isoforms
were not sufficient to explain decreases in the expression of
Gs and D1 dopaminergic receptors, which occurred as if to
inhibit the D1 dopaminergic pathway.
/
--
If either or both D1 and D2
dopaminergic signals were attenuated in AC5
/
leading to
motor dysfunction in vivo, then stimulation of dopaminergic receptors, D1 and/or D2, with specific agonists may restore the function. Administration of SKF38393 (25 or 50 mg/kg), a D1
dopaminergic agonist, increased locomotor activity in both WT and
AC5
/
. In particular, locomotor activity response
appeared pronounced, and might be supersensitive, in
AC5
/
relative to WT (Fig.
5A). This finding was
reminiscent of the supersensitive response of the direct pathway
neurons observed in dopamine depletion of Parkinson's disease in which
the D1 dopaminergic function becomes supersensitive but is accompanied
by an actual reduction of D1 dopamine receptor levels (21, 22) (Fig.
4A). SKF38393 did not improve Rotarod performance in both WT
and AC5
/
(Fig. 5B). We then examined the
effect of cabergoline (0.2 or 1.0 mg/kg), a D2 dopaminergic agonist
that has been used in the treatment of Parkinson's disease.
Cabergoline had no significant effect on locomotor activity in both WT
and AC5
/
, although both showed a tendency of small
increases (Fig. 5D). In contrast, cabergoline improved
Rotarod performance selectively in AC5
/
; their
performance reached an equivalent level to that of WT (Fig.
5E), while cabergoline essentially had no effect on WT, suggesting that coordination in AC5
/
was restored by D2
dopaminergic stimulation. We also examined the effect of these agonists
on pole test performance (Fig. 5, C and F). Both
SKF38393 and cabergoline improved pole test performance in
AC5
/
, the latter of which induced a dramatic
improvement even with a lower dose (0.2 mg/kg).
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Fig. 5.
Effect of dopaminergic agonists on motor
functions. Effects of SKF38393 on locomotor activity
(A), Rotarod test (B), and pole test
(C) were compared. SKF38393, a D1 dopaminergic agonist, was
administered to WT (+/+) and AC5 /
(
/
)
subcutaneously (open bars, vehicle; shaded bars,
25 mg/kg; closed bars, 50 mg/kg). Means ± S.E. are
shown. *, p < 0.05; **, p < 0.01 compared with vehicle; n = 7-14 in A and
B and n = 9-14 in C. In Rotarod
test, the best performance of five trials in each individual was
evaluated. Effects of cabergoline on locomotor activity (D),
Rotarod performance (E), and pole test (F) were
compared. Cabergoline, a D2 dopaminergic agonist, was administered to
WT (+/+) and AC5
/
(
/
) subcutaneously (open
bars, vehicle; shaded bars, 0.2 mg/kg; closed
bars, 1.0 mg/kg). After injection, mice were placed in a holding
cage until testing. Means ± S.E. are shown. *, p < 0.05; **, p < 0.01 compared with vehicle;
n = 7-15 in D, n = 8-14 in
E, and n = 8-12 in F.
DISCUSSION
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS
DISCUSSION
REFERENCES
/
and that D2 dopaminergic signal targets AC5 as a
major effector isoform. Locomotor activity was also attenuated and
restored by selective D1 dopaminergic stimulation, suggesting that this
dopaminergic signal also targets AC5. In contrast, both
dopaminergic signals may be able to couple to other AC isoforms as well
because D1 or D2 dopaminergic stimulation could restore specific motor
function, i.e. coordination or locomotion, respectively.
Nevertheless such selective dopaminergic agonist stimulation could not
restore all of the motor disorders, indicating that AC5 is essential in
balancing and maintaining both coordination and locomotion and may
provide the site of convergence of both D1 and D2 dopaminergic signals. D1 and D2 are the most abundant dopaminergic receptors expressed in the
brain, and both are involved in the two major striatal output pathways,
i.e. the "direct" and the "indirect" pathways, which
are dominantly mediated by D1 and D2 receptors,
respectively. Although it is still unknown whether these receptor
subtypes are expressed in the distinct populations of striatal neurons
(23) or within the same populations (24), it has been believed that the
parallel and balanced activation of these two pathways and their
synergistic action control striatal motor functions. Our findings
indicate that the parallel and balanced activation is maintained by the
presence of AC5 that is coupled to both dopaminergic pathways. In the
absence of AC5, AC6 and AC1 are still present but cannot fully
compensate for the function of AC5.
/
also had
decreased D1 dopaminergic receptor expression (21, 22). Because there
was no up-regulation of G protein or PKA expression, changes
responsible for this supersensitization must be located
downstream of PKA, although we do not deny that compensation in
the AC pathway could include increased translation and/or
post-translational activation of remaining AC isoforms or other pathway
components. The exact molecular mechanisms for this paradoxical
phenomenon have also remained unexplained in Parkinson's disease, but
a very recent study suggested that a switch in the regulation of
downstream mitogen-activated protein kinase signal may be involved
(25). The dopamine depletion in Parkinson's disease and the lack of its major effector enzyme isoform may be similar in many aspects, and
thus AC5
/
may be useful to explore the molecular
mechanisms for supersensitization in future studies.
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ACKNOWLEDGEMENTS |
---|
We thank Dr. Kazushige Touhara (University of Tokyo) for helpful discussion and Dr. Hideaki Hori (Yokohama City University) for editorial assistance.
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FOOTNOTES |
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* This study was supported in part by National Institutes of Health Grants HL59729 and HL59139 and grants from the Ministry of Labor and Welfare, the Kitsuen Research Foundation, and the Mochida Research Foundation.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.
§ Both authors contributed equally to this work.
** To whom correspondence should be addressed. Tel.: 973-972-8925; Fax: 973-972-8929; E-mail: ishikayo@umdnj.edu.
Published, JBC Papers in Press, March 28, 2003, DOI 10.1074/jbc.C300075200
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ABBREVIATIONS |
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The abbreviations used are: AC, adenylyl cyclase; WT, wild type; PKA, cAMP-dependent protein kinase.
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