Isoproterenol potentiates
-adrenergic and muscarinic
receptor-mediated Ca2+ response in
rat parotid cells
Akihiko
Tanimura,
Akihiro
Nezu,
Yosuke
Tojyo, and
Yoshito
Matsumoto
Department of Dental Pharmacology, School of Dentistry, Health
Sciences University of Hokkaido, Ishikari-Tobetsu, Hokkaido 061-0293, Japan
 |
ABSTRACT |
The effects of the cAMP pathway on the
Ca2+ response elicited by
phospholipase C-coupled receptor stimulations were studied in rat
parotid cells. Although 1 µM isoproterenol (Iso) itself had no effect on the cytosolic
Ca2+ concentration, the
pretreatment with Iso potentiated
Ca2+ responses evoked by
phenylephrine. The potentiating effect of Iso was attributed to a
shifting of the concentration-response curves of phenylephrine to the
left and an increase in the maximal response. Half-maximal potentiation
occurred at 3 nM Iso. Iso also potentiated the
Ca2+ response elicited by
carbachol. The potentiating effect of Iso was mimicked by forskolin (10 µM) and dibutyryl adenosine 3',5'-cyclic monophosphate (2 mM) and was blocked by 10 µM H-89. Iso potentiated the
phenylephrine-induced Ca2+
response in the absence of extracellular
Ca2+, but Iso did not increase the
inositol trisphosphate (IP3)
production induced by phenylephrine. These results suggest that the
potentiation of the Ca2+ response
can be attributed to a sensitization of
IP3 receptors by cAMP-dependent
protein kinase.
-adrenergic receptor; adenosine 3',5'-cyclic
monophosphate; calcium release; potentiation
 |
INTRODUCTION |
SECRETORY EVENTS IN PAROTID acinar cells are controlled
by two intracellular messengers:
Ca2+ and cAMP (2, 21).
Ca2+ is the principal mediator for
fluid secretion and is regulated by the phospholipase C (PLC) pathway,
which induces Ca2+ release from
intracellular Ca2+ stores through
the formation of inositol trisphosphate
(IP3). The cAMP pathway is
regulated by
-adrenergic agonists and vasoactive intestinal peptide
(VIP) in parotid cells. This pathway promotes amylase exocytosis
through the activation of cAMP-dependent protein kinase (PKA) (22, 27).
The involvement of
-adrenergic receptors in the regulation of
cytosolic Ca2+ concentration
([Ca2+]i)
has been the subject of considerable debate; however, at present it is
generally accepted that the physiological level of
-adrenergic stimulation does not change the
[Ca2+]i
in parotid acinar cells (15, 28, 32). Although some earlier studies
reported that high concentrations of a
-adrenergic agonist [>10 µM isoproterenol (Iso)] can increase
[Ca2+]i
(1, 14), it has been found that these concentrations of Iso stimulate
-adrenergic receptors, by which
[Ca2+]i
is increased (15, 28). It has also been demonstrated that a direct
application of cAMP does not induce the
Ca2+ release in permeabilized
parotid acinar cells (32). These studies have indicated that the cAMP
pathway by itself does not induce a
Ca2+ response.
Conversely, several studies have suggested that the cAMP pathway is
involved in regulating salivary fluid secretion. It has been shown that
VIP enhances the fluid secretion elicited by PLC-coupled receptor
agonists, such as substance P, ACh, and phenylephrine (4, 7). These
enhancing effects of VIP are mimicked by forskolin (17). These
observations imply that the cAMP pathway modulates the PLC pathway.
In many cell types, the agonist-induced
Ca2+ responses are modulated by
the cAMP pathway; the Ca2+
response is either potentiated (5, 6, 10, 13) or inhibited (30, 34) by
the cAMP pathway. The present study examined the interaction between
the cAMP and PLC pathways in regulating
[Ca2+]i
in rat parotid cells. It demonstrates that the physiological level of
-adrenergic stimulation potentiates the
[Ca2+]i
elevation elicited by phenylephrine or carbachol. The results suggest
that the potentiation of the Ca2+
response can be attributed to the enhancement of
Ca2+ release by sensitizing the
IP3-sensitive
Ca2+ stores in parotid cells.
 |
MATERIALS AND METHODS |
Reagents.
Phenylephrine, carbachol, atropine, Iso, propranolol, forskolin,
dibutyryl adenosine 3',5'-cyclic monophosphate (DBcAMP), collagenase (type II), trypsin (type III), trypsin inhibitor (type II-S), and BSA were obtained from Sigma (St. Louis, MO). The
myo-[2-3H]inositol
was purchased from Muromachi Kagaku Kogyo (Tokyo, Japan). Fura 2-AM
from Dojin Chemicals (Kumamoto, Japan), phentolamine from Ciba-Geigy
(Hyogo, Japan), H-89 from Seikagaku (Tokyo, Japan), and K-252a from
Kyowa Medex (Tokyo, Japan) were used. All other reagents were of
analytical grade.
Cell preparation.
Male Wistar strain rats (2-3 mo) were anesthetized with diethyl
ether and killed by cardiac puncture. Parotid glands were minced and digested with trypsin and collagenase as described elsewhere
(28). The parotid acinar cells were washed and resuspended in Hanks'
balanced salt solution buffered with 20 mM HEPES (pH 7.4) and
containing 0.2% BSA (HBSS-HB).
Measurement of
[Ca2+]i.
Parotid cells were incubated for 30 min with 2 µM fura 2-AM in
HBSS-HB at room temperature. The fura 2-loaded cells were washed twice,
resuspended in fresh HBSS-HB, and stored at room temperature until use.
Fura 2 fluorescence was measured at 37°C with a Hitachi F2000
spectrofluorometer (Hitachi, Tokyo, Japan) with excitation at 340 and
380 nm and emission at 510 nm. The
[Ca2+]i
was calculated from the fluorescence ratio as described by Grynkiewicz
et al. (11).
Measurement of inositol phosphate metabolism.
Inositol phosphates were measured using a method described elsewhere
(29). Briefly, parotid cells were labeled by incubation with
myo-[2-3H]inositol
(1.9 MBq/ml) for 100 min at 37°C, washed twice, and resuspended in
fresh HBSS-HB containing 1% BSA. The labeled cells were preincubated
for 5 min with 10 mM LiCl and then stimulated with either
phenylephrine, Iso, or a combination of phenylephrine and Iso at
37°C. The reactions were stopped by addition of
HClO4 (final concentration 4.5%).
A portion of the extract was then neutralized with 0.5 M KOH-9 mM
Na2B4O7.
The labeled inositol phosphates were separated using a Bio-Rad AG1-X8
column using the method of Berridge et al. (3).
 |
RESULTS |
-Adrenergic stimulation potentiates the
phenylephrine-induced
[Ca2+]i
elevation.
Figure 1 shows the increase in
[Ca2+]i
evoked by phenylephrine (0.3-10 µM) in the presence
(trace
1) or absence
(trace
2) of 1 µM Iso. Iso (1 µM)
itself did not alter the basal
[Ca2+]i,
but the pretreatment with Iso potentiated the
Ca2+ response elicited by
phenylephrine (Fig. 1,
A-C).
Application of 0.3 µM phenylephrine did not stimulate the
Ca2+ response in the control cells
(Fig. 1A,
trace
2), whereas it evoked a biphasic
Ca2+ response in Iso-treated cells
(Fig. 1A,
trace
1), indicating that the pretreatment
with 1 µM Iso lowered the threshold for the
Ca2+ response. Stimulation with 1 and 10 µM phenylephrine induced a biphasic
Ca2+ response, and the extent of
the peak and the sustained
[Ca2+]i
elevation were increased in the presence of 1 µM Iso (Fig. 1,
B and
C). Figure
1D shows the extent of the peak
[Ca2+]i
elevation after addition of various concentrations of phenylephrine in
the presence and the absence of 1 µM Iso. Iso shifted the
concentration-effect relationship of phenylephrine to the left and
elevated the maximum increase in
[Ca2+]i.

View larger version (15K):
[in this window]
[in a new window]
|
Fig. 1.
Effect of isoproterenol (Iso) on phenylephrine-induced
Ca2+ response.
A-C:
parotid cells were stimulated with 0.3 µM
(A), 1 µM
(B), or 10 µM
(C) phenylephrine (PhL) in presence
(trace 1) and absence
(trace 2) of 1 µM Iso. Iso or
phenylephrine was added to fura 2-loaded parotid cells as indicated by
black arrowheads (trace 1) or gray
arrowheads (trace 2).
D: increase in cytosolic
Ca2+ concentration
([Ca2+]i)
above basal level measured 10 s after stimulation with various
concentrations of phenylephrine in presence ( ) or absence ( ) of 1 µM Iso. Values are means ± SE of 4 independent experiments.
|
|
The potentiating effect was also observed when Iso was applied after
phenylephrine stimulation (Fig.
2A).
After the sustained [Ca2+]i
elevation with 1 µM phenylephrine, the application of 100 nM Iso
increased the
[Ca2+]i
to a higher sustained
[Ca2+]i
level within 1 min. The Iso-induced increase in
[Ca2+]i
after the phenylephrine stimulation was blocked by propranolol, a
-adrenergic antagonist, confirming that the effect of Iso is mediated by
-adrenergic receptors. The effects of various
concentrations of Iso in elevating the
[Ca2+]i
above the phenylephrine-induced sustained
[Ca2+]i is
demonstrated by Fig. 2B. Half-maximal
potentiation of the Ca2+ response
was attained at an Iso concentration of ~3 nM. To examine whether the
potentiating effect of Iso specifically acts on the
-adrenergic
receptors, the effect of Iso on the carbachol-induced Ca2+ response was examined. Figure
2C shows that the 100 nM
carbachol-induced sustained
[Ca2+]i
was also potentiated after application of 100 nM Iso, suggesting that
Iso commonly potentiates the effect of PLC-coupled receptor agonists on
Ca2+ responses.

View larger version (19K):
[in this window]
[in a new window]
|
Fig. 2.
Effect of Iso on sustained
[Ca2+]i
after stimulation with phenylephrine.
A: for
trace
1, 1 µM phenylephrine, 100 nM Iso,
100 nM propranolol (Pro), and 100 nM phentolamine (Pt) were added as
indicated. Trace 2 is apparent
[Ca2+]i
in unstimulated parotid cells. B:
Iso-dependent increase above 1 µM phenylephrine-induced sustained
[Ca2+]i
measured 60 s after application of various concentrations of Iso ( ).
Apparent changes in
[Ca2+]i
in absence of phenylephrine were also determined by 60-s incubation
with or without 1 µM Iso ( ). Values are means ± SE of 4 independent experiments. C: in
trace
1, 100 nM carbachol (CCh), 100 nM Iso,
100 nM propranolol, and 10 nM atropine (Atr) were added as indicated.
Trace
2 is apparent
[Ca2+]i
in unstimulated parotid cells.
|
|
Potentiation of phenylephrine-induced
[Ca2+]i
is mediated by PKA.
Next the effect of the PKA inhibitor H-89 on the Iso-induced
potentiation was examined. Application of 10 µM H-89 had little or no
effect on the sustained increase in
[Ca2+]i
elicited by 1 µM phenylephrine, but it blocked a subsequent [Ca2+]i
elevation by 100 nM Iso almost completely (Fig.
3A).
When
[Ca2+]i
was elevated with 1 µM phenylephrine and 100 nM Iso, the additional application of H-89 reduced the
[Ca2+]i
to the level before the application of Iso (Fig.
3B). A similar inhibition of the
Iso-induced potentiation was observed with 10 µM K-252a, another
protein kinase inhibitor (n = 4; data
not shown).

View larger version (17K):
[in this window]
[in a new window]
|
Fig. 3.
Effect of H-89 on Iso-induced potentiation of
Ca2+ response. As indicated, 1 µM phenylephrine, 10 µM H-89, and 100 nM Iso were added.
A: H-89 added before Iso.
B: Iso added before H-89. Results
shown are typical representations of 4 independent experiments.
|
|
In addition, we examined the effect of an adenylate cyclase activator,
forskolin, and the cell-permeant cAMP analog DBcAMP on the
[Ca2+]i.
Forskolin potentiated the phenylephrine-induced
[Ca2+]i
elevation, although forskolin itself did not change the basal [Ca2+]i
(Fig.
4A). The
increases in
[Ca2+]i
with phenylephrine (1 µM) alone and with phenylephrine plus a 1-min
pretreatment with 10 µM forskolin were 26.1 ± 7.9 and 75.8 ± 11.2 nM (means ± SE, n = 4),
respectively (above the basal level). When
[Ca2+]i
was elevated with 1 µM phenylephrine, the subsequent application of
10 µM forskolin caused an additional increase in
[Ca2+]i
(Fig. 4A,
trace
2). The phenylephrine-induced
[Ca2+]i
elevation was also potentiated by DBcAMP (Fig.
4B). The increases in
[Ca2+]i
with phenylephrine (1 µM) alone and with phenylephrine plus a 5-min
pretreatment with 2 mM DBcAMP were 26.6 ± 7.7 and 52.1 ± 9.1 nM
(means ± SE, n = 3), respectively.
This potentiated
[Ca2+]i
elevation was attenuated by 10 µM H-89. These results strongly suggest that the potentiation of the phenylephrine-induced
Ca2+ response by Iso is mediated
by PKA.

View larger version (20K):
[in this window]
[in a new window]
|
Fig. 4.
Effect of cAMP-elevating agents on
Ca2+ response. Black arrowheads
are for trace 1, and gray arrowheads
are for trace 2.
A: as indicated, 10 µM forskolin (F)
and 1 µM phenylephrine were added.
B: as indicated, 1 µM phenylephrine
and 10 µM H-89 were added after 5-min incubation with
(trace 1) or without
(trace
2) 2 mM dibutyryl adenosine
3',5'-cyclic monophosphate (DBcAMP). Results shown are
typical representations of 4 independent experiments.
|
|
Iso potentiates
Ca2+ release
from intracellular stores.
To determine whether Iso potentiates the phenylephrine-induced
Ca2+ release from intracellular
Ca2+ stores,
Ca2+ responses were examined in
the absence of extracellular Ca2+
(Fig. 5). In
Ca2+-free medium containing 0.2 mM
EGTA, the increases in
[Ca2+]i
with phenylephrine (1 µM) alone and with phenylephrine plus a 1-min
pretreatment with 100 nM Iso were 19.0 ± 5.4 and 34.0 ± 7.7 nM (means ± SE, n = 4), respectively. Furthermore, when 100 nM Iso was added after the
transient increase in
[Ca2+]i
elicited by 1 µM phenylephrine, Iso evoked an additional transient response in the
[Ca2+]i
(Fig. 5, trace
2). These results clearly
demonstrate that Iso induces Ca2+
release from intracellular Ca2+
stores by potentiating the phenylephrine-coupled signaling pathway.

View larger version (14K):
[in this window]
[in a new window]
|
Fig. 5.
Ca2+ response induced by
phenylephrine and Iso in absence of extracellular
Ca2+. As indicated, 0.2 mM EGTA
(E), 100 nM Iso, and 1 µM phenylephrine were added to cells in
Ca2+-free HBSS-HB. Black
arrowheads are for trace
1, and gray arrowheads are for
trace
2. Results shown are typical
representations of 4 independent experiments.
|
|
As shown in Fig. 6, it was verified that
Iso has no effect on the Ca2+
response elicited by thapsigargin, an inhibitor of microsomal Ca2+ pumps. In the absence of
extracellular Ca2+, 0.5 µM
thapsigargin induced a transient increase in
[Ca2+]i
by leakage of Ca2+ from
intracellular Ca2+ stores, and the
subsequent addition of CaCl2 (2 mM) resulted in a sustained increase in
[Ca2+]i
by Ca2+ entry through
store-operated Ca2+ channels.
Neither of these thapsigargin-dependent
Ca2+ responses are altered by Iso.
It was also observed that 10 mM caffeine, an activator of
ryanodine-sensitive Ca2+ channels,
did not induce any detectable change in
[Ca2+]i
in the presence or absence of Iso (data not shown). These observations suggest that Iso does not potentiate
Ca2+ responses other than the
Ca2+ release from
IP3-sensitive
Ca2+ stores.

View larger version (19K):
[in this window]
[in a new window]
|
Fig. 6.
Effect of Iso on thapsigargin-induced
Ca2+ response. As indicated, 0.2 mM EGTA, 100 nM Iso, 0.5 µM thapsigargin (ThG), and 2 mM
CaCl2 were added to cells in
Ca2+-free HBSS-HB. Black
arrowheads are for trace
1, and gray arrowheads are for
trace
2. Results shown are typical
representations of 5 independent experiments.
|
|
Effect of Iso on the phenylephrine-induced inositol phosphate
production.
The above data indicate that Iso potentiates
IP3-dependent
Ca2+ release. We further examined
whether this potentiation can be attributed to the enhancement of
IP3 production. The changes for phenylephrine-induced accumulation of inositol phosphates are shown in
Fig. 7A,
where the maximum accumulation of
IP3 was 10 min after stimulation
with 1 µM phenylephrine in the presence of 100 nM Iso and also in its
absence. In Fig. 7B, the accumulation of inositol phosphates is represented as a percent increase above the
basal value (before stimulation). In this experiment, the basal values
of inositol monophosphate (IP1),
inositol bisphosphate (IP2), and
IP3 were 22,778 ± 3,151, 6,151 ± 1,643, and 717 ± 74 dpm/ml
(n = 6), respectively. After 10 min of
incubation with 1 and 10 µM phenylephrine,
IP3 increased ~1.7-fold and
3.7-fold, respectively. These phenylephrine-induced accumulations of
IP3 were not enhanced by 100 nM
Iso. During the 10-min incubation with phenylephrine,
IP1 and
IP2 increased slightly (1.3- to
1.7-fold), whereas there was no enhancement by 100 nM Iso. These data
suggest that the Iso-induced potentiation of the
Ca2+ response cannot be attributed
to the enhancement of the IP3
production.

View larger version (22K):
[in this window]
[in a new window]
|
Fig. 7.
Effect of phenylephrine and Iso on formation of inositol phosphates.
A:
[3H]inositol-labeled
parotid cells were incubated for 2-20 min in absence of Iso ( )
or in presence of 100 nM Iso ( ), 1 µM phenylephrine ( ), or Iso + phenylephrine ( ). B:
[3H]inositol-labeled
parotid cells were incubated for 10 min in absence of Iso or presence
of Iso (100 nM), phenylephrine (1 or 10 µM), or Iso + phenylephrine. Results are expressed as percent increase above basal
level (before incubation). Values are means ± SE of 6 independent
experiments. IP1,
IP2, and
IP3, inositol monophosphate,
inositol bisphosphate, and inositol trisphosphate, respectively.
|
|
 |
DISCUSSION |
The present study demonstrates that the physiological level of
-adrenergic stimulation potentiates the
[Ca2+]i
elevation elicited by
-adrenergic and muscarinic stimulations in
parotid cells. Iso potentiated the
[Ca2+]i
elevation in a concentration-dependent manner, with half-maximal potentiation at 3 nM. This concentration range of Iso closely agreed
with that needed to promote cAMP formation (31) and amylase exocytosis
(26). Although it is known that high concentrations of Iso (>10 µM)
stimulate
-adrenergic receptors, by which
[Ca2+]i
is increased (28), those concentrations are more than three orders of
magnitude higher than that needed to potentiate the Ca2+ response. It is clear from
the data here that Iso potentiates the
Ca2+ response through the
activation of
-adrenergic receptors. It is also demonstrated that
the effect of Iso was mimicked by cAMP-elevating agents, forskolin and
DBcAMP, and that it was inhibited by PKA inhibitors, H-89 and K-252a,
indicating that the potentiating effect of Iso is mediated by PKA.
In addition, we showed that Iso induces
Ca2+ release from intracellular
Ca2+ stores through the
potentiation of the PLC-dependent signaling pathway, whereas Iso does
not alter the Ca2+ response
elicited by thapsigargin. These results are strong arguments that the
potentiation must be attributed to the enhancement of the
Ca2+ release from intracellular
Ca2+ stores but not to the
enhancement of Ca2+ entry or
attenuation of Ca2+ extrusion.
Because caffeine failed to induce any
Ca2+ response in the absence or
presence of Iso, it is verified that ryanodine-sensitive
Ca2+ release is not involved in
the Ca2+ response in rat parotid
cells. Taken together, the results here indicate that PKA potentiates
the PLC-dependent Ca2+ release
from IP3-sensitive
Ca2+ stores in rat parotid cells.
Because phenylephrine-induced production of inositol phosphates was not
enhanced by Iso, we speculate that the potentiation of the
agonist-induced Ca2+ response can
be attributed to the sensitization of the
IP3-sensitive Ca2+ release. This would be
consistent with an earlier observation by Rubin and Adolf (23) that
cAMP potentiates the IP3-induced Ca2+ release in permeabilized
parotid cells. Although it has been reported that the PKA-coupled
receptor stimulates PLC through 
-subunits of GTP-binding protein
(25, 35) or that it sensitizes a PLC-coupled receptor (20, 24), the
results here suggest that these types of cross talk are not substantial
in rat parotid cells. Because Iso (or cAMP-elevating agents) alone did
not change the basal
[Ca2+]i,
the possibility that the enhanced
Ca2+ release is secondary to an
inhibition of the Ca2+ uptake can
be eliminated. Furthermore, it is also unlikely that the enhanced
Ca2+ response can be attributed to
an increase in Ca2+ loading and a
resultant increase in Ca2+
contents in the stores. Although the increased
Ca2+ loading may enhance the peak
[Ca2+]i
elevation, it should then reduce the sustained
[Ca2+]i
by sequestration of the released
Ca2+. Taken together, our results
argue strongly in favor of a direct effect of PKA on the
IP3-sensitive
Ca2+ channel
(IP3 receptor). This type of
synergistic cross talk has been reported in hepatocytes (5, 12),
pancreatic
-cells (18), and articular chondrocytes (6). In support
of this view, it is known that IP3
receptor protein is a good substrate for PKA (8, 9, 19). In addition,
Wojcikiewicz and Luo (33) recently demonstrated that the PKA-dependent
phosphorylation of IP3 receptors
correlates with the sensitivity for
Ca2+ release in several cultured
cell types. Although the substrate for PKA causing the potentiation has
not been determined, PKA-dependent phosphorylation of
IP3 receptors is the most likely
mechanism for the synergism between cAMP- and PLC-coupled signaling
pathways on the Ca2+ response in
rat parotid cells.
The synergistic interaction between cAMP- and PLC-coupled receptors has
been reported for many cell types. It has been considered that this
synergistic interaction plays a role in the modulation or fine tuning
of multiple receptor-signaling pathways (25). It may be postulated that
the potentiating effect of PKA for the Ca2+ response is physiologically
relevant for the regulation of salivary fluid secretion. In particular,
norepinephrine, the neurotransmitter released from sympathetic nerves,
stimulates
- and
-adrenergic receptors simultaneously. In fact,
Jirakulsomchok and Schneyer (16) reported that the administration of a
-adrenergic blocker, propranolol, significantly attenuates the
salivary fluid secretion elicited by electrical stimulation of
sympathetic nerves in rats. In addition, it has been reported that the
activation of the cAMP pathway with VIP or forskolin enhances salivary
fluid secretion elicited by PLC-coupled receptor agonists, such as
substance P, phenylephrine, and carbachol (4, 7, 17). Because
Ca2+ is the principal regulator
for the salivary fluid secretion, the synergism between the cAMP and
PLC pathways on salivary secretion may be thought to be mediated by the
potentiation of the PLC-dependent Ca2+ response by PKA.
In conclusion, the present study demonstrated that the
-adrenergic
agonist potentiates the Ca2+
response elicited by PLC-coupled receptor agonists. This potentiation is considered to be mediated by PKA and can probably be attributed to
the sensitization of IP3
receptors. This PKA-induced potentiation of the
Ca2+ response is thought to
account for the synergism between cAMP- and PLC-coupled receptors for
salivary fluid secretion.
 |
FOOTNOTES |
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. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: A. Tanimura,
Dept. of Dental Pharmacology, School of Dentistry, Health Sciences
University of Hokkaido, Ishikari-Tobetsu, Hokkaido 061-0293, Japan
(E-mail: tanimura{at}hoku-iryo-u.ac.jp).
Received 9 November 1998; accepted in final form 16 February 1999.
 |
REFERENCES |
1.
Arkle, S.,
R. Michalek,
and
D. Templeton.
The relationship of intracellular free calcium activity to amylase secretion in substance P- and isoprenaline-stimulated rat parotid acini.
Biochem. Pharmacol.
38:
1257-1261,
1989[Medline].
2.
Baum, B. J.
Regulation of salivary secretion.
In: The Salivary System, edited by L. M. Sreebny. Boca Raton, FL: CRC, 1987, p. 123-134.
3.
Berridge, M. J.,
R. M. C. Dawson,
C. P. Downes,
J. P. Heslop,
and
R. F. Irvine.
Changes in the levels of inositol phosphates after agonist-dependent hydrolysis of membrane phosphoinositides.
Biochem. J.
212:
473-482,
1983[Medline].
4.
Bobyock, E.,
and
W. S. Chernick.
Vasoactive intestinal peptide interacts with alpha-adrenergic-, cholinergic-, and substance-P-mediated responses in rat parotid and submandibular glands.
J. Dent. Res.
68:
1489-1494,
1989[Abstract].
5.
Burgess, G. M.,
G. S. J. Bird,
J. F. Obie,
and
J. W. Putney, Jr.
The mechanism for synergism between phospholipase C- and adenylylcyclase-linked hormones in liver: cyclic AMP-dependent kinase augments inositol trisphosphate-mediated Ca2+ mobilization without increasing the cellular levels of inositol polyphosphates.
J. Biol. Chem.
266:
4772-4781,
1991[Abstract/Free Full Text].
6.
D'Andrea, P.,
V. Paschini,
and
F. Vittur.
Dual mechanism for cAMP-dependent modulation of Ca2+ signaling in articular chondrocytes.
Biochem. J.
318:
569-573,
1996[Medline].
7.
Ekström, J.,
and
L. Olgart.
Complementary action of substance P and vasoactive intestinal peptide on the rat parotid secretion.
Acta Physiol. Scand.
126:
25-31,
1986[Medline].
8.
Ferris, C. D.,
A. M. Cameron,
D. S. Bredt,
R. L. Huganir,
and
S. H. Snyder.
Inositol 1,4,5-trisphosphate receptor is phosphorylated by cyclic AMP-dependent protein kinase at serines 1755 and 1589.
Biochem. Biophys. Res. Commun.
175:
192-198,
1991[Medline].
9.
Ferris, C. D.,
and
S. H. Snyder.
Inositol 1,4,5-trisphosphate-activated calcium channels.
Annu. Rev. Physiol.
54:
469-488,
1992[Medline].
10.
Fournier, L.,
J. F. Whitfield,
J.-L. Schwartz,
and
N. Bégin-Heick.
Cyclic AMP triggers large [Ca2+]i oscillations in glucose-stimulated
-cells from ob/ob mice.
J. Biol. Chem.
269:
1120-1124,
1994[Abstract/Free Full Text].
11.
Grynkiewicz, G.,
M. Poenie,
and
R. Y. Tsien.
A new generation of Ca2+ indicators with greatly improved fluorescence properties.
J. Biol. Chem.
260:
3440-3450,
1985[Abstract].
12.
Hajnóczky, G.,
E. Gao,
T. Nomura,
J. B. Hoek,
and
A. P. Thomas.
Multiple mechanisms by which protein kinase A potentiates inositol 1,4,5-trisphosphate-induced Ca2+ mobilization in permeabilized hepatocytes.
Biochem. J.
293:
413-422,
1993[Medline].
13.
Hezareh, M.,
W. Schlegel,
and
S. R. Rawlings.
Stimulation of Ca2+ influx in
T3-1 gonadotrophs via the cAMP/PKA signaling system.
Am. J. Physiol.
273 (Endocrinol. Metab. 36):
E850-E858,
1997[Abstract/Free Full Text].
14.
Horn, V. J.,
B. J. Baum,
and
I. S. Ambudkar.
-Adrenergic receptor stimulation induces inositol trisphosphate production and Ca2+ mobilization in rat parotid acinar cells.
J. Biol. Chem.
263:
12454-12460,
1988[Abstract/Free Full Text].
15.
Hughes, A. R.,
H. Takemura,
and
J. W. Putney, Jr.
Does
-adrenoceptor activation stimulate Ca2+ mobilization and inositol trisphosphate formation in parotid acinar cells?
Cell Calcium
10:
519-525,
1989[Medline].
16.
Jirakulsomchok, D.,
and
C. A. Schneyer.
Effects on rat parotid amylase and Ca of
- and
-adrenergic sympathetic stimulation.
Am. J. Physiol.
236 (Endocrinol. Metab. Gastrointest. Physiol. 5):
E371-E385,
1979[Medline].
17.
Larsson, O.,
and
L. Olgart.
The enhancement of carbachol-induced salivary secretion by VIP and CGRP in rat parotid gland is mimicked by forskolin.
Acta Physiol. Scand.
137:
231-236,
1989[Medline].
18.
Liu, Y.-J.,
E. Grapengiesser,
E. Gylfe,
and
B. Hellman.
Crosstalk between the cAMP and inositol trisphosphate-signalling pathways in pancreatic
-cells.
Arch. Biochem. Biophys.
334:
295-302,
1996[Medline].
19.
Marshall, I. C.,
and
C. W. Taylor.
Regulation of inositol 1,4,5-trisphosphate receptors.
J. Exp. Biol.
184:
161-182,
1993[Abstract/Free Full Text].
20.
Morgan, N. G.,
R. Charest,
P. F. Blackmore,
and
J. H. Exton.
Potentiation of
1-adrenergic responses in rat liver by a cAMP-dependent mechanism.
Proc. Natl. Acad. Sci. USA
81:
4208-4212,
1984[Abstract].
21.
Putney, J. W., Jr.
Identification of cellular activation mechanisms associated with salivary secretion.
Annu. Rev. Physiol.
48:
75-88,
1986[Medline].
22.
Quissell, D. O.
Stimulus-exocytosis coupling mechanism in salivary gland cells.
In: Biology of The Salivary Glands, edited by K. Dobrosielski-Vergona. Boca Raton, FL: CRC, 1993, p. 181-200.
23.
Rubin, R. P.,
and
M. A. Adolf.
Cyclic AMP regulation of calcium mobilization and amylase release from isolated permeabilized rat parotid cells.
J. Pharmacol. Exp. Ther.
268:
600-606,
1994[Abstract].
24.
Sanchez-Bueno, A.,
I. Marrero,
and
P. H. Cobbold.
Different modulatory effects of elevated cyclic AMP on cytosolic Ca2+ spikes induced by phenylephrine or vasopressin in single rat hepatocytes.
Biochem. J.
291:
163-168,
1993[Medline].
25.
Selbie, L. A.,
and
S. J. Hill.
G protein-coupled-receptor cross-talk: the fine-tuning of multiple receptor-signalling pathways.
Trends Pharmacol. Sci.
19:
87-93,
1998[Medline].
26.
Takuma, T.
Evidence against direct involvement of cyclic AMP-dependent protein phosphorylation in the exocytosis of amylase.
Biochem. J.
256:
867-871,
1988[Medline].
27.
Takuma, T.,
and
T. Ichida.
Catalytic subunit of protein kinase A induces amylase release from streptolysin O-permeabilized parotid acini.
J. Biol. Chem.
269:
22124-22128,
1994[Abstract/Free Full Text].
28.
Tanimura, A.,
Y. Matsumoto,
and
Y. Tojyo.
Evidence that isoproterenol-induced Ca2+-mobilization in rat parotid acinar cells is not mediated by activation of
-adrenoceptors.
Biochim. Biophys. Acta
1055:
273-277,
1990[Medline].
29.
Tanimura, A.,
Y. Matsumoto,
and
Y. Tojyo.
Mastoparan increases membrane permeability in rat parotid cells independently of action on G-proteins.
Biochem. Biophys. Res. Commun.
177:
802-808,
1991[Medline].
30.
Tertyshnikova, S.,
and
A. Fein.
Inhibition of inositol 1,4,5-trisphosphate-induced Ca2+ release by cAMP-dependent protein kinase in a living cell.
Proc. Natl. Acad. Sci. USA
95:
1613-1617,
1998[Abstract/Free Full Text].
31.
Tojyo, Y.,
A. Tanimura,
S. Matsui,
Y. Matsumoto,
H. Sugiya,
and
S. Furuyama.
NaF-induced amylase release from rat parotid cells is mediated by PI breakdown leading to Ca2+ mobilization.
Am. J. Physiol.
260 (Cell Physiol. 29):
C194-C200,
1991[Abstract/Free Full Text].
32.
Tojyo, Y.,
A. Tanimura,
A. Nezu,
and
Y. Matsumoto.
Activation of
-adrenoceptors does not cause any change in cytosolic Ca2+ distribution in rat parotid cells.
Eur. J. Pharmacol.
360:
73-79,
1998[Medline].
33.
Wojcikiewicz, R. J.,
and
S. G. Luo.
Phosphorylation of inositol 1,4,5-trisphosphate receptors by cAMP-dependent protein kinase: type I, II, and III receptors are differentially susceptible to phosphorylation and are phosphorylated in intact cells.
J. Biol. Chem.
273:
5670-5677,
1998[Abstract/Free Full Text].
34.
Yang, C.-M.,
H.-L. Tsao,
C.-T. Chiu,
L.-W. Fan,
and
S.-M. Yu.
Regulation of 5-hydroxytriptamine-induced calcium mobilization by cAMP-elevating agents in cultured canine tracheal smooth muscle cells.
Pflügers Arch.
432:
708-716,
1996[Medline].
35.
Zhu, X.,
and
L. Birnbaumer.
G protein subunits and the stimulation of phospholipase C by Gs- and Gi-coupled receptors: lack of receptor selectivity of G
16 and evidence for a synergic interaction between G
and the
subunit of a receptor-activated G protein.
Proc. Natl. Acad. Sci. USA
93:
2827-2831,
1996[Abstract/Free Full Text].
Am J Physiol Cell Physiol 276(6):C1282-C1287
0002-9513/99 $5.00
Copyright © 1999 the American Physiological Society