Characterization of CCKA receptor affinity states
and Ca2+ signal transduction in vagal nodose ganglia
Tim O.
Lankisch,
Yasuhiro
Tsunoda,
Yuanxu
Lu, and
Chung
Owyang
Gastroenterology Research Unit, Department of Internal
Medicine, University of Michigan Medical Center, Ann Arbor,
Michigan 48109
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ABSTRACT |
CCKA receptors are present on
vagal afferent fibers. The objectives of this study were to identify
the presence of high- and low-affinity CCKA receptors on
nodose ganglia and to characterize the intracellular calcium signal
transduction activated by CCK. Stimulation of acutely isolated nodose
ganglion cells from rats with 1 nM CCK-8 primarily evoked a
Ca2+ transient followed by a sustained Ca2+
plateau (45% of cells responded), whereas 10 pM CCK-8 evoked Ca2+ oscillations (37% of cells responded). CCK-OPE, a
high-affinity agonist and low-affinity antagonist of CCKA
receptors, primarily elicited Ca2+ oscillations (29% of
cells responded). CCK-OPE inhibited the Ca2+ transient
induced by 1 nM CCK-8 but not by carbachol and high K+.
This result suggests the presence of high- and low-affinity states of
CCKA receptors on nodose ganglia. We further demonstrated that nicardipine (10 µM) but not
-conotoxins GVIA and MVIIC
(10-100 nM) abolished Ca2+ signaling induced by CCK-8,
indicating that an L-type voltage-dependent Ca2+ channel
and not an N- or Q-type Ca2+ channel is coupled to
CCKA receptors. In a separate study, we showed that the G
protein activator NaF (10 mM) elicited a Ca2+ transient and
inhibited CCK-8-evoked Ca2+ signaling, indicative of G
protein(s) involvement in CCKA receptor activity. The
Gq protein antagonist Gp antagonist-2A (10 µM) also abolished the action of CCK-8. This study indicates that
CCKA receptors exist in both high- and low-affinity states
in the nodose ganglia. Activation of high-affinity CCKA
receptors elicits Ca2+ oscillations, whereas stimulation of
low-affinity CCKA receptors evokes a sustained
Ca2+ plateau. These Ca2+-signaling modes are
mediated through the L-type Ca2+ channel and involve the
participation of Gq protein.
cholecystokinin; cholecystokinin A receptors; Ca2+
signaling
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INTRODUCTION |
CCK, WHICH BELONGS TO
THE brain-gut peptide family, regulates gastrointestinal
functions such as pancreatic enzyme secretion, gallbladder contraction,
gastrointestinal motility, and cell growth (6, 7, 8a,
12-14). In the central nervous system (CNS), CCK may regulate anxiety, behavior, and learning/memory processes
(11). These actions are mediated through two different CCK
receptors, CCAA and CCKB, which have been
cloned and characterized in different tissues. CCKA and
CCKB receptors each consist of seven hydrophobic transmembrane domains homologous to other members of the G
protein-coupled receptor superfamily (8, 23).
CCKA and CCKB receptors are distributed
throughout the gastrointestinal tract, and they are localized in
several regions of the CNS. In addition, CCK receptors have been
detected in the rat vagus nerve (12, 25, 28). These
receptors are transported from the nodose ganglion to the peripheral
nerve ending.
The existence of two different affinity sites of the CCKA
receptor was first demonstrated in pancreatic acini (10).
The high affinity of the CCKA receptor elicits
Ca2+ oscillations and amylase secretion, whereas the
low-affinity state evokes a large Ca2+ transient and may
mediate both stimulation and inhibition of enzyme secretion, depending
on experimental conditions. These different affinity states of the
CCKA receptor may also exist and function in the autonomic
nervous system. In vivo studies in rats have shown that high-affinity
CCKA receptors on the vagus nerve mediate CCK-8-stimulated
pancreatic enzyme secretion (9). Conversely, low-affinity
vagal CCKA receptors appear to mediate satiety
(24). Evidence of high- and low-affinity CCKA
receptors on the vagus nerve has not been directly demonstrated in
vitro, and the mode of calcium signal transduction activated by CCK has yet to be determined. The objectives of this study were to identify the
presence of high- and low-affinity CCKA receptors on vagal nodose ganglia by performing intracellular Ca2+ studies
using various CCKA-receptor agonists and antagonists and to
characterize the intracellular Ca2+ signaling activated by CCK.
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MATERIALS AND METHODS |
Materials.
Chemicals were purchased from the following sources: CCK-8, collagenase
type IA, trypsin, soybean trypsin inhibitor (SBTI), nicardipine, and
NaF from Sigma (St. Louis, MO); CCK-OPE from Research Plus (Bayonne,
NJ); Hanks' balanced salt solution (HBSS) from Life Technologies
(Grand Island, NY); fura 2-AM,
-conotoxin GVIA, and
-conotoxin
MVIIC from Calbiochem (San Diego, CA); Gp antagonist-2A from Biomol
(Plymouth Meeting, PA); and Cell-Tak from Collaborative Biomedical
Products (Bedford, MA). All chemicals were dissolved in either dimethyl
sulfoxide, ethanol, acetic acid, or distilled water, the final
concentrations being 0.01-0.1%, which did not affect cell responses.
Methods.
Acutely isolated nodose ganglion neurons were obtained from 4-wk-old
male Sprague-Dawley rats and prepared by collagenase digestion
described previously (6). Rats were anesthetized with an
intramuscular injection of xylazine and ketamine; then nodose ganglia
were removed from connective tissues and minced into fine pieces. In
each experiment, three rats were used to obtain isolated nodose
ganglion cells. The tissue fragments were incubated with 3 ml HBSS
containing 1 mg/ml collagenase (type I-A), 0.5 mg/ml trypsin (type 1),
and 1 mg/ml BSA for 30 min at 37°C. After incubation, the ganglia
fragments were gently triturated six times to disperse the cells under
dissecting microscope, and the solution was diluted with 3 ml HBSS
followed by centrifugation at 900 revolutions/min (rpm). The neurons
were then incubated in 3 ml HBSS containing 1.5 ml SBTI (type II-S) and
1 mg/ml BSA for 8 min at 37°C. The incubation was stopped by
centrifugation at 900 rpm, and the nodose ganglion cells were
resuspended in a physiological salt solution (PSS) and washed twice
followed by centrifugation (900 rpm). The PSS contained 0.1% BSA and
(in mM) 137 NaCl, 4.7 KCl, 0.56 MgCl2, 1.28 CaCl2, 1 NaH2PO4, 10 HEPES, Eagle's minimum essential amino acid neutralized with NaOH, 2 L-glutamine, and 5.5 D-glucose. The PSS was
adjusted to pH 7.4 and equilibrated with 100% O2. The
intracellular Ca2+ concentration
([Ca2+]i) measurements were performed as
previously described (20). In brief, isolated nodose
ganglion cells were incubated with 2 µM fura 2-AM in 3 ml PSS for 30 min at 37°C. All experiments were done using a dual-excitation
wavelength (340/380 nm emitted at 505 nm) modular fluorometer system
(SPEX) coupled to a Nikon Diaphot inverted microscope magnification
(×40). Isolated nodose ganglion cells were attached to a glass
coverslip that was coated with the natural adhesive Cell-Tak. These
coverslips were mounted on a closed chamber and superfused with PSS
from a reservoir (1 ml/min). A fluoroscence ratio was converted to
[Ca2+]i according to in vitro calibration
with an external standard and 50 µM fura 2-AM potassium salt
(5). All animal experiments were carried out in accordance
with the National Institutes of Health Guide for the Care
and Use of Laboratory Animals. Every effort was made to
minimize animal suffering and reduce the number of animals used.
Statisitical analysis was performed by the Student's t-test. Results were expressed as means ± SE.
P < 0.05 was considered significant.
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RESULTS |
CCK-8 and the high-affinity CCKA receptor agonist
CCK-OPE induce Ca2+ signaling in
individual nodose ganglion cells.
To investigate whether CCK analogs stimulate Ca2+ signaling
in nodose ganglia, we measured [Ca2+]i in
fura 2-AM-loaded single cells. Mean basal
[Ca2+]i in individual nodose ganglion cells
was 67 ± 3 nM (n = 48). Some nodose ganglion
cells demonstrated Ca2+ oscillation in the resting state
(~15% occurrence); these cells were not used for
[Ca2+]i measurement. On stimulation with 1 nM
CCK-8, an initial transient followed by a sustained increase in
[Ca2+]i to 182 nM was observed in 21 of 47 cells (Fig. 1A and Table 1). In contrast, 10 pM CCK-8 elicited
repetitive Ca2+ oscillations in 15 of 41 cells.
Ca2+ oscillations occurred with a frequency of 2.5 ± 0.4 cycles/5 min and an amplitude (peak-basal) of 113 ± 16 nM
(Fig. 1B). The threshold of CCK-8 concentration to evoke
Ca2+ oscillations was 1 pM, with two of nine cells
responding. Application of the high-affinity CCKA
receptor agonist CCK-OPE (100 nM) to nodose ganglion cells elicited
repetitive Ca2+ oscillations in 12 of 41 cells (Fig.
1C). Ca2+ oscillations occurred with a frequency
of 2.1 ± 0.3 cycles/5 min and an amplitude of 86 ± 11 nM.
The threshold CCK-OPE concentration to evoke Ca2+ spiking
was 10 nM, with two of nine cells responding. No response was observed
when lower concentrations of CCK-8 (0.5 pM) or CCK-OPE (5 nM) were used
(9 of 9 cells). These data indicate that stimulation of low-affinity
CCKA receptors evokes an initial transient followed by a
sustained increase in [Ca2+]i, whereas
activation of high-affinity CCKA receptors elicits Ca2+ oscillations. Administration of the CCKA
receptor antagonist L-364,718 (10
6 M) but not the
CCKB receptor antagonist L-365,260 (10
6M)
inhibited calcium oscillations evoked by CCK-8 (1 nM and 10 pM; 57 ± 6 mM vs. 171 ± 7 nM, P < 0.05, and 63 ± 10 vs. 185 ± 10 nM, P < 0.05; n = 6) or CCK-OPE (100 nM), indicating that these CCK analogs were acting
via CCKA receptors. All calculations and statistical
analyses, including the Ca2+ spike amplitude and frequency,
were made with cells responding to CCK analogs.

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Fig. 1.
Effects of CCK-8 and CCK-OPE on Ca2+
signaling in fura 2-AM-loaded individual nodose ganglion cells from
4-wk-old rats. A: 1 nM CCK-8 induced a sustained
intracellular Ca2+ concentration
([Ca2+]i) plateau. B: application
of 10 pM CCK-8 stimulated Ca2+ oscillations. C:
100 nM CCK-OPE elicited Ca2+ oscillations. Each panel is
representative of 21 (A), 15 (B), and 12 (C) separate determinations.
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Table 1.
Amplitude and frequency of Ca2+
signaling induced by high and low concentrations of CCK-8 and
CCK-OPE in individual nodose ganglion cells
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High- and low-affinity CCKA receptors exist in nodose
ganglion cells.
As shown in Fig. 2A, a low
concentration (10 pM) of CCK-8 induced Ca2+ oscillations
(n = 8). When the concentration of CCK-8 was increased to 1 nM, a transient increase in [Ca2+]i
occurred, followed by a prolonged but smaller elevation of [Ca2+]i without oscillations
(n = 8). CCK-OPE as well as JMV-180 act as
high-affinity agonists and as low-affinity antagonists of the CCKA receptor (4). CCK-OPE (100 nM) evoked
Ca2+ oscillations and blocked Ca2+ signalings
elicited by 1 nM CCK-8 (n = 11, P < 0.05; Fig. 3). However, subsequent
application of 10 µM carbachol evoked a transient increase in
[Ca2+]i even in the presence of CCK-OPE
(n = 5; Fig. 2B; Fig. 3), suggesting that
CCK-OPE acts as a specific antagonist of the low-affinity CCKA receptor. Similarly, CCK-8 (1 nM) evoked a
Ca2+ transient, which was inhibited by application of
CCK-OPE (n = 11, P < 0.05; Fig.
2C). In separate experiments, we showed that CCK-OPE (100 nM) inhibited Ca2+ transients induced by 10 nM CCK-8 (Fig.
3), but it did not affect Ca2+ transient stimulated by 50 mM K+ (n = 4; Fig.
4). This indicates that the inhibitory
action of CCK-OPE on CCK-8-induced Ca2+ signalings is
agonist specific. These results suggest that high- and low-affinity
CCKA receptors are present in nodose ganglion cells.

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Fig. 2.
Effects of CCK-8 and CCK-OPE on Ca2+
signaling in nodose ganglion cells. A: 10 pM CCK-8 elicited
Ca2+ oscillations, whereas 1 nM CCK-8 evoked a
Ca2+ transient in the same cell. B: 100 nM
CCK-OPE elicited Ca2+ oscillations but inhibited the
Ca2+ transient in response to 1 nM CCK-8. C: 1 nM CCK-8 induced a Ca2+ transient, which was inhibited by
100 nM CCK-OPE. Each panel is representative of 8 (A) and 10 (B and C) separate determinations.
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Fig. 3.
Effects of CCK-OPE on the amplitude of Ca2+
signaling induced by high concentration of CCK-8 in nodose ganglion
cells. CCK-8 induced an initial transient followed by a sustained
increase in [Ca2+] (n = 8). CCK-OPE 100 nM inhibited Ca2+ transients induced by 1 nM of CCK-8
(P < 0.01; n = 10), but it did not
affect Ca2+ spikes evoked by 100 µM carbachol
(n = 5). **P < 0.01.
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Fig. 4.
Representative tracings to demonstrate the effects of
CCK-OPE, CCK-8, and K+ on Ca2+ signaling in the
nodose ganglia. CCK-OPE (100 nM) stimulated a Ca2+
transient but inhibited Ca2+ signaling evoked by CCK-8 (10 nM). CCK-OPE did not inhibit Ca2+ transient elicited by
K+ (50 mM; n = 4). When K+ was
increased from 5 to 50 mM in physiological saline, concentration of
Na+ in medium was reduced to 90 mM.
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Elimination of extracellular Ca2+ and
an L-type Ca2+ channel blocker inhibit
Ca2+ signaling in response to CCK-8.
We next examined whether extracellular Ca2+ was required
for Ca2+ signaling induced by CCK-8 and CCK-OPE.
Elimination of extracellular calcium abolished the Ca2+
plateau induced by 1 nM CCK-8 and the Ca2+ oscillations
evoked by 10 pM CCK-8 in seven of seven cells (P < 0.01; Fig. 5, A and
B). These changes were reversible with the reintroduction of
extracellular Ca2+ (1.28 mM). CCK-OPE (100 nM) also failed
to elicit Ca2+ signaling in the absence of extracellular
Ca2+ in three of three cells (data not shown). These
results indicate that CCK analogs elicit Ca2+ signaling
using an extracellular Ca2+ source. We further
characterized the type of Ca2+ channel coupled to the
CCKA receptor in nodose ganglion cells. The L-type
Ca2+ channel blocker nicardipine (10 µM) abolished 1 nM
CCK-8-stimulated Ca2+ signaling in all eight cells tested
(P < 0.01; Figs. 6 and
7A). Nicardipine also
abolished Ca2+ oscillations elicited by 10 pM CCK-8 in all
six cells tested. In contrast, neither the N-type Ca2+
channel blocker
-conotoxin GVIA (10-100 nM) nor the Q type
channel blocker
-conotoxin MVIIC (10 nM) inhibited Ca2+
signaling evoked by 1 nM CCK-8 in the 13 cells that responded to CCK-8
(Figs. 6 and 7, B and C). Our results showed that
the voltage-dependent Ca2+ channel coupled to the vagal
CCKA receptor in the nodose ganglia is an L-type channel.

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Fig. 5.
Representative tracings to demonstrate the effect of
elimination of extracellular Ca2+ on CCK-8-induced
Ca2+ signaling. Extracellular Ca2+
([Ca2+]o) was removed from medium, and 1 mM
EGTA was added 1 min before administration of CCK-8. Neither high nor
low doses of CCK-8 induced Ca2+ signaling in the absence of
[Ca2+]o. These changes were reversible with
the reintroduction of extracellular Ca2+ (1.28 mM, no lines
indicated). A and B are representative tracings
of 7 separate determinations.
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Fig. 6.
Effects of elimination of
[Ca2+]0 and various Ca2+-channel
blockers on Ca2+ signaling induced by CCK-8. Elimination of
extracellular Ca2+ abolished Ca2+ transient and
plateau induced by 1 nM CCK-8 (P < 0.01;
n = 7). Similarly, the L-type Ca2+-channel
blocker nicardipine (10 µM) also abolished Ca2+ signaling
evoked by 1 nM CCK-8 (P < 0.01; n = 8). In contrast, neither the N-type Ca2+-channel blocker
-conotoxin GVIA (100 nM) nor the Q-type channel blocker
-conotoxin MVIIC (10 nM) had any effect on Ca2+
signaling evoked by 1 nM CCK-8 (n = 13). , Change
in. **P < 0.01.
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Fig. 7.
Representative tracings to demonostrate the effects of
Ca2+-channel blockers on Ca2+ signaling induced
by CCK-8. A: preincubation of cells with the L-type
Ca2+-channel blocker nicardipine (10 µM) for 8 min
inhibited the 1 nM CCK-8-mediated Ca2+ transient. Data
represent 8 separate determinations. B and C: the
N-type channel blocker -conotoxin GVIA (10-100 nM) and the
Q-type channel blocker -conotoxin MVIIC (10 nM) did not affect
CCK-8-induced Ca2+ signaling. B and C
represent 13 separate experiments.
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G protein(s) is involved in mediating
Ca2+ signaling evoked by CCK-8.
It is well accepted that activation of G protein(s) will inactivate
receptors coupled to G protein(s) (16). As shown in Fig.
8A, the G protein activator
NaF (10 mM) evoked a Ca2+ transient and abolished the
Ca2+ signaling evoked by CCK-8 (1 nM) in five of five cells
[CCK-8: 115 ± 10.5 nM (n = 21) vs. CCK-8 + NaF: 28.5 ± 9.7 nM (n = 5); P < 0.05 by unpaired t-test]. This suggests that
CCKA receptors in the nodose ganglia are coupled to G
protein(s). To further confirm this observation and characterize the
type of G protein coupled to CCKA receptors in the nodose
ganglion cells, we used the Gq protein antagonist Gp
antagonist-2A (19). Administration of Gp antagonist-2A (10 µM) caused a marked reduction of the Ca2+ signaling
stimulated by 1 nM CCK-8 in nine of nine cells (Fig. 8B),
suggesting that Gq protein is involved in CCKA
receptor activity [CCK-8: 115 ± 10.5 nM (n = 21)
vs. CCK-8 + Gp antagonist-2A: 49.6 ± 11.5 nM
(n = 9); P < 0.05 by unpaired
t-tests].

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Fig. 8.
Representative tracings to demonstrate the effects of
NaF, a G protein activator, and Gp antagonist-2A, a Gq protein
inhibitor, on Ca2+ signaling elicited by CCK-8.
A: NaF (10 mM) evoked a Ca2+ transient and
inhibited Ca2+ spiking elicited by CCK-8 (1 nM;
n = 5). B: Gp antagonist-2A (10 µM)
abolished the Ca2+ signaling stimulated by CCK-8 (1 nM;
n = 9).
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DISCUSSION |
This study showed that, in rat vagal nodose ganglia, 1)
30-45% of nodose ganglion cells responded to CCK stimulation;
2) high doses of CCK-8 elicited a sustained Ca2+
plateau, whereas low doses caused Ca2+ oscillations;
3) CCK-OPE, a high-affinity CCKA receptor
agonist, elicited Ca2+ oscillations and inhibited the
CCK-induced Ca2+ signaling, indicating the presence of
high- and low-affinity CCKA receptors; 4)
extracellular Ca2+ is required for Ca2+
signaling elicited by CCK; 5) the voltage-dependent
Ca2+ channel coupled to the CCKA receptor is L
type; and 6) CCKA receptors in the nodose
ganglia are coupled to Gq protein.
The presence of CCKA receptors on the neurons of the nodose
ganglion has been demonstrated by receptor autoradiography (25, 28, 29). Recent functional studies have demonstrated that postprandial satiety appears to be mediated by vagal low-affinity CCKA receptors (24), whereas high-affinity
CCKA receptors mediate pancreatic enzyme secretion
(9). Using [Ca2+]i recording
systems in single nodose ganglion cells, we demonstrated that 37% of
cells (48 of 129 cells) responded to CCK analogs. In a variety of cell
systems, submaximal concentrations of Ca2+-mobilizing
agonists elicit Ca2+ oscillations, whereas supramaximal
doses evoke an initial large Ca2+ transient followed by a
sustained Ca2+ plateau (17). This phenomenon
is also found in nodose ganglion cells. The Ca2+ response
to CCK-8 was blocked by CCKA receptor antagonist L364,718 and not by CCKB receptor antagonist L365,260, indicating
mediation by CCKA receptor. The main objective of this
study was to identify the presence of high- and low-affinity
CCKA receptors on nodose ganglia. CCK-OPE is a synthetic
decapeptide that acts as an agonist to high-affinity CCKA
receptors and as an antagonist to low-affinity CCKA
receptors (4). We showed that CCK-OPE elicited
Ca2+ oscillations. It also blocked the Ca2+
signaling stimulated by high doses of CCK-8 in individual nodose ganglion cells. This finding indicates the presence of high- and low-affinity CCKA receptors in single nodose ganglion cells.
In pancreatic acini, intracellular Ca2+ is used for the
Ca2+ oscillations or the large initial Ca2+
transient stimulated by CCK analogs (17, 26), whereas in nodose ganglion cells, the Ca2+ source was strictly
extracellular. We further showed that the L-type
Ca2+-channel blocker nicardipine abolished the
Ca2+ signaling induced by CCK. L-type voltage-dependent
Ca2+ channels are concentrated on neuronal cell bodies and
at the base of the dendrites in the brain, spinal cord, and retinal
neurons, whereas N-type voltage-dependent Ca2+ channels are
clustered on the presynaptic plasma membrane of neural fibers mediating
neuromuscular functions (15). Thus it is not surprising
that the voltage-dependent Ca2+ channel coupled to the
CCKA receptors found on the cell bodies of the nodose
ganglia is type L and not N or Q. However, our finding requires
confirmation by patch-clamp studies.
CCKA receptors are Gq protein-coupled
heptahelical receptors. They are coupled to well-characterized
intracellular effectors and second-messenger systems and mediate
Ca2+ signal transduction in a variety of cell types
(22). For example, it has been shown that the low-affinity
CCKA receptor in pancreatic acinar cells is coupled to the
conventional G
q/11/PLC-
1 pathway, resulting in production of 1,4,5-inositol trisphosphate (to release Ca2+ and activate calmodulin) and diacylglycerol (to
activate protein kinase C) (26). These low-affinity
CCKA receptors also appear to be coupled to the nonreceptor
protein tyrosine kinase pathway that mediates extracellular
Ca2-dependent pancreatic exocytosis (21). In
contrast, high-affinity CCKA receptors are coupled to the
G
8 subunit of the Gq protein, which is
linked to the cPLA2 pathway, resulting in production of
arachidonic acid, which enhances intracellular Ca2+
oscillations (18, 19). It remains to be determined whether high- and low-affinity CCKA receptors in the nodose ganglia
use intracellular pathways similar to those used in pancreatic acini. However, the source of Ca2+ used for Ca2+
oscillations or the large Ca2+ transient is completely
different in these two cell systems.
To investigate whether the CCKA receptors in the nodose
ganglia are coupled to G protein(s), we examined the effect of NaF, a G
protein activator. It is well recognized that activation of G
protein(s) will inhibit binding to receptors coupled to G protein(s) (20). In this study, we showed that NaF elicited a
Ca2+ transient and inhibited the Ca2+ signaling
evoked by CCK-8. Because NaF abolished the action of CCK-8, it suggests
that the CCKA receptor in the nodose ganglia is coupled to
a G protein. This is likely to be Gq, because
CCKA receptors are in general linked to
G
q/11 in a variety of tissues, including pancreatic
acinar cells and neurons (26). To exclude coupling of
CCKA receptors to Gi, we showed that pertusis
toxin treatment did not affect Ca2+ signaling evoked by
CCK-8 in the nodose ganglia (unpublished data). In other neuronal
systems, such as the substantia nigra dopaminergic neurons,
G
q/11 mediates CCK-8 activiation of the cationic
conductance (27). In the thalamic reticular neurons and
hippocampal neurons, CCK-8 increases neuronal excitability by
suppressing the resting K+ conductance by an as yet to be
determined mechanism (1). Our study indicates that the
Gq protein coupled to the CCKA receptor in rat
nodose ganglia is involved in the opening of the L-type Ca2+ channels.
In conclusion, this study indicates that CCKA receptors
exist in both high- and low-affinity states in the nodose ganglia. Activation of high-affinity CCKA receptors elicits
Ca2+ oscillations, whereas stimulation of low-affinity
CCKA receptors evokes a Ca2+ transient
followed by a small sustained Ca2+ plateau. These
Ca2+-signaling modes are mediated through L-type
Ca2+ channels and involve the participation of
Gq proteins.
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ACKNOWLEDGEMENTS |
This work was supported by the National Institute of Diabetes and
Digestive and Kidney Diseases Grants R01-DK-32830 and 5P 30-DK-34933.
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FOOTNOTES |
Address for reprint requests and other correspondence: C. Owyang, 3912 Taubman Center, Box 0362, Univ. of Michigan Health System,
Ann Arbor, MI 48109 (E-mail: cowyang{at}umich.edu).
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.
10.1152/ajpgi.00313.2001
Received 18 July 2001; accepted in final form 15 January 2002.
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