Chem. Senses 28: 415-422,
2003
© Oxford University Press 2003
Inward currents and increases in cytosolic Ca2+ concentration induced by cyclic ADP-ribose in turtle olfactory receptor cells
Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan
Correspondence to be sent to: Dr Makoto Kashiwayanagi, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan. e-mail: yanagi{at}hucc.hokudai.ac.jp
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Abstract |
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In olfactory receptor cells, it is well established that cyclic AMP (cAMP) and inositol-1,4,5-trisphosphate (IP3) act as second messengers during odor responses. In previous studies, we have shown that cAMP-increasing odorants induce odor responses even after complete desensitization of the cAMP-mediated pathway. These results suggest that at least one cAMP-independent pathway contributes to the generation of odor responses. In an attempt to identify a novel second messenger, we investigated the possible role of cyclic ADP-ribose (cADPR) in olfactory transduction. Turtle olfactory receptor cells were isolated using an enzyme-free procedure and loaded with fura-2/AM. The cells responded to dialysis with cADPR with an inward current and an increase of the intracellular Ca2+ concentration, [Ca2+]i. Flooding of cells with 100 µM cADPR from the pipette also induced an inward current without changes in [Ca2+]i in Na+-containing and Ca2+-free Ringer solution. In an Na+-free and Ca2+-containing Ringer solution, cADPR induced only a small inward current with a concomitant increase in [Ca2+]i. Inward currents and increases in [Ca2+]i induced by cADPR were completely inhibited by removal of both Na+ and Ca2+ from the outer solution. The experiments suggest that cADPR activates a cation channel at the plasma membrane, allowing inflow of Na+ and Ca2+ ions. The magnitudes of the inward current responses to cAMP-increasing odorants were greatly reduced by prior dialyses of a high concentration of cADPR or 8-bromo-cyclic ADP-ribose (8-Br-cADPR), an antagonist. It is possible that the cADPR-dependent pathway contributes to the generation of olfactory responses.
Key words: Ca2+, cyclic ADP-ribose, inward current, odor response, olfactory cell
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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It has been well established that cyclic AMP (cAMP) acts as a second messenger in olfactory transduction. There is good evidence that the binding of one set of chemical stimuli to odorant receptors leads to stimulation of adenylyl cyclase via GTP-binding protein (G protein) (Pace et al., 1985
;
Sklar et al., 1986;
Breer and Boekhoff, 1991). In
turn, an increase in the cAMP level activates cAMP-gated cation channels
(Nakamura and Gold, 1987;
Suzuki, 1987;
Kurahashi, 1990), causing cell
depolarization and a discharge of action potentials
(Trotier, 1986;
Frings et al., 1991).
We have previously shown that cAMP-increasing odorants induce a large
olfactory response, even after complete desensitization of the cAMP-dependent
pathway (Kashiwayanagi et al.,
1994; Kashiwayanagi and
Kurihara, 1995). These results suggested that cAMP-independent
pathways contribute to the generation of odor responses. Until now, however,
it has remained unclear as to how odor responses are generated via the
cAMP-independent pathway.
In several cases, odorant-induced responses are accompanied by increases in
cytosolic Ca2+ concentrations ([Ca2+]i) and
intraciliary Ca2+ concentrations
(Sato et al., 1991;
Restrepo et al.,
1993b; Kashiwayanagi and
Lindemann, 1995;
Leinders-Zufall et al.,
1998). Cyclic ADP-ribose (cADPR), which is converted from
nicotinamide adenine dinucleotide (NAD+) by ADP-ribosyl cyclase,
has been shown to mobilize Ca2+ in various cells, including central
and peripheral neurons (Berridge,
1993; Guse, 1999;
Galione et al.,
1991). It is possible that odorant-induced cADPR may contribute to
[Ca2+]i increases in olfactory receptor cells. In the
present study, we found that the flooding of turtle olfactory cells with cADPR
from a patch pipette induces inward currents, and that inward currents in
response to cAMP-increasing odorants can be greatly reduced by prior dialysis
with high concentrations of cADPR or 8-Br-cADPR, an antagonist
(Guse et al., 1995).
It is possible that this cADPR-dependent pathway contributes to the generation
of odor responses.
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Methods |
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All experiments were carried out in accordance with the Guidelines for the Use of Laboratory Animals of the Graduate School of Pharmaceutical Sciences, Hokkaido University.
Animals
Turtles, Geoclemys reevesii, weighing 150–300 g, were obtained from commercial suppliers and maintained at 25°C. Animals were fed porcine and bovine liver ad libitum. For the isolation of olfactory receptor cells, animals were cooled to 0°C and decapitated. The nasal cavities were opened, and the olfactory epithelia were quickly removed.
Isolation of olfactory receptor cells
The olfactory receptor cells were isolated as described previously
(Kashiwayanagi et al.,
1994). The epithelia were cut into slices of 
150–200
µm thickness in normal Ringer solution at 0°C and stored at 4°C.
Slices were incubated for 2 h at 37°C in Ca2+-free Ringer
solution for the isolation of olfactory receptor cells. Immediately prior to
recording, one slice of the epithelium was placed in 500 µl normal Ringer
solution in a recording chamber and shaken. No enzymes (such as proteases)
were added. Once cells had settled on the bottom of the chamber and a tight
seal had been established on a cell, the chamber was continuously perfused
with normal Ringer solution. Turtle olfactory receptor cells were readily
distinguished from other types of cells (e.g. respiratory and basal cells)
based on their characteristic morphology, such as possessing several long
motile cilia.
Whole-cell recordings
The conventional whole-cell patch clamp method was used to measure
transmembrane currents (Hamill et
al., 1981). Recordings were made with an Axopatch 1D
amplifier (Axon Instruments, Inc., Burlingame, CA) using patch electrodes of
borosilicate glass with an inner filament (GD 1.5, Narishige Co., Tokyo,
Japan), which were sealed on the cell body. The holding potential was -70 mV.
Electrodes with a resistance of 5–10 M
were manufactured on a
Narishige PP83 puller (Narishige Co.) using a double stage pull. Gigaohm seals
were obtained by applying negative pressure (-30 to -100 cmH2O).
The whole-cell configuration was attained by the application of additional
negative pressure. The current signal was digitized and stored on
videotape.
Stimulation
Isolated olfactory receptor cells were irrigated by extracellular solutions
according to the method described by Frings and Lindemann
(Frings and Lindemann, 1991).
Gravity was used to deliver a constant stream of extracellular solutions from
the irrigating tube. Extracellular solutions were switched by four
electrically actuated valves. The stimulating tube, which had a lumen
160–200 µm in diameter, was placed under visual control within
500 µm of the cell. The delay due to dead space was 1–40 s,
depending on the flow rate and the distance between cells and the tip of the
tube.
Recording of [Ca2 +]i
Fura-2/AM of 10 µM was loaded for 30–60 min at room temperature. An inverted microscope (Aviovert 135, Carl Zeiss, Jena, Germany) was used with a Fluor x100 objective (Carl Zeiss). Pulses of excitation light (340 and 380 nm) were coupled to the microscope with a light guide. Images were recorded with AttofluorTM ICCD camera (Carl Zeiss). Concentrations of free cytosolic Ca2+ were recorded under the whole-cell voltage-clamp condition (holding potential: -70 mV), and were calculated from pixel ratios by Attofluor Ratio Vision software. In vitro calibration curves were obtained with calibration buffer solutions.
Preparation of solutions
Normal Ringer solution contained (mM) 116 NaCl, 4 KCl, 2 CaCl2,
2 MgCl2, 15 glucose, 5 sodium pyruvate and 10
N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid
(HEPES)–NaOH (pH 7.4). Na+-free Ringer solution contained
(mM) 116 N-methyl-D-glucamine (NMDG), 4 KCl, 2
CaCl2, 2 MgCl2, 15 glucose and 10 HEPES–NaOH (pH
7.4). Ca2+-free Ringer solution contained (mM) 116 NaCl, 4 KCl, 2
MgCl2, 15 glucose and 10 HEPES–NaOH (pH 7.4).
Na+-, Ca2+-free Ringer solution contained (mM) 116
N-methyl-D-glucamine (NMDG), 4 KCl, 2 MgCl2, 1
EGTA, 15 glucose and 10 HEPES–NaOH (pH 7.4). Patch pipettes were filled
with an inner solution (mM): 120 K acetate, 2 MgCl2, 5 ATP and 10
HEPES–KOH (pH 7.4). For the stimulation with cADPR and 8-Br-cADPR from
the patch pipette, chemicals of varying concentrations were dissolved in the
inner solution. The odorant cocktails were vigorously stirred with the
magnetic stirrer for >30 min at room temperature. The final concentration
of each odorant in cAMP-increasing odorant cocktails I (citralva, hedione,
eugenol, L-carvone and cineole) and II (L-citronellal,
geraniol and menthone), which increased the cAMP concentration in rat,
bullfrog and turtle olfactory cells but did not change the IP3
concentration in those of rats (Sklar
et al., 1986; Breer
and Boekhoff, 1991; Okamoto
et al., 1996), was 200 µM. The final concentrations of
odorants in the IP3-increasing odorant cocktail, which increased
IP3 concentration in rat olfactory cells but not the cAMP
concentration in those of rats, bullfrogs and turtles
(Sklar et al., 1986;
Breer and Boekhoff, 1991;
Okamoto et al.,
1996), were 20 µM lilial, 20 µM lyral and 10 µM ethyl
vanillin.
Chemicals
Fura2/AM was purchased from Wako (Tokyo, Japan). All volatile odorants were kindly supplied by Takasago International (Tokyo, Japan). All chemicals used were of the highest grade available.
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Results |
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To examine the effects of cADPR on turtle olfactory receptor cells, 100 µM cADPR was dialyzed into cells from a patch pipette. On the breaking of the patch, 100 µM cADPR induced inward currents in 22 out of 27 cells under the voltage-clamp conditions (holding potential: -70 mV). The current was desensitized in 14 cells (Figure 1A). Desensitization of the response to cADPR was slower than that to cAMP (P < 0.001). It took 4.9 ± 0.8 s (n = 12) to reduce the magnitude of the response to cADPR to 80% of the peak, whereas it took 1.8 ± 3.1 s (n = 14) to similarly reduce that to 1 mM cAMP (data not shown). The peak magnitude of inward currents in response to 100 µM cADPR ranged, typically, from 0 to 661 pA. The mean magnitude of the inward currents was 86.4 ± 21.5 pA (n = 21), which is comparable to that of the currents induced by odorants (Kashiwayanagi and Kurihara, 1995
). Dialysis of the control inner solution (data not shown,
n = 17) or 8-Br-cADPR (n = 38), which has a similar
molecular structure to cADPR (Guse et
al., 1995), did not induce changes in the membrane current
(Figure 2A). The
voltage-dependence of 100 µM cADPR was examined by applying a voltage ramp
from -120 to 80 mV (500 mV/s) to voltage-clamped cells during and after
responses (Figure 1B), and our
results suggest that cADPR increases membrane conductance. The slope during
responses was steeper than that after responses. The mean reversal potential
was estimated to be 6.0 ± 3.6 mV (n = 10;
Figure 1C). Inward currents
induced by the dialysis of cADPR reached a peak at 0.5–5 s and returned
to a steady current level within 50 s after the breakthrough. A voltage
ramp was applied after 8 s (during responses) and 50 s (after responses) after
the breakthrough using the patch pipette containing 8-Br-cADPR
(Figure 2A). There was no
significant difference in the slopes of the I–V curves after 8
and 50 s (n = 9; Figure
2B).
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Figure 3A shows the membrane
currents recorded from individual olfactory cells dialyzed with different
concentrations of cADPR. Figure
3B shows a plot of the mean magnitudes of inward currents induced
by dialysis of cADPR from the patch pipette as a function of cADPR
concentrations. The magnitude of the response to cADPR increased with
increases in cADPR concentration up to 100 µM but decreased above this
level. It is possible that dialysis of a high concentration of cADPR induces
unexpected toxic effects on olfactory cells. Therefore, we applied 100 µM
cADPR in the following experiments. cADPR has been reported to be a
Ca2+-mobilizer (Galione et
al., 1991; Berridge,
1993; Guse, 1999).
Hence, it is possible that cADPR also mobilizes Ca2+ in turtle
olfactory cells. This possibility was tested by measuring cytosolic
Ca2+ concentrations in the somas of these cells
([Ca2+]i) when cADPR was dialyzed under the
voltage-clamp conditions in normal Ringer solution. In response to the cADPR
diffusing into the cell, [Ca2+]i increased with inward
currents in 19 out of 22 cells. In the cell shown in
Figure 4A, the increase was
from 100 to 190 nM. While the current adapted spontaneously,
[Ca2+]i remained high in this cell. In 3 of the 19
cells, detectable inward currents did not appear, although [Ca2+]
did increase (data not shown), suggesting that cADPR induces a Ca2+
release from inner Ca2+ stores in these cells. The dialysis of 100
µM 8-Br-cADPR changed neither the [Ca2+]i nor the
membrane currents (Figure
4B).
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To test the ion selectivity, changes in [Ca2+]i and
membrane currents in response to cADPR were measured in various outer
solutions. The mean resting [Ca2+]i in normal,
Ca2+-free, Na+-free and Ca2+-,
Na+-free Ringer solutions were 102.0 ± 9.0 (n =
18), 56.0 ± 7.0 (n = 9), 96.5 ± 6.2 (n = 24)
and 53.1 ± 6.5 nM (n = 12), respectively. In
Ca2+-free Ringer solution, the dialysis of 100 µM cADPR from the
pipette induced an inward current without changes in
[Ca2+]i in all eight cells
(Figure 4C). The magnitude of
the inward current in Ca2+-free Ringer solution was 4 times
that in normal Ringer solution, suggesting that outer Ca2+
suppresses the inward current in response to cADPR. In Na+-free
Ringer solution, cADPR induced only small inward currents, while the magnitude
of increases in [Ca2+]i was similar to that in normal
Ringer solution (Figure 4D). Inward currents induced by cADPR were inhibited by the substitution of
Na+ with NMDG+ and the removal of free Ca2+
by chelating with EGTA (Figure
4E). These results suggest that cADPR activates cation channels at
the plasma membranes, allowing an inflow of Na+ and
Ca2+.
In Ca2+-free Ringer solution and Ca2+-, Na+-free Ringer solution, cADPR did not induce a significant increase in [Ca2+]i, suggesting that an influx of Ca2+ from the extracellular solution, not a release from Ca2+ stores, is responsible for the increase in cytosolic Ca2+ concentrations under these experimental conditions.
Figure 5 summarizes changes in the membrane current and [Ca2+] i induced by 100 µM cADPR in bathing solutions of different Na+ and Ca2+ concentrations. cADPR did not induce significant inward currents when Na+ was substituted with NMDG+, and most of the free Ca2+ was chelated with EGTA. [Ca2+]i increases in Ca2+-free and Na+-,Ca2+-free Ringer solutions were no larger than when measured with a pipette having no cADPR, indicating that there was no large cADPR-induced Ca2+ release in the soma under the employed experimental conditions.
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In a previous study, we showed that the application of cAMP-increasing
odorants (cocktail I) after desensitization of the cAMP-dependent pathway
induces a large inward current, suggesting that the cAMP-independent pathway
contributes greatly to the generation of responses to cAMP-increasing odorants
(Kashiwayanagi et al.,
1994; Kashiwayanagi and
Kurihara, 1995). As shown in
Figure 1, inward current
responses to cADPR were desensitized when cADPR was continuously dialyzed from
a patch pipette. After the 100 µM cADPR-induced inward current was adapted,
the odorant cocktails were applied. The magnitudes of the responses to
cAMP-increasing odorant cocktails I and II after adaptation of the
cADPR-current were approximately half that recorded in the normal inner
solution (Figure 6). In
contrast, the response to the IP3-increasing odorant cocktail was
not changed by cADPR.
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The application of 8-Br-cADPR, which is a cADPR-antagonist, also inhibited the responses to cAMP-increasing odorant cocktails I and II (Figure 7). The magnitude of the responses to the IP3-increasing odorant cocktail was not inhibited by 8-Br-cADPR. These results suggest that cADPR contributes to the generation of the responses to cAMP-increasing odorants.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The present study supplies evidence for a physiological role for the candidate messenger cADPR in the turtle olfactory transduction. We have shown that the dialysis of cADPR to olfactory receptor cells induces inward currents and increases [Ca2+]i under the voltage-clamp conditions, and that the magnitudes of inward current responses to cAMP-increasing odorants is greatly reduced by inhibition of a cADPR-dependent pathway. However, we cannot entirely exclude the possibility that cADPR activates cAMP-gated ion channel directly or indirectly.
Voltage-gated Ca2+ channels exist at the somal membranes of
olfactory cells (Frings et al.,
1991; Schild et al.,
1995). Depolarization induced by elevation of a K+
concentration in the outer solution increased [Ca2+]i
without stimulation with odorants (data not shown). It is therefore
theoretically possible that the increase in [Ca2+]i
caused by cADPR is due to the opening of olfactory transduction channels at
the cilia, followed by the opening of voltage-gated Ca2+ channels
at the soma. This possibility must be excluded, however, because a holding
potential of -70 mV prevails at the somal membrane.
In general, cADPR induces Ca2+ release from endogenous
Ca2+ stores in various types of cells
(Berridge, 1993;
Guse, 1999). In the olfactory
cells, however, [Ca2+]i remains low during a flow of
inward currents induced by the dialysis of cADPR in a Ca2+-free
solution. This result indicates that Ca2+-release from
intracellular somal stores is not a primary source of the increase in
[Ca2+]i under these experimental conditions. In
T-lymphocytes, the microinjection of cADPR dose-dependently induces repetitive
Ca2+ spikes that are almost completely dependent on extracellular
Ca2+, indicating that cADPR induces Ca2+ entry into T
cells (Guse et al.,
1997). The present results are in agreement with these
observations.
The present results show that cADPR induces an inward current both in Ca2+-containing and Ca2+-free solutions. The magnitude of the inward currents in response to cADPR in Na+-free Ringer solution is much less than that in normal Ringer solution, suggesting that the current is mainly carried by Na+. These results suggest that cADPR activates a cation channel at the plasma membrane, allowing inflow of Na+ and Ca2+ ions. The magnitude of inward current induced by cADPR in Ca2+-free Ringer solution is larger than that in normal Ringer solution, suggesting that cADPR-induced currents are inhibited by the presence of extracellular Ca2+.
Membrane-bound and soluble ADP-ribosyl cyclases catalyze the cyclization of
NAD+ to produce cADPR. The receptor-mediated formation of cADPR has
been reported in intestinal longitudinal muscle cells
(Kuemmerle and Makhlouf, 1995)
and in NG 108-15 neural cells (Higashida
et al., 1997). Until now, the biochemical processes of
formation of cADPR via receptors are not clear. The soluble enzymes from
ascidian oocytes (Grumetto et
al., 1997) and phenochromocytoma (PC12) cells
(Clementi et al.,
1996) are activated by NO via cGMP. The stimulation of rat
olfactory cilia with a high dose of odorants elicits a delayed and sustained
elevation of cGMP, which is eliminated by an inhibitor of nitric oxide
synthesis (Breer et al.,
1992) Therefore, it is possible that NO/cGMP participates in the
formation of cADPR in response to odorants during sustained responses.
Receptors coupled with the accumulation of cADPR in response to odorants in
olfactory cells remains to be investigated. Acetylcholine changes the activity
of ADP-ribosyl cyclase in membranes of NG108-15 neuronal cells in a muscarinic
receptor subtype-specific manner. The activation or inhibition of the cyclase
activity is mimicked by GTP and blocked by cholera toxin, suggesting that G
protein-coupled receptors modulate ADP-ribosyl cyclase via G proteins within
cell membranes (Higashida et al.,
1997). Hence, it is possible that G protein-coupled receptors are
linked to ADP-ribosyl cyclase. The binding of odorants to odorant receptors
may lead to the activation of ADP-ribosyl cyclase via G proteins. This problem
requires further experimentation.
Disruption of a cAMP-gated channel
(Brunet et al., 1996),
Golf (Belluscio et al.,
1998) or adenylyl cyclase III gene
(Wong et al., 2000)
leads to anosmia in transgenic mice, suggesting that odor responses are
generated entirely via cAMP-dependent pathways in the mouse. However, not all
odorants activated adenylyl cyclase in olfactory cells of various animals
(Sklar et al., 1986;
Breer and Boekhoff, 1991;
Restrepo et al.,
1993a; Fabbri et al.,
1995; Okamoto et al.,
1996). Some of these odorants increased IP3
concentrations in rat and sheep olfactory cilia preparations
(Breer and Boekhoff; 1991;
Fabbri et al., 1995),
suggesting that IP3-dependent pathways may also play roles in the
generation of odor responses. Application of cAMP-increasing odorants induced
inward current responses in the sensory neurons of the Xenopus water
nose, whereas dialysis of high concentration cAMP did not induce inward
currents in these neurons (Iida and Kashiwayanagi,
1999,
2000). In addition, after
complete desensitization of the cAMP-dependent pathway, various odorants
induced large odor responses in these neurons
(Kashiwayanagi et al.,
1994; Kashiwayanagi and
Kurihara, 1995). These results suggest that odor responses to
cAMP-increasing odorants are also generated via cAMP-independent transduction
pathways.
Odorants, which increase cAMP concentration, have no effect on
IP3 concentration in rat and sheep olfactory cilia
(Breer and Boekhoff; 1991;
Fabbri et al., 1995),
suggesting that the cAMP-independent responses to cAMP-increasing odorants are
not generated via IP3. In the present study, we showed that the
mean magnitude of the inward currents in response to 100 µM cADPR is
comparable to or larger than that of the currents induced by odorants. The
magnitudes of inward current responses to cAMP-increasing odorants are greatly
reduced after desensitization of the cADPR-dependent pathway, which was
achieved by previous dialysis of a high concentration of cADPR. The dialysis
of 8-Br-cADPR, an antagonist, also inhibits responses to cAMP-increasing
odorants. Therefore, it is likely that a part of the odor responses to the
cAMP-increasing odorants is generated via a cADPR-dependent pathway.
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Acknowledgments |
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We gratefully thank Prof. Kenzo Kurihara for his support and for his critical review of the manuscript. This work was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, and Culture, Japan.
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Accepted April 28, 2003
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