Effects of cGMP and sodium nitroprusside on odor responses in turtle olfactory sensory neurons

Kouhei Inamura, Makoto Kashiwayanagi, and Kenzo Kurihara

Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan

    ABSTRACT
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Abstract
Introduction
Materials & Methods
Results
Discussion
References

The effects of cGMP and sodium nitroprusside (SNP) on odor responses in isolated turtle olfactory neurons were examined. The inward current induced by dialysis of a mixture of 1 mM cAMP and 1 mM cGMP was similar to that induced by dialysis of 1 mM cAMP or 1 mM cGMP alone. After the neurons were desensitized by the application of 1 mM cGMP, 3 mM 8-(4-chlorophenylthio)-cAMP, a membrane-permeable cAMP analog, did not elicit any current, indicating that both cAMP and cGMP activated the same channel. Extracellular application of SNP, a nitric oxide (NO) donor, evoked inward currents in a dose-dependent manner. However, application of SNP did not induce any currents after desensitization of the cGMP-induced currents, suggesting that SNP-induced currents are mediated via the cGMP-dependent pathway. Application of the cAMP-producing odorants to the neurons induced a large inward current even after neurons were desensitized to a high concentration of cGMP or SNP. These results suggest that the transduction pathway independent of cAMP, cGMP, and NO also contributes to the generation of odor responses in addition to the cAMP-dependent pathway.

guanosine 3',5'-cyclic monophosphate; nitric oxide; olfactory transduction

    INTRODUCTION
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Abstract
Introduction
Materials & Methods
Results
Discussion
References

THE VERTEBRATE OLFACTORY system is able to distinguish among a large number of odorants with diverse molecular structures and to discriminate them. Olfactory responses are generally thought to be generated via the cAMP- or inositol 1,4,5-trisphosphate (IP3)-mediated cascades; an increase in second messenger concentration in olfactory cilia (2, 17) causes opening of cyclic nucleotide-gated (CNG) channels (13) or IP3-gated cation channels (15), resulting in cell depolarization and the generation of action potentials.

Stimulation of isolated rat olfactory cilia with relatively large concentrations of odorants causes not only rapid and transient increases in cAMP or IP3 concentrations but also delayed and sustained increases in the concentration of cGMP (3). The concentration of cGMP in the olfactory cilia preparation is about 1/30th that of cAMP, but, in olfactory sensory neurons, cGMP also activates the CNG channel. Because cGMP has a higher affinity for the CNG channel than cAMP, the potential of cGMP to act as an activator may equal that of cAMP. Application of sodium nitroprusside (SNP), a nitric oxide (NO)-generating agent, to the rat cilia preparation (3) also increases cGMP concentration by activation of soluble guanylyl cyclase. Application of NO donors to Xenopus laevis (12) and salamander olfactory sensory neurons (5) evoked an inward current. These observations suggest that, in addition to cAMP and IP3, cGMP and NO play a functional role in olfactory transduction (4).

The goal of this study is to ascertain whether cGMP and/or NO function as second messengers in odor reception in turtle olfactory neurons. The results obtained suggest that both cGMP and SNP induce the responses via a cAMP-dependent pathway.

    MATERIALS AND METHODS
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Abstract
Introduction
Materials & Methods
Results
Discussion
References

Isolation of olfactory cells. Turtles, Geoclemys reevesii, weighing 150-300 g, were obtained from commercial suppliers. Isolated olfactory neurons were prepared as described previously (9). Briefly, the turtles were cooled to 0°C and decapitated. The epithelia were quickly removed and, while in normal Ringer solution at 0°C, cut into slices ~300 µm thick and then incubated for 0.5-2 h at 37°C in Ca2+-free Ringer solution. Immediately before recordings were made, one slice of the epithelium was placed in 500 µl of normal Ringer solution in the recording chamber and shaken. No enzymes were added. Olfactory neurons with motile cilia were used for this study.

Whole cell recordings. Recordings were made with an Axopatch 1D amplifier (Axon Instruments, Foster City, CA) using patch electrodes with resistance of 5-10 MOmega . Gigaohm seals were obtained by applying negative pressure (-30 to -100 cmH2O), and the whole cell configuration was attained by application of additional negative pressure. Holding potential was -70 mV. All recordings were performed at room temperature. Analysis was carried out on a personal computer using pCLAMP software (Axon Instruments). All values are given as means ± SE. No corrections were made for junction potentials at the pipette tip; junction potentials between the solutions used in this paper never exceeded 7 mV. Three electrically actuated valves were used to switch adapting Ringer solution and odorant cocktail solutions, which were delivered from the stimulating tube placed within ~500 µm from the cell.

Preparation of solutions and chemicals. Normal Ringer solution contained (in mM) 116 NaCl, 4 KCl, 2 CaCl2, 2 MgCl2, 15 glucose, 5 sodium pyruvate, and 10 HEPES-NaOH (pH 7.4). Patch pipettes were filled with an internal solution consisting of (in mM) 115 KCl, 5 NaCl, 2 MgCl2, and 10 HEPES-KOH (pH 7.4). Stocked IBMX solution was prepared by dissolution of IBMX in DMSO at 100 mM, and appropriate volumes were added to 1 mM cGMP solution. The final concentration of DMSO never exceeded 0.4%. This concentration of DMSO alone had no measurable effect on the electrical properties of the neurons. SNP solutions were used within 2 h after mixing. The cAMP-producing odorant cocktail consisted of 200 µM each of citralva, hedione, eugenol, l-carvone, and cineole, which increased cAMP concentration in the membrane preparation of the turtle olfactory epithelium (14), without affecting IP3 concentration in the rat cilia preparation (2). All odorants were supplied by Takasago International (Tokyo, Japan). SNP, cAMP, NaCN, and IBMX were obtained from Wako Pure Chemical Industries (Osaka, Japan), and 8-(4-chlorophenylthio) (CPT)-cAMP was obtained from Boehringer Mannheim (Mannheim, Germany).

    RESULTS
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Abstract
Introduction
Materials & Methods
Results
Discussion
References

Whole cell current induced by intracellular dialysis of cGMP. First, the current induced by cGMP of varying concentrations dialyzed into freshly isolated olfactory sensory neurons was recorded using the whole cell voltage-clamped technique. When the pipette was filled with a cGMP-free internal solution, the neurons held a steady baseline over the test interval for ~5 min after membrane rupture. Intracellular dialysis of cGMP into the cells immediately evoked inward currents after membrane rupture in all cells examined (Fig. 1A). The magnitude of inward current induced by cGMP increased with increases in cGMP concentrations. Figure 1B shows the magnitude of the responses induced by cGMP plotted as a function of cGMP concentration. Data points were fitted by the Hill equation, giving concentration for half-maximal activation (K1/2) = 215 µM and a Hill coefficient (n) of 1.3. The value of K1/2 is different from that obtained from excised inside-out patches (13) but is close to that obtained from whole cell recordings (11). The currents appeared between 0 and 0.1 mM, increased with an increase in cGMP concentrations, and plateaued at 1 mM. The threshold concentration of cGMP and the magnitude of current were similar to those reported with isolated olfactory neurons of the newt (11).


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Fig. 1.   Responses to cGMP dialyzed into turtle olfactory sensory neurons. A: response induced by intracellular dialysis of cGMP from the patch pipette to a turtle olfactory sensory neuron. Concentrations of cGMP contained in the pipette are shown at the top of each trace. Holding potential was -70 mV. B: dose dependence of response induced by intracellular application of cGMP into turtle olfactory sensory neurons. Data were fitted by the Hill equation with n = 1.3, concentration for half-maximal activation (K1/2) = 215 µM, and maximal current (Imax) = 412 pA. Each point is mean ± SE of data obtained from n preparations indicated in parentheses. C: whole cell current-voltage relationships for the current evoked by intracellular application of 1 mM cGMP. Current was measured by applying a voltage ramp (500 mV/s) from -120 to 80 mV during (a) and after (b) response induced by 1 mM cGMP. Inset: record of the cGMP-induced response of this cell under whole cell voltage-clamp condition at -70 mV. D: cGMP-induced current was obtained by subtracting current after the response from that obtained during the response in C. Reversal potential was estimated to be -2 mV.

As shown in Fig. 1C, the current-voltage (I-V) relationship was examined by applying a voltage ramp from -120 to +80 mV (500 mV/s) to voltage-clamped olfactory sensory neurons during and after the response induced by 1 mM cGMP. The slope of the I-V curve measured during the response was steeper than that measured after the response, indicating that dialysis of cGMP increases the membrane conductance. Figure 1D shows a subtracted current before the response from that during the response. The reversal potential for the response to cGMP was estimated to be -2 mV from the intersection of the line at 0 pA and the line extrapolated in which no voltage-sensitive currents were activated. The mean reversal potential was estimated to be 6.8 ± 1.7 mV (n = 67), which was similar to the potential for the response to cAMP in isolated turtle olfactory neurons (17.0 ± 9.5 mV, n = 9; Kashiwayanagi and Kurihara, unpublished observations) and isolated newt olfactory neurons (11), as well as the potentials for the responses to cAMP and cGMP observed with patch membranes excised from the cilia of the frog (13) and the olfactory knob of the frog and rat (7).

Characterization of cGMP and cAMP responses. As shown above, the reversal potential of the response to cGMP is closely similar to the response to cAMP. To confirm whether cAMP and cGMP activate the same conductance, measurements were made of the inward current induced by 3 mM CPT-cAMP, a membrane-permeable cAMP analog, after the desensitization of the response to cGMP. That is, after the response to 1 mM cGMP had decayed, 3 mM CPT-cAMP was applied extracellularly, but no inward current was induced in any of the seven neurons examined (Fig. 2B). Figure 2A shows an inward current induced by 3 mM CPT-cAMP applied extracellularly alone. Figure 2C plots the mean magnitudes of inward currents induced by 3 mM CPT-cAMP after the decay of cGMP-induced current as a function of cGMP concentration. The magnitude of the response to CPT-cAMP after intracellular application of cGMP decreased with increasing cGMP concentration and reached zero after 1 mM cGMP. It is possible that high phosphodiesterase activity in the cilia might result in a concentration gradient along the cilia. To confirm whether the CNG channels completely desensitized under dialysis of cGMP, we added 0.5 mM IBMX, a nonspecific inhibitor of phosphodiesterase, to 1 mM cGMP to inhibit phosphodiesterase activity. The mean amplitude of response was unchanged (395 ± 77 pA, n = 10), indicating that the dialysis of saturated concentration of cGMP alone was sufficient to fully desensitize the CNG channels. These results are similar to those found in a previous study on the effects of cAMP and CPT-cAMP on the CNG channel in the turtle (10).


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Fig. 2.   Characterization of cGMP and cAMP response. A: inward current induced by 3 mM 8-(4-chlorophenylthio) (CPT)-cAMP applied extracellularly. B: 1 mM cGMP was applied first from the patch pipette and then 3 mM CPT-cAMP was applied extracellularly after adaptation to cGMP. C: mean amplitude of inward currents to 3 mM CPT-cAMP applied extracellularly after the responses to varying concentrations of cGMP were desensitized as a function of cGMP concentration. Data were fitted by the equation, I = Imax + (Imin - Imax) × [cGMP]n/([cGMP]n + Kn1/2) with n = 3.7, K1/2 = 222 µM, minimal current (Imin) = 0 pA, and Imax = 178 pA, where [cGMP] is cGMP concentration. Numbers in parentheses are no. of tested cells. D: mean amplitude of inward currents induced by 1 mM cAMP, 1 mM cGMP, and a mixture of 1 mM cAMP and 1 mM cGMP. Numbers in parentheses are no. of tested cells.

Saturation was observed when the concentration of either cGMP (Fig. 1B) or cAMP (10) was 1 mM. If the responses to cAMP and cGMP are mediated via different CNG channels and/or the Ca2+-activated Cl- channel contributes to the response to cAMP in a different way from that to cGMP, the response to simultaneous application of cAMP and cGMP should increase additively. Figure 2D shows the response obtained when an internal solution containing both 1 mM cAMP and 1 mM cGMP was dialyzed into the neurons. The mean amplitude of the response was 362 ± 33 pA (n = 16), which was similar to that induced by intracellular dialysis of 1 mM cAMP or 1 mM cGMP alone. These results suggest that both cAMP and cGMP activate the same channel in turtle olfactory sensory neurons.

Large odor responses after complete desensitization of the cGMP-mediated cascade. As in a previous study, in which the responses to odorants occurred even after desensitization of the cAMP-dependent transduction pathway in the turtle olfactory system (8, 10), here the application of an odorant cocktail elicited an inward current after the complete desensitization of cGMP-induced response by intracellular dialysis of 1 mM cGMP (Fig. 3A). The mean amplitudes of inward currents in response to the odorant cocktail when the patch pipette contained no cGMP, 1 mM cGMP, and 2 mM cGMP were 30.4 ± 14.7 pA (n = 32), 20.0 ± 10.3 pA (n = 14), and 14.7 ± 8.9 pA (n = 9), respectively (Fig. 3B). In addition, the odor response was evoked after the desensitization of the response to 1 mM cGMP + 0.5 mM IBMX (48.0 ± 33.4 pA, n = 6). These results together with the previous ones suggest that odorants induced large responses even after complete desensitization of cGMP- and/or cAMP-mediated cascade in turtle olfactory sensory neurons.


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Fig. 3.   Odor response evoked after desensitization of cGMP-dependent pathway. A: inward current in response to odorant cocktail after desensitization of the response to 1 mM cGMP. B: mean amplitude of odor responses when the patch pipettes contained no cGMP (control), 1 mM cGMP, and 2 mM cGMP. Test stimuli are not significantly different from control level when data were analyzed by t-test (P > 0.2). Numbers in parentheses are no. of tested cells.

SNP-evoked inward currents. Extracellular application of 10 mM SNP induced an inward current that was observed in 20 of 27 neurons (Fig. 4A). The amplitude of the inward current varied from 0 to 276 pA with a mean magnitude of 50.2 ± 12.2 pA (n = 27), and the inward currents were desensitized to spontaneous levels. The time-to-peak for the response to 10 mM SNP was 43.1 ± 4.5 s (n = 20). This time was slower than that for 1 mM cGMP-induced response (3.4 ± 0.3 s, n = 52) but similar to that for the response to 3 mM CPT-cAMP (60.8 ± 8.3 s, n = 8). Long-lasting response to SNP and CPT-cAMP may be due to extracellular application. Ten millimolar SNP, which had been voided by exposure to light for 2 days, showed only a small inward current in any of the seven neurons tested (6.3 ± 3.2 pA). SNP often generates an active by-product, cyanide. However, 10 mM cyanide solution did not elicit a large inward current (1.5 ± 0.6 pA, n = 8). These results suggest that the response to SNP was not generated by cyanide. Figure 4B shows a dose-response relation of SNP-stimulated inward currents. The response appeared at 10 µM and increased with increasing SNP concentration. The maximal current induced by SNP when saturation occurred was ~50 pA. To characterize further the SNP-stimulated currents, the voltage-dependence of 10 mM SNP-induced currents was examined by applying a voltage ramp to voltage-clamped neurons before, during, and after the response (Fig. 4C). Figure 4D shows subtraction of current before the response from one at the peak of the response. The mean reversal potential was estimated to be 31.9 ± 6.6 mV (n = 17), which was more positive than the potential observed with cGMP (6.8 ± 1.7 mV) and that with cAMP (17.0 ± 9.5 mV; Kashiwayanagi and Kurihara, unpublished observations) but not statistically significant (P > 0.2; t-test).


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Fig. 4.   Responses to sodium nitroprusside (SNP) applied to turtle olfactory sensory neurons. A: response induced by extracellular application of 10 mM SNP to a turtle olfactory sensory neuron. Holding potential was -70 mV. B: dose dependence of response induced by SNP. Data were fitted by the Hill equation with n = 2.0, K1/2 = 30.3 µM, and Imax = 51.7 pA. Each point is mean ± SE of data obtained from n preparations indicated in parentheses. C: whole cell current-voltage relationships for current evoked by extracellular application of 10 mM SNP in A. Current was measured by applying a voltage ramp (500 mV/s) from -120 to 80 mV before (a), during (b), and after (c) the response induced by 10 mM SNP. D: SNP-induced current was obtained by subtracting current before the response from that obtained during the response in C. Reversal potential was estimated to be 26 mV.

After the cGMP-dependent pathway was desensitized by intracellular dialysis of 1 mM cGMP, the response to 10 mM SNP was measured (Fig. 5A). Application of 10 mM SNP induced only a small response, 2.8 ± 1.5 pA (n = 14) (Fig. 5B), suggesting that the SNP-induced response was mediated via the CNG channel.


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Fig. 5.   Effects of SNP on cGMP-dependent pathway. A: inward current in response to 10 mM SNP after desensitization of the response to 1 mM cGMP. B: mean amplitude of SNP-induced responses when patch pipettes contained no cGMP (control) and 1 mM cGMP. Test stimulation is significantly different from control level when data were analyzed by the t-test (*** P < 0.001). Numbers in parentheses are no. of tested cells.

Effects of SNP on odor response. Finally, we examined whether NO contributes to the generation of odor response. Even after the neurons were desensitized by the extracellular application of 1 mM SNP, the odorant cocktail elicited a large odor response (Fig. 6, A and B). The mean magnitude of inward currents evoked by the odorant cocktail after desensitization to SNP was 47.7 ± 16.6 pA (n = 14). This value was not statistically different from that of the control response, 30.4 ± 14.7 pA (P > 0.2). These results suggest that the NO-dependent pathway did not significantly contribute to odor responses in turtle olfactory sensory neurons.


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Fig. 6.   Odor response evoked after desensitization of nitric oxide-dependent pathway. A: inward current in response to the odorant cocktail after desensitization of the response to 1 mM SNP. B: mean amplitude of odor responses after complete desensitization of the response to 1 mM SNP and before application of 1 mM SNP (control). Test stimulation is not significantly different from control level when data were analyzed by the t-test (P > 0.2). Numbers in parentheses are no. of tested cells.

    DISCUSSION
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Abstract
Introduction
Materials & Methods
Results
Discussion
References

It is generally thought that the olfactory response is generated by the cascade reactions in which cAMP is a second messenger for most of the odorants. We previously found that a cAMP-independent pathway also existed in turtle olfactory sensory neurons; odor responses occurred even after the complete desensitization of the cAMP-dependent pathway caused by intracellular dialysis of high concentrations of cAMP into the turtle olfactory sensory neurons (10).

It is possible that an NO/cGMP-cascade is responsible for the cAMP-independent pathways in the odor reception. Stimulation of isolated rat olfactory cilia with relatively large concentrations of odorants caused an increase in cGMP concentration as well as an increase in cAMP concentration (3). Although immunoreactivity with neuronal NO synthase antibody was not found in mature rat olfactory neurons (1, 16), specific staining for NADPH diaphorase in mature olfactory neurons in rat and catfish olfactory epithelia (6) suggests the presence of NO synthase in the neurons. Although the existence of NO synthase in mature olfactory neurons remained unclear, Breer et al. (3) showed that application of odorants increased cGMP concentration mediated via NO in the rat cilia preparation. As shown in the present study, application of SNP to the turtle olfactory sensory neurons induced inward currents, which in turn were caused by an increase in cGMP concentration. These data suggest the possibility of NO/cGMP-cascade present in the cAMP-independent pathways.

The following results, however, suggested that SNP-induced currents are generated via the cyclic nucleotide-dependent pathway. After the response to intracellular dialysis of cGMP was desensitized, the response to CPT-cAMP applied extracellularly decreased with increasing cGMP concentration in the pipette, and no response to CPT-cAMP appeared when the cGMP response reached the saturated level. The mean amplitude of the response induced by simultaneous dialysis of cAMP and cGMP at 1 mM each was similar to that induced by dialysis of 1 mM cAMP or cGMP alone. The reversal potential of the cGMP response was similar to that of the cAMP response. These results suggest that both cAMP and cGMP activate the same channel in turtle olfactory sensory neurons. On the other hand, it is reported that NO directly activated the CNG channels by modification of sulfhydryl groups and elicited an inward current (5). Hence, NO may activate the CNG channels by modification of channels in the turtle olfactory neurons, or NO may indirectly activate the CNG channels via cGMP production. The response to 10 mM SNP after the desensitization of the response to 1 mM cGMP was very small, suggesting that SNP-induced inward currents are mediated via the CNG channel. Thus it appears that the NO/cGMP-cascade is mediated via activation of the CNG channel.

The present studies demonstrate that large odor responses are elicited even after complete desensitization of the NO- and/or cGMP-dependent pathways achieved by application of high concentrations of cGMP or SNP. As described above, odorants induced the responses after the complete desensitization of the cAMP-dependent pathway. These results suggest that cAMP-, cGMP-, and NO-independent pathways also contribute to the generation of odor response in the turtle in addition to the cAMP-dependent pathway.

    ACKNOWLEDGEMENTS

We express our gratitude to Takasago International for supplying highly pure odorants. This work was supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, and Culture, Japan, and by a grant from the Human Frontier Science Program.

    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 reprint requests to M. Kashiwayanagi.

Received 27 January 1998; accepted in final form 10 July 1998.

    REFERENCES
Top
Abstract
Introduction
Materials & Methods
Results
Discussion
References

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Am J Physiol Cell Physiol 275(5):C1201-C1206
0002-9513/98 $5.00 Copyright © 1998 the American Physiological Society




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