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Previous Article | Next Article
The Journal of Neuroscience, May 15, 1999, 19(10):3818-3826
Nitric Oxide Stimulates cGMP Production and Mimics Synaptic Responses in Metacerebral Neurons of Aplysia
Hae-Young Koh and Jon W. Jacklet Department of Biological Sciences, University at Albany, State University of New York, Albany, New York 12222
ABSTRACT
TOP
ABSTRACT
INTRODUCTION
Nitric oxide (NO) acts as a neurotransmitter and neuromodulator in the nervous systems of many vertebrates and invertebrates. We investigated the mechanism of NO action at an identified synapse between a mechanoafferent neuron, C2, and the serotonergic metacerebral cell (MCC) in the cerebral ganglion of the mollusc Aplysia californica. Stimulation of C2 produces a decreasing conductance, very slow EPSP in the MCC. C2 is thought to use histamine and NO as cotransmitters at this synapse, because both agents mimic the membrane responses. Now we provide evidence that treatment with NO donors stimulates soluble guanylyl cyclase (sGC) in the MCC, and as a result cGMP increases. S-Nitrosocysteine (SNC, an NO donor) and 8-bromo-cGMP (8-Br-cGMP) both induced the membrane depolarization and increase in input resistance that are characteristic of the very slow EPSP. Two inhibitors of sGC, 6-anilino-5,8-quinolinequinone (LY83583) and 1H-[1,2,4]oxadiazolo[4,3-a]quinoxaline-1-one (ODQ), suppressed both the very slow EPSP and the membrane responses to SNC but not the histamine membrane responses. NO-induced cGMP production was determined in the MCC using cGMP immunocytochemistry (cGMP-IR). In the presence of 3-isobutyl-1-methylxanthine (IBMX), 10 µM SNC was sufficient to induce cGMP-IR, and the staining intensity increased as the SNC dose was increased. This cGMP-IR was suppressed by ODQ in a dose-dependent manner and completely blocked by 10 µM ODQ. Histamine did not induce cGMP-IR. The results suggest that NO stimulates sGC-dependent cGMP synthesis in the MCC and that cGMP mediates the membrane responses. The cotransmitter histamine induces essentially the same membrane responses but seems to use a separate and distinct second messenger pathway.
Key words: Aplysia; cGMP; nitric oxide; soluble guanylyl cyclase; immunoreactivity; histamine; cotransmitters; synapses; EPSP
INTRODUCTION
Nitric oxide (NO) is a versatile signaling molecule. Its roles in a variety of physiological functions in mammals (Bredt and Snyder, 1994
) and invertebrates (Jacklet, 1997
NO is a water-soluble free radical gas that readily diffuses through membranes and reacts with heme-containing proteins and other effector molecules. NO is produced from arginine by the Ca2+/calmodulin-dependent enzyme nitric oxide synthase (NOS). NOS has been localized by NADPH diaphorase histochemistry in the mammalian nervous systems, and it has been shown that the distribution of NOS immunoreactivity is identical to that of NADPH diaphorase activity in central and peripheral mammalian tissues (Hope et al., 1991
Large identifiable neurons in the mollusc Aplysia have been used very successfully to identify the synaptic mechanisms involved in a variety of behaviors [e.g., feeding (Weiss et al., 1986b
NO is thought to be a cotransmitter at the C2-MCC synapse because NADPH diaphorase histochemical treatment indicates that C2 contains NOS, and the MCC responds to the NO generators 3-morpholino-synonimine (SIN-1) and S-nitrosocysteine (SNC) by the membrane depolarization and decreased conductance that are characteristic of the vsEPSP (Jacklet, 1995
To understand how the cotransmitters histamine and NO contribute to the vsEPSP in the MCC, we investigated the second messenger system that was likely to be used. Soluble GC is the most common target for NO in many nervous systems (Garthwaite, 1991
MATERIALS AND METHODS
Animals and chemicals. Aplysia californica (100-150 gm) were supplied by Marinus (Long Beach, CA), kept in an aquarium tank at 16-20°C, and fed dried seaweed. SNC stock solution (100 mM) was made by dissolving 100 mM L-cysteine (C-7755; Sigma, St. Louis, MO) and 100 mM sodium nitrite (23721-3; Aldrich, Milwaukee, WI) in 959 µl of distilled water on ice and adding 41 µl of HCl (12.1N; Fisher Scientific, Houston, TX), which makes the solution turn red. The stock solution was kept on ice and used within 2 hr (Lei et al., 1992
20°C); 20 mM 6-anilino-5,8-quinolinequinone (LY83583; 440205; Calbiochem, La Jolla, CA), 20 mM 1H-[1,2,4]oxadiazolo[4,3-a]quinoxaline-1-one (ODQ; 0880; Tocris Cookson), and 0.5 M 3-isobutyl-1-methylxanthine (IBMX; 410957; Calbiochem) stock solutions were made in DMSO (dimethylsulfoxide; D-128; Fisher Scientific) and kept frozen at
Electrophysiology. Isolated cerebral ganglia were incubated in 1% protease (type IX, P-6141; Sigma) in 2 ml of ASW [460 mM NaCl, 10 mM KCl, 10 mM CaCl2, 48 mM MgCl2, and 10 mM HEPES (H-3375; Sigma), pH 7.8] for 1 hr at 36°C before desheathing at room temperature. A desheathed ganglion was pinned down on a sylgard dish (1 inch in diameter) and superfused with ASW (20-25 ml) containing varying concentrations of SNC, 8-Br-cGMP, or histamine (flow rate, 2.5-3 ml/min) to measure the subthreshold membrane depolarization and increase in input resistance of the MCC in response to each drug. Intracellular recording micropipettes (10-20 M
) were filled with 3 M potassium acetate and 0.1 M KCl. The membrane depolarization and change in input resistance were recorded immediately after the end of the superfusion (8-10 min). Input resistance was measured as the voltage deflection caused by a
cGMP immunocytochemistry. Isolated and desheathed cerebral ganglia pinned down on separate dishes (2 ml volume) were pretreated for 30 min with 1 mM IBMX in ASW and treated for 2 min with ASW containing varying concentrations of SNC, histamine, or degassed SNC in the presence of 1 mM IBMX. When used, the sGC inhibitor (ODQ or LY83583) was included in the IBMX pretreatment solution as well as in the actual SNC or histamine treatment solution. Immediately after the treatment, 4% paraformaldehyde in 0.1 M sodium phosphate, pH 7.4, was added to each dish for overnight fixation (4°C). After a wash in 0.5% Triton X-100 in PBS, pH 7.4 (PBST), the ganglia were incubated with 1.5% normal rabbit serum (R-9133; Sigma) in PBST for 5 hr and then with a 1:20,000 dilution of anti-cGMP sheep antiserum (gift from Dr. Jan De Vente, University of Limburg) in PBST overnight. After being washed in PBST, they were incubated with a 1:2000 dilution of peroxidase-conjugated anti-sheep or -goat rabbit antiserum (A-5420; Sigma) and 1.5% normal rabbit serum in PBST for 2 hr, followed by another wash in PBST. The ganglia were then pinned down in a glass dish for peroxidase reaction with 3,3'-diaminobenzidine (DAB) substrate solution (peroxidase substrate kit, SK-4100; Vector Laboratories, Burlingame, CA). Color-developed ganglia were dehydrated with an ethanol series (50, 75, 95, and 100%), cleared in xylene, and mounted on slide glasses with Permount (SP15-100; Fisher Scientific). Each step was done at room temperature except fixation (4°C). The relative optical density of the MCC was measured using a Metamorph video imaging software (Universal Imaging Corporation, West Chester, PA) (gray levels 0-256), with background density being measured as an average of the densities of three unstained nearby cells.
RESULTS
8-Br-cGMP mimics the response of the MCC to an NO generator, SNC
NO released from exogenous NO-donor compounds, such as SNC and SIN-1, mimics the membrane depolarization and increase in input resistance that are characteristic of the vsEPSP that occurs in the MCC during stimulation of NOS-containing neuron C2 (Jacklet, 1995
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Figure 1. A representative recording of the membrane response of the MCC to 8-Br-cGMP. Input resistance was measured with one electrode as the size of voltage deflection caused by a negative current pulse (
The compounds were tested over a range of doses (Fig. 2) to make a quantitative comparison of the MCC responses. When cerebral ganglion was superfused with ASW containing SNC (10-200 µM), the membrane depolarized and input resistance increased in a dose-dependent way. These responses reached the threshold for spike initiation in the MCC (depolarization by ~10 mV and ~90% increase in input resistance; Fig. 2A) at ~100 µM SNC. The MCC response to 8-Br-cGMP (5-100 µM) was also dose dependent (Fig. 2B), and the membrane potential reached spike threshold at approximately the same level (~10 mV depolarization and ~120% increase in input resistance). The response to 100 µM SNC was approximately equivalent to the response to 40 µM 8-Br-cGMP. 8-Br-cAMP and 8-Br-GMP (10-100 µM for each one) were used as controls for the specificity of 8-Br-cGMP effects. They had essentially no effect on the membrane of the MCC (0.67 ± 0.82 mV depolarization and 0 ± 0% increase in input resistance for 40 µM 8-Br-GMP; n = 3; 0.33 ± 0.58 mV depolarization and 0 ± 0% increase in input resistance for 40 µM 8-Br-cAMP; n = 3).
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Figure 2. MCC membrane responses to the NO generator SNC and to 8-Br-cGMP. Changes in membrane potential and input resistance were measured during superfusion of the ganglion with ASW containing various concentrations of either drug at a flow rate of 3 ml/min. Each point with error bar represents a mean ± SE. Top graphs, Depolarization from the resting potential. Bottom graphs, Percent increase in input resistance, calculated from the voltage deflection caused by a 1 sec negative current pulse (see Fig. 1). The resting membrane potential and input resistance were usually
ODQ and LY83583 suppress the vsEPSP in the MCC
The results above show that 8-Br-cGMP mimics the MCC membrane responses that are characteristic of the responses to NO donors and the vsEPSP evoked by C2 stimulation. This suggested that the portion of the vsEPSP induced by the cotransmitter NO is mediated by elevation of intracellular cGMP level via activation of sGC. To examine this further, we tested the effects of two membrane-permeable inhibitors of sGC, ODQ and LY83583, on the vsEPSP produced by the firing of C2.
The vsEPSP, as its name suggests, rises and decays very slowly. The typical speed of depolarization in the MCC vsEPSP induced by a train of C2 spikes (Fig. 3) at 10-20 spikes/sec is ~2-5 mV/sec. It starts to decay at approximately one-half a second after the end of C2 firing. If the duration of C2 activation is long enough and the frequency high enough, the depolarization reached spike threshold at ~10 mV above resting potential. The C2 firing rate for a constant current of stimulation was stable through several hours of experimentation, if 10-20 spikes/sec firing for 2-3 sec was used to evoke the vsEPSP. At least a 3 min rest between trials was required for the vsEPSP to recover to its original size.
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Figure 3. Effects of sGC inhibitors (ODQ and LY83583) on the vsEPSP evoked in the MCC by C2 stimulation. An isolated cerebral ganglion was superfused with ASW containing either drug at the flow rate of 3 ml/min. A, ODQ (20 µM) reduced the vsEPSP size to 44.4% of the control value. The change was complete 40 min after the start of superfusion with ODQ. After washout for 90 min, the vsEPSP partially recovered (~75%). B, LY83583 (5 µM) reduced the vsEPSP size to 43% in 30 min. After washout for 60 min, it recovered fully.
When the cerebral ganglion was superfused with ASW containing ODQ (20 µM) or LY83583 (5 µM), the vsEPSP was reduced to approximately one-half of its normal amplitude (Fig. 3A,B). Partial block was expected, because the vsEPSP is thought to be partly mediated by the cotransmitter histamine (Jacklet, 1995
ODQ and LY83583 block the membrane response to SNC but not the response to histamine
We hypothesize that the vsEPSP in the MCC is composed of two distinct components, a histamine-induced component not mediated by sGC and an NO-induced component mediated by sGC, because there was a consistent partial suppression of the vsEPSP by the two sGC inhibitors (Fig. 3) and because the bath application of histamine and SNC together seemed to result in a simple additive depolarization and increase in input resistance (H.-Y. Koh and J. W. Jacklet, unpublished observations). This hypothesis was further tested by comparing the abilities of the sGC inhibitors to block the MCC's membrane responses to either histamine or SNC.
The cerebral ganglion was pretreated with 5 µM LY83583 for 30 min, and the suppression of the vsEPSP was monitored regularly (at 5 min intervals) until there was not further change. This confirmed the suppressive activity of LY83583 before either SNC or histamine. Then the membrane depolarization and change in input resistance caused by either SNC (10-100 µM) or histamine (0.05-0.25 mM) were measured in the presence of LY83583 and compared with the control values. The SNC response was reduced by 5 µM LY83583 to approximately one-third (33.1 ± 3.48% for depolarization; n = 8; p < 0.0001; 25.4 ± 7.13% for the increase in input resistance; n = 8; p < 0.005; paired t test). The MCC response to histamine was unaffected (117 ± 11.2% for depolarization; n = 5; p = 0.2420; 109 ± 6.06% for the increase in input resistance; n = 4; p = 0.1915). The incomplete suppression of SNC responses by LY83583 suggests that 5 µM LY83583 could not block all the sGC enzymes or that the unsuppressed part of the NO effect is mediated by another second messenger. Because nonspecific effects of LY83583 have been reported (Mulsch et al., 1988
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Figure 4. Effects of ODQ on the responses to SNC and to histamine (HA) in the MCC. A, The response to SNC in the presence of 20 µM ODQ was measured by superfusing the preparation with ASW containing both SNC and ODQ after the effect of ODQ pretreatment reached a plateau. Circles are control responses (absence of ODQ), and squares are experimental responses (presence of 20 µM ODQ). Input resistance was measured as the size of the voltage deflection caused by a
SNC, but not histamine, increases cGMP-IR in the MCC in a dose-dependent manner
To determine whether cGMP is indeed synthesized in the MCC in response to NO, we determined cGMP production by whole-mount cGMP-IR after bath application of SNC. In cGMP-IR, cGMP produced by the chemical or physiological treatment of tissues is fixed to the protein matrix of the cell by paraformaldehyde treatment of the tissue, and then an antiserum against formaldehyde-fixed cGMP is used for immunodetection (De Vente and Steinbusch, 1993
In the presence of 1 mM IBMX, SNC increased cGMP-IR in the MCC. Representative immunoreactive neurons in Figure 5A-D show that the staining intensity increased in proportion to the dose of SNC used. The results of the all the cGMP-IR experiments were quantified using optical density measurements, and the summary graphs of the data from Figure 5 and similar experiments are shown in Figure 6. Figure 6A shows the SNC dose dependence. The minimal dose for full staining for a 2 min exposure was 100 µM. There was no substantial staining of the MCC in the ganglia treated either with IBMX alone or with 100 µM SNC that was degassed overnight (Fig. 5E). Without IBMX in combination with SNC, SNC did not induce cGMP-IR, i.e., ganglia were not different from untreated ganglia. A group of three to five unidentified tiny cells (<20 µm in diameter) located between the bases of cerebropedal and cerebropleural connectives was consistently stained by the antiserum, regardless of the SNC treatment. Staining of these cells was so reliable that it was an indicator of a successful immunocytochemical procedure. A few other groups of cells in the cerebral ganglion were stained after SNC treatment, but the results are not presented here. Histamine (250 µM) did not induce immunostaining (Fig. 5F) at the dose that caused the maximum depolarization and increase in input resistance. This result is consistent with the failure of sGC inhibitors to suppress the MCC's membrane response to histamine (Fig. 4B).
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Figure 5. cGMP-IR in the MCC induced by exposure to SNC at several concentrations and times and during inhibition by ODQ. The huge cell body (150-200 µm, diameter) at the center of each photograph is the MCC. A-D, cGMP-IR induced by treatment for 2 min with increasing doses of SNC. E, Treatment for 2 min with 100 µM SNC that was degassed overnight. F, Treatment for 2 min with 250 µM histamine (HA). G-L, The time dependence of cGMP-IR in the MCC induced by 100 µM SNC. Note the decreased staining intensity after 10 min. M-O, The effect of increasing ODQ concentration on the NO-induced cGMP-IR in the MCC. Note that 10 µM ODQ almost completely blocked the cGMP-IR in the MCC (O).
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Figure 6. Summary of SNC-induced cGMP-IR in the MCC. The relative optical density of staining was measured using a Metamorph video imaging system (background density was measured as an average of the densities of three unstained nearby cells). Each point in the graphs represents a mean ± SE. Data were collected from three sets of experiments for all three graphs. A, Dose dependency of cGMP-IR induced by SNC (0-200 µM for 2 min). B, cGMP-IR induced by 100 µM SNC for durations of 0-20 min. C, Dose-dependent inhibition by ODQ (10 nM to 10 µM) of cGMP-IR induced by SNC (100 µM for 2 min).
cGMP-IR in the MCC resulting from treatments of various durations (0-20 min) of exposure to 100 µM SNC was examined (Fig. 5G-L). This allowed us to determine an optimal SNC treatment time for cGMP-IR. The highest density was observed in durations between 2 and 5 min (Figs. 5I,J, 6B), so all other cGMP-IR experiments were done with a 2 min SNC treatment.
ODQ blocks NO-induced cGMP-IR in the MCC in a dose-dependent manner
The involvement of the sGC-cGMP system in NO signaling in the MCC was further tested by determining whether the sGC inhibitors block the cGMP-IR in the MCC induced by SNC application. The cGMP-IR induced by 100 µM SNC was suppressed by ODQ in a dose-dependent way (Fig. 5M-O). It was almost completely blocked by 10 µM ODQ (Fig. 5O). Quantification of the results of all ODQ experiments shows a clear proportionality between ODQ dose and block of the cGMP-IR (Fig. 6C). This further supports the hypothesis that NO acts by stimulating sGC and consequently increasing cGMP in the MCC.
DISCUSSION
Soluble GC is known as a major target protein for NO in the CNS (Luo et al., 1994
The present study shows that two specific sGC inhibitors (ODQ and LY83583) suppress both the vsEPSP and the membrane responses to SNC in the MCC. We found that even supramaximal doses of these sGC inhibitors always partially suppressed the vsEPSP, to ~45%. Partial vsEPSP suppression has also been observed in the previous experiments using the NOS inhibitor L-NAME (Jacklet, 1995
The membrane input resistance and the depolarization in response to SNC were reduced to ~25 and 33%, respectively, by LY83583, but not completely blocked, whereas the ODQ block was virtually complete. This difference is presumed to be caused by the additional action of LY83583 on other activities, such as NOS (Mulsch et al., 1988
The SNC-induced cGMP-IR in the MCC increased in proportion to the SNC dose, and the response profile was similar to the membrane responses to SNC. The cGMP-IR in the MCC was progressively suppressed by increasing doses of ODQ and completely blocked at the dose that inhibits the SNC membrane responses almost completely. These results are consistent with the hypothesis that the membrane responses induced by SNC (NO) are the outcome of an increase in intracellular cGMP level in the MCC. In addition, the inability of histamine to induce cGMP-IR in the MCC and the inability of sGC inhibitors to block the membrane response to histamine imply a separate and distinct second messenger pathway for histamine in the MCC.
Most of the cGMP-IR disappeared after 10 min of SNC treatment, suggesting that either the cGMP molecules are not produced for >5-10 min or there is another cGMP-quenching system that is not inhibited by IBMX in this system. This is unlike many other studies in which substantial cGMP-IR was obtained after 15 min treatments with NO generators in the presence of IBMX [crab stomatogastric nervous system (Scholz et al., 1996
Several unsuccessful attempts were made to induce cGMP-IR in the MCC by synaptic activation provoked by electrically stimulating C2. The cell body of the MCC did not stain, and any stain along the neurite was not detectable. The synaptic contacts from C2 are not on the MCC cell body but likely occur along the neurite at >400 µm from the cell body, deep within the ganglion. Successful detection of a synaptically induced increase in cGMP-IR will likely require a precise anatomical localization of the synaptic contacts by dye marking the terminals, deep tissue detection using confocal microscopy, and rapid fixation to allow for the short duration of the enhanced cGMP-IR. An additional complication is that, although the NO release sites are presumed to be at the synaptic terminals of C2, they are not known.
The vsEPSP in the MCC seems to be mediated by the closing of a potassium channel (Weiss et al., 1986a
NO depolarizes the MCC by reducing a resting membrane potassium conductance, and this effect is mimicked by 8-Br-cGMP. Some neurons in the abdominal ganglion of another species (Aplysia kurodai) are depolarized by either NO or cGMP (Sawada et al., 1995
Neuron C2 is a mechanoafferent neuron that conveys sensory information from the mouth of Aplysia to the neural circuit for feeding. It contributes to the maintenance of food arousal (Weiss et al., 1986b
Our finding that NO seems to be used as a cotransmitter with histamine in C2 serves as an example of what might be found in other systems. NO may serve as a cotransmitter or modulator in many systems, because NOS is commonly colocalized in presynaptic neurons with a conventional transmitter. For example, in the cerebellum NOS is found in granule cells along with glutamate and in basket cells along with GABA (Vincent, 1986
The morphological and functional homologs of paired serotonergic cerebral giant neurons in the gastropods Aplysia, Helix, Lymnaea, and Pleurobranchaea have been extensively studied at both the physiological and behavioral levels (e.g., Yeoman et al., 1994
FOOTNOTES Received Nov. 16, 1998; revised Feb. 16, 1999; accepted Feb. 18, 1999.
We gratefully acknowledge support for this research from the National Institute of Mental Health Grant 1R01MH5774601A1 and from State University of New York Research Foundation funds. We thank Dr. Jan De Vente for providing the cGMP antiserum used in this study.
Correspondence should be addressed to Dr. Jon W. Jacklet, Department of Biological Sciences, University at Albany, State University of New York, Albany, NY 12222.
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