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Am J Physiol Heart Circ Physiol 281: H457-H462, 2001;
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Vol. 281, Issue 1, H457-H462, July 2001

RAPID COMMUNICATION
Expression of metabotropic glutamate receptors in nodose ganglia and the nucleus of the solitary tract

Caroline J. Hoang and Meredith Hay

Dalton Cardiovascular Research Center and Department of Veterinary Biomedical Sciences, University of Missouri at Columbia, Columbia, Missouri 65211


    ABSTRACT
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

The purpose of this study was to identify the complement of metabotropic glutamate receptors (mGluRs) expressed in nodose ganglia and the nucleus tractus solitarius (NTS). mRNA from these tissues was isolated and amplified with standard RT-PCR with primers specific for each mGluR subtype. The results of this analysis showed that the NTS expresses all eight mGluR subtypes, whereas nodose ganglia express only group III mGluRs: mGluR4, mGluR6, mGluR7, and mGluR8. Application of the group III-specific mGluR agonist L-(+)-2-amino-4-phosphonobutyric acid (100 µM) reversibly inhibited voltage-gated calcium currents isolated from DiI-labeled aortic baroreceptor neurons and unlabeled nodose neurons. The results of this study suggest that group III mGluRs are the primary mGluR subtype expressed in visceral afferent neurons and that these receptors may be involved in afferent central transmission.

nodose neurons; baroreceptors; L-(+)-amino-4-phosphonobutyric acid


    INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

THE VISCERAL AFFERENT NEURONS in nodose ganglia transmit cardiovascular, respiratory, and gastrointestinal sensory information to neurons of the nucleus tractus solitarius (NTS) in the medulla. One of the primary neurotransmitters utilized by these afferents, including baroreceptor afferents, is glutamate (18, 25, 31). In general, glutamate binds to both ion channel-associated (ionotropic glutamate receptors) and G protein-coupled [metabotropic glutamate receptors (mGluRs)] receptor types, which mediate fast excitatory and second messenger-evoked transmission, respectively (3, 4). At present, eight different mGluR subtypes plus several splice variants have been cloned. These subtypes are classified into three groups based on amino acid sequence homology, pharmacology, and signal transduction mechanisms (4, 22). Group I mGluRs consist of mGluR1 and mGluR5, are found mainly on postsynaptic terminals, and are positively coupled to phospholipase C. In contrast, the two remaining groups are negatively coupled to adenylate cyclase. Whereas group II mGluRs (mGluR2 and mGluR3) are found on both pre- and postsynaptic terminals, group III mGluRs (mGluR4, mGluR6, mGluR7, and mGluR8) are predominantly located in or near presynaptic zones (3, 4).

In several central nervous system tissues, activation of presynaptic mGluRs has been found to inhibit synaptic transmission (for a review, see Ref. 3). Interactions between different visceral afferent systems at the level of the NTS also demonstrate the potential to be modulated by presynaptic mechanisms (7, 20, 21). Multiple studies, both in vitro and in vivo, have demonstrated that increasing the frequency of stimulation of baroreceptor afferents results in a reduction of the excitatory response recorded from the NTS neurons (20, 21), without concomitant changes in resting membrane potential (21). One potential mechanism thought to contribute to this response involves a decrease in neurotransmitter release from presynaptic terminals (21). Factors involved in modulating transmitter release from these terminals include an influx of Ca2+ from voltage-gated calcium channels (14, 21, 26) and a cascade of synaptic protein-protein interactions (28).

Because glutamate has been suggested to be a neurotransmitter for these visceral afferents (25, 31), we hypothesized that activation of presynaptic mGluRs may be involved in the regulation of visceral afferent neurotransmission. At present, the complement of mGluR subtypes expressed in visceral sensory neurons and the NTS has yet to be identified. Therefore, the purpose of this study was to identify which mGluR subtypes are expressed in visceral sensory neurons.


    METHODS
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

Molecular analyses. All animal protocols were approved by the Institutional Animal Care and Use Committee of the University of Missouri-Columbia. Adult male Sprague-Dawley rats were anesthetized with halothane and then decapitated. Nodose ganglia were surgically removed and frozen under liquid nitrogen. During the NTS isolation, the cerebellum (CB) and brain stem were quickly removed and placed in 4°C phosphate-buffered saline. A 500-µm-thick horizontal medullary slice was obtained using a vibratome. Under a dissecting microscope, the NTS was visually identified as the region medial to the solitary tract, ventral to the area postrema, and dorsal to the central canal and was cut away +0.5 mm rostral to the calamus scriptorium with the caudal limit at the calamus scriptorium. The NTS was then frozen under liquid nitrogen. Both tissue type samples from individual rats were kept frozen in a -70°C freezer until mRNA isolation. mRNA was isolated using Dynal's mRNA Isolation Micro Kit as per the manufacturer's protocol. Briefly, lysis/binding buffer (500 µl) was added to the frozen tissue sample. This mixture was then homogenized and added to a microcentrifuge tube containing 20 µl of Dynabeads. The lysate was mixed with the beads for 5 min on a vortex and then washed four times. Elution of mRNA in 20 µl of a 10 mM Tris · HCl buffer subsequently followed. The mRNA was then kept frozen at -70°C until used for RT-PCR.

First strand cDNA synthesis and PCR were performed using the Stratagene RT-PCR kit. First strand cDNA synthesis was performed as per the manufacturer's protocol. PCR was performed by mixing 5 µl of the cDNA template with 5 µl of 10× PCR buffer, 0.5 µl of 100 mM dNTPs, and 20 pmol of each oligonucleotide primer in a thin-walled 0.2-µl PCR tube. The reaction was then brought up to 49.5 µl using diethyl pyrocarbonate-treated H2O. Subsequent incubation at 90°C for 5 min and then at 54°C for 5 min was followed by the addition of 0.5 µl of Taq polymerase into the reaction tubes.

PCR was initiated with a denaturation step at 94°C (for 5 min). This was followed by 30 cycles at 95°C (for 15 s), 52°C (for 1 min), and 72°C (for 2 min). PCR was terminated with a final step at 72°C (for 7 min). The PCR-amplified products were electrophoresed on a 2.0% agarose gel and visualized with ethidium bromide staining. All mGluR and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) primer sequences are listed in Table 1. cDNAs generated in the presence or absence of reverse transcriptase underwent amplification with primers of the housekeeping gene GAPDH. The results of this amplification were used to ensure successful mRNA isolation without genomic DNA contamination.

                              
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  		Table 1.   mGluR and GAPDH primer sets used for PCR amplification

Rat CB, olfactory bulb (OB), and cerebral cortex (CC) served as positive controls for the mGluR primers due to the prominent expression of each tissues specific mGluR subtype. The CB served as positive control tissue for mGluR1, mGluR2, and mGluR4 (15, 30), whereas the OB prominently expresses mGluR6, mGluR7, and mGluR8 (5, 23, 27). The CC served as positive control tissue for mGluR3 and mGluR5 (1, 30). Adult male Sprague-Dawley rats were anesthetized with halothane and decapitated. Tissues of interest were removed and then frozen under liquid nitrogen. mRNA isolation and subsequent RT-PCR were performed as described above. Evaluation of PCR products was performed as described above. Sequencing of all PCR products was performed by Qiagen.

Neuronal culture and preparation. The methods for labeling of nodose neurons are similar to those described previously (19). Briefly, aortic baroreceptor neurons were identified with the use of the diffusible fluorescent dye DiI. Adult male Sprague-Dawley rats ranging from 70 to 90 days old were anesthetized with isoflurane and artificially ventilated. From a midline incision, the right aortic depressor nerve was isolated from the surrounding tissue. A small piece of Parafilm was placed along the length of the isolated nerve. To prevent any dye from spilling out to the adjacent tissue, the area was covered with Wacker-Silicone gel, which was allowed to dry before surgical closure. The left aortic nerve was exposed but not labeled and served as the control. Nodose ganglion neurons from adult male Sprague-Dawley rats were isolated and placed in cold Eagle's minimal essential media (MEM) containing 5% fetal bovine serum (FBS) and 0.1% serum extender. The tissue was incubated in MEM containing 14 mg/ml collagenase for 35 min, followed by a second incubation for 35 min after the addition of 125 µl papain. The tissue was then triturated in MEM containing 5% FBS and 0.4% bovine serum albumin with serially smaller pipettes until most of the tissue was dissociated. Dissociated cells were then rinsed in MEM containing 5% FBS, 0.1% serum extender, and 8 ng/ml nerve growth factor and plated on poly-D-lysine-coated coverslips. Neuronal cells were maintained in the rinsing solution and used 1-2 days after they were plated.

Patch-clamp techniques. Calcium currents were recorded using whole cell patch-clamp techniques (10) with polished glass electrodes (resistance, 1-3 MOmega ). The reference electrode was an Ag-AgCl plug immersed in a 150 mM KCl-agar bridge, which was placed in the bath. Recordings were made at room temperature using an Axopatch 1D patch-clamp amplifier and filtered at 3 kHz using a four-pole Bessel filter. Currents were digitized on-line at 10 kHz and stored for analysis. Currents were analyzed using the Axograph program (Axon Instruments). The bath solution contained (in mM) 140.0 tetraethylammonium chloride, 5.0 4-aminopyridine, 15.0 glucose, 10.0 HEPES, and 5.0 CaCl2; pH 7.35. The pipette solution contained (in mM) 124.0 CsCl, 11.0 EGTA, 4.0 ATP, 0.3 GTP, 2.0 MgCl2, and 10.0 HEPES; pH 7.3.

L-(+)-Amino-4-phosphonobutyric acid (L-AP4), a group III-specific mGluR agonist, and (RS)-alpha -cyclopropyl-4-phosphonophenyl-glycine (CPPG), a group III-specific mGluR antagonist, were obtained from Tocris Cookson. Solutions were gravity fed into the recording chamber; solution exchange was complete in <10 s. Maximal effects of 100 µM L-AP4 were observed 3-5 min after application. Neurons recovered within 3-5 min. After recovery, a bath solution containing 100 µM L-AP4 and 100 µM CPPG was applied. Again, maximal effects were observed 3-5 min after application.

Statistical analysis. Data are reported as means ± SE, with differences between groups determined by Student's t-test.


    RESULTS
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

mGluR expression in nodose ganglia and NTS tissues was analyzed utilizing RT-PCR. cDNAs made from nodose ganglia, NTS, CB, OB, and CC were used during PCR amplification. Each mGluR primer was cycled in reaction tubes containing either the experimental cDNA template or control cDNA template. The primers specific for each mGluR subtype are listed in Table 1.

Figure 1A shows the results of RT-PCR analysis during amplification of group I mGluRs. The CB and NTS were positive for mGluR1 expression, with the expected band of 361 nucleotides, whereas nodose ganglia were negative for mGluR1. A 210-bp band, specific for mGluR5, was also expressed in the CC and NTS, whereas no expression was observed in nodose ganglia. Figure 1B shows the results of RT-PCR analysis during amplification of group II mGluRs. The CB and NTS were positive for mGluR2 expression, with the expected band at 251 bp, whereas nodose ganglia were negative. mGluR3 expression was observed in the CC and NTS, with the expected band at 261 bp, whereas no expression was observed in nodose ganglia. Figure 2 shows the results of RT-PCR analysis during amplification of group III mGluRs. The CB was positive for mGluR4, whereas the OB was positive for mGluR6, mGluR7, and mGluR8 expression, with expected bands at 340, 363, 321, and 440 bp, respectively. The NTS and nodose ganglia were also positive for mGluR4, mGluR6, mGluR7, and mGluR8 expression. However, in nodose ganglia, to detect message for mGluR6, the volume of mRNA template used for RT had to be doubled. Subsequent RT-PCR analysis for the remaining seven mGluRs using this twofold increase in mRNA volume during RT resulted again in detection of mGluR4, mGluR7, and mGluR8. Expression of group I and group II mGluRs was still not observed. RT-PCR analysis was verified after we subcloned and sequenced the PCR products (Qiagen). These results suggest that the NTS expresses the genes encoding all eight mGluR subtypes, whereas nodose ganglia express the genes encoding mGluR4, mGluR6, mGluR7, and mGluR8 (all group III mGluRs) only.


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  		Fig. 1.   PCR analysis of cDNAs with group I and group II mGluR primers. A: photo of an ethidium bromide-stained 2.0% agarose gel displaying PCR amplification of group I metabotropic glutamate receptors (mGluRs) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Amplification with GAPDH primers demonstrated successful mRNA isolation without genomic DNA contamination. Amplification of mGluR1 and mGluR5 in the cerebellum (CB) and cerebral cortex (CC), respectively, served as positive controls for each primer. The nucleus of the solitary tract (NTS) expressed both group I subtypes, whereas nodose ganglia (NG) did not. +, RT in the presence of reverse transcriptase; -, RT in the absence of reverse transcriptase. B: amplification of mGluR2 and mGluR3 in the CB and CC, respectively, served as positive controls for each primer. The NTS expressed both group II subtypes, whereas NG did not.



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  		Fig. 2.   Photos of ethidium bromide-stained 2.0% agarose gels displaying PCR amplification of group III mGluRs. Amplification of mGluR4 in the CB and mGluR6, mGluR7, and mGluR8 in the olfactory bulb (OB) served as positive controls for each primer. The NTS and NG were positive for all group III subtypes.

It has been suggested that activation of presynaptic mGluRs in baroreceptor neurons may inhibit neurotransmission via inhibition of voltage-gated calcium channels (2, 11). To determine whether the expressed group III mGluRs in nodose ganglion neurons affect these voltage-gated calcium currents, the whole cell patch-clamp technique was utilized on cultured nodose ganglion neurons from both identified labeled aortic baroreceptor neurons and unlabeled nodose neurons. Figure 3A illustrates the effect of the group III-specific mGluR agonist L-AP4 (100 µM) on evoked calcium currents from the cell body of a nodose neuron. After a step depolarization to 0 mV from a holding potential of -80 mV, the evoked calcium current was inhibited by 65% in this particular cell. Similar results were observed in nine other cells (Fig. 3B; 52 ± 5.9%, P < 0.05; five cells were aortically labeled). The percent inhibition by 100 µM L-AP4 was not statistically different between aortical-labeled and non-aortic-labeled nodose neurons. In the presence of the group III-specific antagonist CPPG (100 µM), the inhibitory effects of L-AP4 were almost completely attenuated (Fig. 3B; 87 ± 2.4%, n = 3), suggesting that the inhibitory response to L-AP4 is mediated primarily by activation of group III mGluRs.


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  		Fig. 3.   L-(+)-Amino-4-phosphonobutyric acid (L-AP4) inhibition of voltage-gated calcium currents. A: typical trace demonstrating the effects of 100 µM L-AP4 on nodose neuron somatic voltage-gated calcium currents evoked by a 500-ms step depolarization to 0 mV from a holding potential of -80 mV. B: average effects of 100 µM L-AP4 in the presence and absence of the group III mGluR antagonist (RS)-cyclopropyl-4-phosphonophenyl-glycine (CPPG; 100 µM). Data are expressed as means ± SE and normalized to the evoked maximal calcium current. *P < 0.05.


    DISCUSSION
TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES

The results from this study provide new information regarding the specific mGluR subtypes that may be involved in modulating synaptic transmission in baroreceptor afferents. With the use of RT-PCR analysis, nodose ganglia were shown to express the genes encoding mGluR4, mGluR6, mGluR7, and mGluR8, which are all group III mGluRs. Activation of these mGluRs by the group III-specific mGluR agonist L-AP4 was also shown to reversibly inhibit voltage-gated calcium currents recorded from labeled aortic baroreceptor and unlabeled nodose neurons. Together, these data suggest that group III mGluRs are the primary mGluR subtypes expressed in visceral afferent neurons and that these receptors may be involved in afferent central transmission.

Previous in vitro studies with L-AP4 have demonstrated that activation of group III mGluRs reduces exocytosis in cultured aortic baroreceptor neurons (11). In neonatal nodose neurons, activation of mGluRs with trans-(±)-1-aminocyclopentane-1,3-dicarboxylic acid, a nonspecific mGluR agonist, also inhibited N-type voltage-gated calcium channels (12). In addition, studies using hindbrain slices demonstrated that application of the broad-spectrum mGluR agonist (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid [(1S,3R)-ACPD] presynaptically decreased the solitary tract-evoked excitatory postsynaptic current (8), whereas application of the relatively nonspecific mGluR antagonist alpha -methyl-4-carboxyphenylglycine resulted in posttetanic potentiation of the excitatory postsynaptic current in NTS neurons in response to low-frequency tetanus of the solitary tract (7). The results from the present study suggest that these presynaptic or afferent actions of mGluRs are most likely due to action on group III mGluRs.

In the present study, mGluR expression was also analyzed in mRNA isolated from the NTS. The results of these experiments showed that the NTS expresses the genes for all eight mGluR subtypes. Expression of the genes encoding mGluR1, mGluR2, mGluR3, mGluR5, and mGluR7 in the NTS are corroborated by previous immunocytochemical studies performed in transverse medullary brain stem slices (13). In those studies, protein immunoreactivity was observed in the NTS using antibodies against mGluR1a, mGluR2/3, mGluR5, and mGluR7. Functional studies examining the effects of mGluR activation in the NTS also support the present RT-PCR results. Application of the broad-spectrum mGluR agonist (1S,3R)-ACPD in the NTS has been shown to decrease arterial pressure, heart rate, and lumbar sympathetic nerve activity (6, 24). This effect is consistent with the activation of neurons in the NTS that are involved in baroreflex inhibition of heart rate and sympathetic outflow. Recent studies have shown that NTS activation with group I (6, 17), group II (17), and group III (17) mGluR agonists produce cardiovascular effects similar to those of (1S,3R)-ACPD, suggesting that all subgroups of mGluRs are expressed in the NTS. Microiontophoresis studies in anesthetized rabbits have shown that application of the putative group II mGluR agonist (2S,1',2'S)-2-(carboxycyclopropyl)glycine (L-CCG-I) attenuated NTS responses evoked by vagal stimulation, whereas application of the putative group II-specific antagonist alpha -methyl-4-phophonophenylglycine (MPPG) augmented NTS responses to high-frequency stimulation of both the vagus and aortic depressor nerve (16). However, L-CCG-I has been demonstrated to act nonselectively on all mGluR subtypes, whereas MPPG has also been demonstrated to act on group I and group III mGluRs (3). Therefore, due to the selectivity limitations of some of these mGluR ligands, it is difficult to unambiguously determine the mGluR subtypes involved in these studies.

In summary, the results from this study have shown that 1) the NTS expresses the genes encoding all eight mGluR subtypes; 2) nodose ganglia express the genes encoding mGluR4, mGluR6, mGluR7, and mGluR8; and 3) activation of group III mGluRs with L-AP4 reversibly inhibits voltage-gated calcium currents. Expression of group III mGluRs in nodose ganglia and group III mGluR-mediated inhibition of voltage-gated calcium currents in cultured nodose neurons suggest that these subtypes may act as autoreceptors at visceral afferent presynaptic terminals. Expression of all eight mGluR subtypes in the NTS suggests that these receptors may function both pre- and postsynaptically in the NTS.


    ACKNOWLEDGEMENTS

The authors thank Dr. Eileen Hasser for helpful discussions and Kathy Lindsley for expert technical assistance. We are also grateful to Dr. Min Li for assistance with molecular techniques.


    FOOTNOTES

This work was supported by National Heart, Lung, and Blood Institute Grants T32 HL-07094, HL-59676, HL-03620, and HL-54669.

Address for reprint requests and other correspondence: M. Hay, Dalton Cardiovascular Research Center, Research Park, Univ. of Missouri at Columbia, Columbia, MO 65211 (E-mail: HayM{at}missouri.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.

Received 16 December 2000; accepted in final form 9 April 2001.


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DISCUSSION
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Am J Physiol Heart Circ Physiol 281(1):H457-H462
0363-6135/01 $5.00 Copyright © 2001 the American Physiological Society


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