Chemical Senses vol. 30 no. 2 © Oxford University Press 2005; all rights reserved.
Glutamate-induced Cobalt Uptake Elicited by Kainate Receptors in Rat Taste Bud Cells
1 Department of Physiology and Neuroscience, Kangnung National University, Kangnumg, Republic of Korea, 2 Research Institute of Oral Science, Kangnung National University, Kangnung, Republic of Korea, 3 Department of Preventive Dentistry, College of Dentistry, Kangnung National University, Kangnung, Republic of Korea and 4 Department of Oral Anatomy, College of Dentistry, Seoul National University, Seoul, Republic of Korea
Correspondence to be sent to: Kyung-Nyun Kim, Department of Physiology and Neuroscience, College of Dentistry, Kangnung National University, 123 Chibyun-dong, Kangnung, Kangwon-do, 210-702, Republic of Korea. e-mail: knkim{at}kangnung.ac.kr
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Abstract |
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Glutamate-induced cobalt uptake reveals non-N-methyl-D-aspartate (non-NMDA) glutamate receptors (GluRs) in rat taste bud cells. However, it is not known which type of non-NMDA glutamate receptors is involved. We used a cobalt staining technique combined with pharmacological tests for kainate or
-amino-3-hydroxy-5-methyl-isoxazole-propionic acid (AMPA) receptors and/or immunohistochemistry against subunits of GluRs to examine the presence of non-NMDA receptors in rat foliate tastebud cells. Cobalt uptake into taste cells was elicited by treating taste buds with glutamate, kainate or SYM 2081, a kainate receptor agonist. Treating taste buds with AMPA or fluorowillardiine did not stimulate significant cobalt uptake. Moreover, 6-cyano-7-nitro-quinoxaline-2, 3-dione significantly reduced cobalt staining elicited by glutamate or kainate receptor agonists, but SYM 2206, an AMPA receptor antagonist, did not. Immunohistochemistry against subunits of GluRs reveals GluR6 and KA1-like immunoreactivity. Moreover, most glutamate-induced cobalt-stained cells showed GluR6 and KA1-like immunoreactivity. These results suggest that glutamate-induced cobalt uptake in taste cells occurs mainly via kainate type GluRs.
Key words: AMPA, cobalt staining, foliate papilla, glutamate receptors, kainate, taste bud
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Introduction |
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Taste buds are composed of several kinds of cells, including taste receptor cells and supporting cells. In gustatory perception, synaptic interactions between taste bud cells may play important roles (Roper, 1992
). In rat taste buds, several neurotransmitters have been identified. To date, glutamate (Caicedo et al., 2000b; Kim et al., 2001), serotonin (Herness and Chen, 1997), norepinephrine (Herness et al., 2002) and 
-amino butyric acid (Obata et al., 1997) have been reported in rat taste buds. These neurotransmitters may participate not only in information transfer from receptor cells to afferent neurons, but also among taste bud cells.
Glutamate is a ubiquitous neurotransmitters in the nervous system. There are several types of glutamate receptors (GluRs) including metabotropic and ionotropic. Ionontropic GluRs consist of N-methyl-D-aspartate (NMDA), kainate and -amino-3-hydroxy-5-methyl-isoxazole-propionic acid (AMPA) GluRs. Kainate and AMPA receptors are called non-NMDA GluRs. In rat taste buds, non-NMDA GluRs are present and increase during taste bud maturation (Kim et al., 2001). In the central nervous system, the roles of AMPA and kainate receptors are different. AMPA receptors mediate the majority of rapid excitatory synaptic transmission and participate in synaptic plasticity (Song and Huganir, 2002). In some parts of brain, AMPA GluRs modulate the size of synapses (Passafaro et al., 2003). The kinetics of EPSCs generated at kainate receptors is slower than that of EPSCs from AMPA receptors (Lerma, 2003). A slow, small EPSC such as that mediated by kainate receptors offers the possibility of integrating excitatory inputs over a larger time window (Lerma, 2003). Moreover, gating mechanisms of AMPA and kainate receptors are also different. External ions modulate the amplitude and kinetics of kainate GluRs, but not of AMPA GluRs (Bowie, 2002). Thus it is an important question whether AMPA or kainate GluRs are present in taste bud cells. The answer may have a bearing on the role(s) of non-NMDA GluRs in taste perception.
To investigate the presence and possible functional significance of iGluRs in taste buds, we have used the cobalt staining technique introduced by Pruss et al. (1991) and/or immunohistochemistry against subunits of non-NMDA GluRs. The cobalt staining technique involves the pharmacological stimulation of iGluRs in the presence of CoCl2, which leads to the uptake of Co2+ through Ca2+-permeable iGluRs. Subsequently, one can visualize activated cells by precipitating histochemically and intensifying the intracellular Co2+. This technique serves to identify cells that possess Ca2+-permeable iGluRs of the non-NMDA type in taste bud cells (Caicedo et al., 2000b).
We found that cobalt-stained cells correlated best with kainate GluRs in rat foliate taste bud cells. Parts of these results were presented as an abstract (Chung et al., 2004).
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Materials and methods |
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All experimental protocols were approved by the Animal Care and Use Committee, College of Dentistry, Kangnung National University. The experimental protocol was adopted from procedures published previously (Caicedo et al., 2000; Kim et al., 2001
). Preparation of slices
Tongue slices containing taste buds were obtained from 45- to 60-day-old Sprague–Dawley rats (at least four animals in each group). All animals were weaned at postnatal day 21. Rats were deeply anesthetized with carbon dioxide and decapitated. The tongue was quickly removed and immersed in cold, oxygenated, low sodium, high sucrose uptake buffer containing (in mM): 57.5 NaCl, 5 KCl, 1 CaCl2, 2 MgCl2, 10 HEPES, 12 glucose, 139 sucrose, pH 7.4, 305 mOsm. After removing surrounding muscles, blocks of tissue that included foliate papillae were mounted on a tissue chopper (Stoelting, Wood Dale, IL). Tongue slices (500 µm) containing foliate papillae were cut perpendicular to the long axis of the trenches and incubated in oxygenated uptake buffer for 1 h at room temperature. Usually two slices from each rat were analyzed.
Cobalt uptake
Slices were transferred into a six-well dish containing oxygenated uptake buffer. After two 10 min washes in uptake buffer, slices were stimulated for 5 min at room temperature in uptake buffer containing 5 mM CoCl2 plus 1 mM glutamate and/or other drugs. After pharmacological stimulation, slices were rinsed for 5 min in uptake buffer containing 2 mM EDTA to remove non-specifically bound Co2+, followed by 5 min in uptake buffer. Cobalt ions were then precipitated by incubating the slices for 5 min in uptake buffer containing 1.2% (NH4)2S. Slices were washed again in uptake buffer and then fixed overnight in 4% paraformaldehyde in 0.1 M phosphate buffered saline (pH 7.4) at 4°C. They were cryoprotected in 20% sucrose in 0.1 M phosphate buffered saline and sectioned at 20 µm on a cryostat (Jung Frigocut 2800N, Leica, Germany). Silver enhancement of cobalt precipitates was carried out on floating sections with the intenSEM kit (Amersham, Arlington Heights, IL). Sections were mounted on gelatin-coated slides, counterstained with methylene blue, dehydrated, cleared and coverslipped. We tested 30–300 µm kainate and SYM 2081, a kainate type receptor agonists, 30–300 µM AMPA and 1–10 µM fluorowillardiine (Patneau et al., 1992), an AMPA type receptor agonist, and 100 µM SYM 2206 (Pelletier et al., 1996), an AMPA type receptor antagonist with or without 100 µM CNQX.
Kainate, AMPA, CNQX, SYM 2081, SYM 2206 and fluorowillardiine were purchased from Tocris (Ballwin, MO). Other reagents were obtained from Sigma (St Louis, MO).
Immunohistochemistry
Sprague–Dawley rats were deeply anesthetized with urethane (1.5 g/kg body wt) and perfused intracardially with 0.1 M phosphate-buffered saline (PBS, pH 7.2) followed by 4% paraformaldehyde in PBS. The tissues blocks containing foliate papillae were excised and fixed in the same fixative solution for 2 h. They were then cryoprotected and sectioned at 20 µm using the same procedure as above. Cryostat sections were treated for 1 h at 4°C with a preincubation solution containing 0.3% Triton X-100, 1% bovine serum albumin (BSA) and 10% normal goat serum in PBS. Immunohistochemistry procedure against GluR1–7 and KA1 and 2 (Santa Cruz Biotechnology Inc. Santa Cruz, CA; Table 1) were performed. Sections were incubated overnight at 4°C with primary antibodies against subunits of GluRs (diluted 1:100) in preincubation solution. Sections were blocked for 1 h at room temperature with 10% normal goat serum and 1% BSA in PBS. Sections were rinsed and labeled by the avidin-biotin-peroxidase method (Vectastain ABC, Vector Laboratories, Burlingame, CA). Peroxidase activity was detected with diaminobenzidine (DAB) or 3-amino-9-ethylcarbazole (AEC). Labeling of subunits of GluRs in taste buds was also abolished by omitting the primary antibody (data not shown). For double labeling with cobalt staining, immunohistochemistry procedures against GluR6 or KA1 were performed after cobalt visualization procedure. Other reagents except indicated were obtained from Sigma.
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Data analysis
Sections were examined and photographed on a Nikon E-600 microscope (Japan) with bright-field illumination. Specific immuno- or cobalt staining was defined as being evenly distributed intracellularly (Caicedo et al., 2000; Kim et al., 2001). To quantify staining, we determined the numbers of immuno- or cobalt-stained cells per taste bud in two sections from a slice. We examined differences in the amount of Co2+ uptake between experimental groups by comparing the incidence of stained cells, that is, the average number of stained cells per taste bud in an individual slice. These values were averaged over the individual slices in each group. The data of each group were compared using the Mann–Whitney U-test. All cells counts were done blindly. There were no differences in the cell counts when cells were counted independently by two investigators. Data are expressed as mean ± SEM.
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Results |
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Cobalt uptake in taste cells
As shown in this and previous reports (Caicedo et al., 2000b; Kim et al., 2001), some taste cells in foliate papillae of the tongue showed strong Co2+ uptake when stimulated with 1 mM glutamate (3.31 ± 0.54 cells/taste bud, n = 32 number of rats; Figure 1a,f). Cells in surrounding tissues were not stained. Cobalt precipitate was evenly distributed throughout the cytoplasm but was not present in nuclei of taste cells. In the presence of the competitive non-NMDA GluR antagonist CNQX (100 µM), the number of cobalt-stained cells was significantly reduced (1.60 ± 0.51, n = 34, P < 0.001; Figure 1b,f). Basal cobalt uptake was still observed in the absence of any pharmacological treatment (2.43 ± 0.25, n = 4, P < 0.01; Figure 1c,f). We believe this residual cobalt uptake represents constitutive stimulation of taste cells by a low level of glutamate endogenous to the slices (Caicedo et al., 2000b). When stimulated with 100 µM kainate, all foliate taste buds appeared to contain cobalt-stained cells. The number of stained cells (3.19 ± 0.44, n = 9) was significantly higher than those of CNQX-treated or control (absence of pharmacological treatment) slices (P < 0.001, 0.01 respectively; Figure 1d,f). In taste buds treated with 100 µM AMPA, cobalt uptake did not differ from slices receiving no treatment (2.58 ± 0.24, n = 5, P = 0.32, Figure 1e,f). Treating taste buds with 300 µM AMPA stimulated cobalt uptake (3.29 ± 0.35, n = 8, P < 0.01, Figure 2b).
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Pharmacological test of cobalt uptake
To test whether Co2+ uptake was mediated by AMPA or kainate receptors, we conducted experiments using agonists and antagonists of kainate or AMPA type GluRs.
Stimulating taste buds with SYM 2081, an agonist of kainate GluRs, increased cobalt staining in a dose-dependent manner. At 300 µM, SYM 2081 elicited almost the same extent of cobalt staining as glutamate- or kainate-stimulated slices (3.10 ± 0.46, n = 6, Figure 2a). Moreover, cobalt staining stimulated by SYM 2081 was reduced by adding 100 µM CNQX (Figure 2a). Although SYM 2081 is a potent agonist of kainite receptors, it also rapidly desensitizes the receptors. Thus, we also conducted experiments in the presence of agents that inhibit GluR desensitization (concanavalin A, cyclothiazide) to determine whether this would enhance Co2+ loading. Applying 1 mM glutamate or 300 µM SYM 2081 in the presence of concanavalin A (10–1000 µg/ml) or cyclothiazide (1–100 µg/ml) did not influence cobalt staining (data not shown), suggesting that the initial influx of Co2+ through GluRs when they are maximally stimulated is sufficient to produce complete Co2+ staining.
We also conducted experiments using fluorowillardiine, a potent agonist of AMPA GluRs. Cobalt staining over background levels was not apparent around the EC50 of fluorowillardiine (Patneau et al., 1992), but higher concentrations (10 µM) revealed cobalt uptake in taste bud cells (Figure 2b), possibly due to non-selective activation of kainate GluRs (Patneau et al., 1992). SYM 2206 (2.63 ± 0.33, n = 4), an antagonist of AMPA receptors (Pelletier et al., 1996), did not reduce basal cobalt uptake (P = 0.56) and addition of SYM 2206 with 1 mM glutamate (2.90 ± 0.26, n = 4) did not significantly reduced cobalt uptake induced by glutamate (P = 0.16, Figure 2c).
Immunohistochemistry against subunits of non-NMDA GluRs
In rat taste buds, we found GluR6 and KA1-like immunoreactivity (Figure 3). Other non-NMDA subunits were not detected. The numbers of GluR6- and KA1-immunostained cells per taste bud were 4.34 ± 0.23 and 6.29 ± 0.24 (n = 5), respectively. Immunostaining against both GluR6 and KA1 was distributed throughout the cytoplasm but was not present in nuclei of taste cells. In double labeling with immunostaining combined with cobalt staining (evoked by 1 mM glutamate, n = 6), there was good correlation between cobalt-staining and immunoreactivity: 97% of cobalt-stained cells revealed GluR6 or KA1-like immuoreactivity (Figure 4). The converse correlation showed somewhat less overlap: 79% of GluR6-positive cells and 60% of KA1-positive cells were cobalt stained by 1 mM glutamate stimulation (Figure 4). Even though there were high incidences of immunostained cells with cobalt staining, the numbers of immunostained cells were not changed by cobalt staining procedure.
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Discussion |
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We used the cobalt staining technique and/or immunohistochemistry against subunits of non-NMDA GluRs to visualize the presence of glutamate receptors in taste bud cells and to determine which kind of GluRs are functional in taste bud cells. Stimulating taste buds with agonists for non-NMDA GluRs in the presence of Co2+ revealed the presence of a number of cobalt-stained cells. Cobalt uptake was stimulated by glutamate, kainate or SYM 2081. AMPA and fluorowillardiine only stimulated cobalt uptake at supramaximal concentrations. Immunohistochemistry for GluRs was consistent with these results. GluR6 and KA1-like immunoreactivity, but not immunostaining for AMPA GluRs, was present in rat taste bud cells. We conclude that kainate GluRs are mainly responsible for glutamate-stimulated cobalt uptake in rat foliate taste buds. We cannot exclude a lesser contribution from AMPA receptors that might be present but below our detection level.
Cobalt staining in taste bud cells is mediated by kainate GluRs
The cobalt uptake procedure for labeling cells that have calcium-permeable GluRs is selective for non-NMDA receptors (Caicedo et al., 2000). We and others have shown that NMDA application or depolarization does not stimulate Co2+ uptake in taste cells or brain cells (Caicedo et al., 2000; Pruss et al., 1991). In the present experiments, cobalt staining elicited by kainite receptor agonists in taste bud cells was more pronounced than that elicited by AMPA receptor agonists. Also, we found immunostaining for the kainate receptors GluR6 and KA1, but not the AMPA receptors GluR1–4 in rat taste cells. Caicedo et al. (2004) also reported that immunostaining for the AMPA receptor subunits GluR2/3 was principally located in nerve endings in taste buds and was only rarely found in taste cells. Chaudhari et al. (1996) reported that KA2 subunits were detected with RT-PCR but not GluR6 or KA1 subunits. RNAs of GluR6 and KA1 might be very unstable and might be destructed during the sample preparation procedure. However, KA2 is a kainate GluR, too. Chaudhari et al. (1996) also found no subunits of AMPA GluRs. This could be confirmed by other experiments, such as in situ hybridization.
High concentrations of AMPA (300 µM) and the AMPA receptor agonist fluorowillardiine (10 µM) elicited cobalt staining. These high concentrations might nonselectively stimulate kainite receptors (Patneau et al., 1992). Alternatively, Co2+ staining induced by these concentrations may reveal a small contribution from AMPA type GluRs, consistent with the much reduced (Caicedo et al., 2004) or absent (this report) immunoreactivity for AMPA GluRs.
Do cells in taste buds communicate with each other?
Taste bud cells consist of at least three morphological cell types, the type I (dark) cells, type II (light) cells, and type III cells (Farbman, 1965; Pumplin et al., 1997). Cobalt- and immuno- stained cells showed same morphological characteristics, the cells had a central, enlarged cell body containing a large oval nucleus and processes extending towards the apical and the basal portion of taste bud. They had clear outline and did not show lateral cytoplasmic projections. Our results suggest that cobalt-stained cells elicited by kainate GluRs may be type II or Type III cells (Caicedo et al., 2000b; Kim et al., 2001). Traditionally only type III cells have unambiguous synaptic connections with primary afferent fibers, and they are considered only true receptive cells in taste bud (Lindemann, 1996). However, type II cells as well as type III cells have apical cytoplasmic extensions into the taste pore (Pumplin et al., 1997). Gustducin, an -subunit of a G-protein closely related to the transducins (McLaughlin et al., 1992), is expressed only in type II (light) cells (Boughter et al., 1997). Thus, type II cells may respond to taste stimulation and transmit their signals to type III cells. It is highly probable that taste cells communicate with each other.
Nerve cells may be another source of glutamate in taste buds
Axons of primary gustatory neurons are a possible source of glutamate—they are immunoreactive for glutamate (Jain and Roper, 1991) and release glutamate at their central projections (Bradley et al., 1996). Although there is no direct evidence that taste buds have efferent innervations from the central nervous system, efferent inputs are found in other sensory organs such as the cochlea (Raphael et al., 2003). Even though kainate GluRs are mainly located postsynaptically, a number of these receptors have also been identified presynaptically (Chittajallu, 1996). Furthermore, kainate receptors may occur in both pre- and postsynaptic sites (Lerma, 2003). In the present experiments, cobalt-stained cells showed immunoreactivity for GluR6 and KA1. In the hippocampus, GluR6-containing kainate GluRs modulate neuronal activity (Cossart et al., 1998). Thus activation of kainate GluRs in taste bud cells would produce a modulation of the release of the endogenous neurotransmitters. In the central nervous system, kainate GluRs exhibit much slower EPSCs and integrate excitatory inputs over large time windows (Lerma, 2003). They can mediate excitatory synaptic signals but are they also involved in modulating the presynaptic release of neurotransmitter, and therefore in regulating the strength of synaptic connections (Madden, 2002). In taste bud cells, glutamate receptors, including kainate receptors (this paper) and NMDA receptors (Caicedo et al., 2000a, 2004), might be involved in information transmission from type II cells to type III cells, or efferent glutamatergic control from the central nervous system might modulate communication between taste cells and/or afferent nerve fibers.
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We would like to thank Professor Stephen D. Roper for his comments on the manuscript. This work was supported by grant No. R05-2002-000-00395-0 from the Basic Research Program of the Korea Science & Engineering Foundation.
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References |
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Accepted December 10, 2004
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