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1 Boston University Marine Program, Marine Biological Laboratory, Woods Hole, Massachusetts 02543; 2 Department of Anatomy and Neurobiology, Colorado State University, Fort Collins, 80523; 3 Rocky Mountain Taste and Smell Center, University of Colorado Heath Science Center, Denver, Colorado 80262; and 4 Department of Physiology and Biophysics, University of Miami School of Medicine, Miami, Florida 33101
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ABSTRACT |
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 Abstract
 Introduction
Methods
Results
Discussion
References
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Delay, Rona J., Sue C. Kinnamon, and Stephen D. Roper. Serotonin modulates voltage-dependent calcium current in Necturus taste cells. J. Neurophysiol. 77: 2515-2524, 1997. Necturus taste buds contain two primary cell types: taste receptor cells and basal cells. Merkel-like basal cells are a subset of basal cells that form chemical synapses with taste receptor cells and with innervating nerve fibers. Although Merkel-like basal cells cannot interact directly with taste stimuli, recent studies have shown that Merkel-like basal cells contain serotonin (5-HT), which may be released onto taste receptor cells in response to taste stimulation. With the use of whole cell voltage clamp, we examined whether focal applications of 5-HT to isolated taste receptor cells affected voltage-activated calcium current (ICa). Two different effects were observed. 5-HT at 100 µM increased ICa in 33% of taste receptor cells, whereas it decreased ICa in 67%. Both responses used a 5-HT receptor subtype with a pharmacological profile similar to that of the 5-HT1A receptor, but the potentiation and inhibition of ICa by 5-HT were mediated by two different second-messenger cascades. The results indicate that functional subtypes of taste receptor cells, earlier defined only by their sensitivity to taste stimuli, may also be defined by their response to the neurotransmitter 5-HT and suggest that 5-HT released by Merkel-like basal cells could modulate taste receptor function.
The neurotransmitter serotonin (5-hydroxytryptamine,5-HT) is found in only one cell type in Necturus taste buds, Merkel-like basal cells (Delay et al. 1993 Isolation of taste receptor cells
Mudpuppies (Necturus maculosus) were acquired from commercial vendors and maintained in 5% artificial seawater at 8-10°C. Animals were killed by decapitation after being anesthetized by submersion in ice water for 30 min. Isolated taste receptor cells were prepared by the method described in Kinnamon et al. (1988) Gigaseal whole cell recording
Membrane currents were recorded with the use of the whole cell configuration of the patch-clamp technique (Hamill et al. 1981 Perfusion system and solutions
The recording chamber consisted of either a 35-mm plastic petri dish or a Sylgard "O" ring on a standard 1.0-mm glass microscope slide. The bath perfusion system was gravity fed, with the solution changes controlled by multisolenoid manifold valves (General Valve). Focal application of 5-HT and other drugs was achieved by a modified U tube system, as described by Oxford and Wagoner (1989) We recorded from elongate cells isolated from Necturus taste buds. These cells were identified as taste receptor cells on the basis of morphology and electrical excitability (Kinnamon and Roper 1987
Effect of 5-HT and other amines on voltage-dependent Ca2+ current
In >90% of the taste receptor cells examined, 5-HT (100 µM) altered ICa. The responses fell into two groups. In one subset of taste receptor cells, 5-HT decreased ICa (Fig. 2). The inhibitory effect of 100 µM 5-HT on the peak of ICa (+20 mV) is shown compared with wash in Fig. 2A. (ICa before addition of 5-HT was higher than that obtained after wash.) This decrease in ICa in response to 5-HT was observed at other voltage steps (Fig. 2B). The inhibitory effect of 5-HT was partly reversible (Fig. 2C). To average the inhibitory effects of 100 µM 5-HT, the current before application of 5-HT was normalized to 1.0 and the change in ICa was given by a fraction of this number (n = 11). At 100 µM,5-HT decreases averaged ~45% of ICa before rundown was taken into account (Figs. 1C and 4). However, when corrections were made for rundown, the average decrease in ICa was only 28% (Fig. 4).
5-HT receptor subtypes modulating ICa in taste receptor cells
The observation that taste receptor cells could be subdivided into two different groups on the basis of their response to 5-HT suggested that these different responses could be mediated by different 5-HT receptor subtypes. Seven major 5-HT receptor subtypes have been classified (Bard et al. 1993
Second-messenger pathway for the potentiation of ICa by 5-HT
Both the 5-HT1A and the 5-HT1B receptors couple to pathways that regulate intracellular adenosine 3
Second-messenger pathway for inhibition of ICa by 5-HT
In neurons of the dorsal raphe and the hippocampus,5-HT exerts an inhibitory effect via a PTX-sensitive G protein (Bockaert et al. 1992
In this study we demonstrated that 5-HT modulates ICa in taste receptor cells. On the basis of their response to 5-HT, taste receptor cells can be divided into two categories: cells in which 5-HT potentiates ICa, and those in which 5-HT inhibits ICa. Whether these responses to 5-HT define two morphologically distinct types of taste receptor cells, or different functional states of the same cell type, is unknown. Electrophysiologically distinct groups of taste receptor cells were recently reported by Bigiani and Roper (1993) Potentiation of ICa by 5-HT
Data from the experiments with 8cpt-cAMP, H-89, and PTX suggest that 5-HT potentiation of ICa in taste receptor cells is G protein-mediated and PTX insensitive. That is, a G protein-coupled 5-HT receptor activates AC, thereby raising cAMP, which stimulates a cAMP-dependent kinase.
Inhibition of ICa by 5-HT
The second-messenger pathway mediating the inhibitory actions of 5-HT is different from that mediating the stimulatory action, but it was not fully resolved. 5-HT receptors that inhibit AC, decreasing intracellular cAMP, are probably not mediating this effect, because the experiments with H-7, a nonspecific protein kinase inhibitor, indicate that activation of a protein kinase is involved. Activators of PKC increased ICa, suggesting that the reduction of ICa by 5-HT is not mediated by the phospholipase C-activated PKC pathway. The involvement of a protein kinase also rules out a direct activator, such as that recently demonstrated in the rat dorsal raphe neurons by Penington et al. (1991)
INTRODUCTION
Abstract
Introduction
Methods
Results
Discussion
References
). Three to seven of these small, ovoid cells are found at the base of each taste bud, evenly spaced around the outer edge (Kim and Roper 1995; Kim et al. 1993). Merkel-like basal cells selectively take up 5-HT and release it on depolarization in a Ca2+-dependent fashion (Welton and Roper 1992), as would be expected if 5-HT were a neurotransmitter released by these cells. Merkel-like basal cells do not extend processes to the taste pore and cannot be directly activated by taste stimulation; however, they form synapses with taste receptor cells and with the innervating nerve fibers (Delay and Roper 1988). Thus Merkel-like basal cells are positioned to function as interneurons in the taste bud, and could modify or modulate synaptic transmission between taste cells and afferent nerves (Delay et al. 1993; Reutter 1971).
; Montgomery and Burton 1986a,b; Yen and Fuller 1992). In rats, 5-HT is released by the hypothalamus in response to the presentation of food (Schwartz et al. 1990). Mutant mice lacking 5-HT2C/1C receptors overeat compared with wild-type littermates (Tecott et al. 1995). Furthermore, tricyclic antidepressants, such as imipramine, which are potent blockers of high-affinity 5-HT uptake mechanisms, often have side effects in taste perception (Deems et al. 1991; Finley 1994; Henkin 1994). These data suggest that 5-HT may play a role in taste transduction.
; Roper and Ewald 1992). In semi-intact preparations, Ewald and Roper (1994) found that bath application of 5-HT hyperpolarizes taste receptor cells and increases their membrane resistance. In the present study we have investigated the role of 5-HT in peripheral taste transduction, examining whether 5-HT alters specific electrical properties of isolated taste receptor cells. We demonstrate that there are two functionally different subpopulations of taste receptor cells, on the basis of the modulation of their voltage-activated Ca2+ current (ICa) by focally applied 5-HT. In one subset of taste receptor cells, 5-HT potentiates ICa, whereas in the second subset 5-HT inhibits ICa. The two responses, potentiation and inhibition of ICa, are mediated by the same receptor subtype but different second-messenger systems. These results suggest that Merkel-like basal cells may modulate synaptic transmission between taste receptor cells and the innervating nerve fibers.
METHODS
Abstract
Introduction
Methods
Results
Discussion
References
. Briefly, lingual tissue was removed from the tongue with blunt dissection and pinned out in a Sylgard-coated dish. The tissue was rinsed with amphibian physiological saline (APS) solution and treated with a 0.1% solution of collagenase (Worthington Biochemical) in APS plus 0.1% albumin with 5 mM glucose until the surrounding, nontaste epithelium could be gently peeled away from the taste buds. In this manner, taste buds were left on their pedestals of connective tissue. After a short period of time in calcium-free APS, taste receptor cells could be gently sucked into a fire-polished pipette and plated onto recording chambers coated with Cell-Tak (Collaborative Research). Isolated taste receptor cells were examined immediately after plating into the recording chambers. For experiments involving pertussis toxin (PTX), nontaste epithelium was stripped away as above and exposed taste receptor cells were treated for 12-24 h at 4°C in a PTX (500 ng/ml) APS (plus albumin and glucose). Cells with many different morphotypes were obtained from Necturus taste buds, but only those cells with an elongated or bipolar morphology, indicative of receptor cells, were chosen for electrophysiological recording. This selection criterion excluded nontaste epithelial cells, stem cells, and Merkel-like basal cells.
). Patch pipettes were made from hematocrit capillary tubes and coated with a soft dental wax to reduce electrode capacitance. The resistance of the pipettes was between 2 and 4 M
when filled with intracellular solution.
25 mV) applied to the pipette from the holding potential. These currents were automatically subtracted from the records. Membrane capacitance was estimated by integrating the capacitative transient and dividing by the amplitude of the voltage step. Whole cell input resistances ranged from 1 to 10 G. Cells were held at 80 mV (occasionally, 100 mV) and pulsed from 20 to +40 mV in 10 mV steps. The cells were not compensated for whole cell capacitance or series resistance with the patch clamp so the true series resistance could be monitored continuously and the experiment terminated if the resistance exceeded 15 M.
. The U tube consisted of a tiny loop of No. 10 polyethylene tubing shaped as a "U" with a small hole at the apex of the U. The tubing was connected to a series of solution-filled reservoirs. Solutions flowed from the reservoirs through the tube and into a vacuum trap. When the vacuum was discontinued, the test solution would flow gently but rapidly over a closely positioned cell. All test solutions applied in this manner contained the dye Fast Green to allow visual monitoring of the test solution. Fast Green had no effect on membrane currents in taste cells.
ethanesulphonic acid (HEPES), buffered to pH 7.2 with NaOH. The external bath solution contained 94 mM NaCl, 20 mM BaCl2, 2 mM KCl, 5 mM HEPES, 10 mM tetraethylammonium bromide, and 1 µM tetrodotoxin. The intracellular solution used for measuring Ca2+ current was composed of (in mM) 100 cesium acetate, 10 NaCl, 10 HEPES, 0.23 CaCl2, 1.0 ethylene glycol-bis(
-aminoethyl ether)-N,N,N,N-tetraacetic acid [(EGTA) or 5 bis-(o-aminophenoxy)-N,N,N,N-tetraacetic acid (BAPTA)], 2 MgCl2, 5 ATP, and 0.5 guanosine 5-triphosphate (GTP), with free Ca2+ concentration calculated to be 10
7 M. The GTP and ATP were added fresh daily and the final pH was titrated to 7.2 with tris(hydroxymethyl)aminomethane-OH.
:5-cyclic monophosphate (8cpt-cAMP), Sigma.
RESULTS
Abstract
Introduction
Methods
Results
Discussion
References
). Necturus taste receptor cells can be subdivided into dark cells and two types of light cells on the basis of morphological criteria (Cummings et al. 1987; Delay and Roper 1988; Farbman and Yonkers 1971; McPheeters et al. 1994). Although we did not attempt to identify taste receptor cell subtype because of experimental constraints, it is probable that the majority of cells examined in this study were dark cells, because dark cells tend to survive the isolation procedures better than the other cell types (McPheeters et al. 1994). Approximately 10% of the isolated taste receptor cells had no ICa (see also Bigiani and Roper 1993; Bigiani et al. 1996; McPheeters et al. 1994) and 5-HT could not unmask or evoke an ICa from these cells.
20 to +40 mV from a holding potential of 80 mV. The apparent peak of the inward current was +10 mV (Fig. 1B), although the current varied somewhat from cell to cell (range = 200-6,000 pA). ICa inactivates, even with barium (Ba2+) as the charge carrier (Kinnamon and Roper 1987; Kinnamon et al. 1989). This rundown of the calcium current is displayed in Fig. 1C. We tried to minimize calcium current rundown by recording with perforated patches formed with nystatin rather than standard whole cell mode, but had unreliable results. With whole cell recording, calcium current rundown could be fitted with an exponential curve. In control cells(n = 9), an exponential fit to the first four to five data points and the last point (which would occur after washout in the test cells) produced a predicted rundown for ICa that consistently matched the observed rundown (P > 0.96).
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FIG. 1.
Calcium current activation and rundown over time. A: typical calcium current elicited from a taste cell after blocking the other voltage-activated currents. B: current-voltage (I-V) relationship for the cell in A. Voltage-activated calcium current (ICa) peaks near 10 mV for this cell. C: peak of ICa plotted against time. Dashed line: predicted rundown in ICa over time for this cell.
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FIG. 2.
Inhibitory effects of serotonin (5-HT) on ICa of isolated taste receptor cells. A: change in peak of ICa (+20 mV) by focal application of 100 µM 5-HT. Cell was held at 80 mV, then pulsed in 10 mV steps from 20 to +40 mV. B: I-V relationship for cell in A in the presence of 100 µM 5-HT and after wash. ICa before application of 5-HT was greater than that shown for wash. C: effect of 100 µM 5-HT on ICa plotted as peak of ICa over time. Dashed line: predicted rundown in ICa over time (see Fig. 1C). D: combined data from taste receptor cells responding to 5-HT with a reduction in ICa. Current before application of 5-HT was normalized to 1.0 and change in ICa is given by a fraction of this number (n = 11).
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FIG. 4.
Dose-response relations for the modulation of ICa by 5-HT. Filled circles: reduction in ICa. Open circles: increase in ICa. Data are shown as % changes in ICa in the presence of 5-HT. These values were calculated by subtracting ICa during 5-HT application from projected (extrapolated) values in the absence of 5-HT (see Fig. 1C and Fig. 2C). Mean ± SE for each concentration and the number of observations for each point (values in parentheses) are shown. Curves were fit by the equation Y(% change) = Ymax{1/[1 +(Xmid/XS)]}, where Ymax is the maximum response, Xmid is the midpoint of the curve, s is slope, and X is concentration. The values for the points for the curve to fit the increase in ICa were as follows: Ymax = 56.7, Xmid = 3.95, s = 2.15; whereas the values for the curve to fit the decrease in ICa were Ymax = 28, Xmid = 9, s = 0.87.
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FIG. 3.
Potentiation effects of 5-HT on ICa. A: potentiation of peak ICa by 100 µM 5-HT. Cell was held at 80 mV and pulsed in 10 mV steps from 20 to +40 mV. Shown is the effect of 5-HT on ICa (+10 mV). B: I-V relationship for cell in A in the presence of 100 µM 5-HT and after wash. C: time course of effect of application of 10 µM 5-HT. 5-HT was applied during the solid bar shown above the graph. Dashed line: predicted rundown in ICa over time. D: average increase in ICa by 100 µM 5-HT in the 2nd subset of taste receptor cells (n = 11).
; Humphrey et al. 1993; Matthes et al. 1993; Ruat et al. 1993a,b) on the basis of molecular cloning and intracellular coupling systems. The 5-HT receptors (except for 5-HT3) can be grouped into the following families: receptors that inhibit adenylyl cyclase (AC; 5-HT1A, 5-HT1B, and 5-HT1D receptors, although the 5-HT1A receptor has also been reported to activate AC) (Barbaccia et al. 1983; Hoyer and Schoeffter 1991; Shenker et al. 1985); receptors that activate phospholipase C (5-HT1C and 5-HT2) (Kaneko et al. 1992; Pritchett et al. 1988); and receptors that stimulate AC (5-HT4, 5-HT5, 5-HT6, and 5-HT7) (Monsma et al. 1993; Ruat et al. 1993a,b; Tsou et al. 1994). A series of experiments was undertaken to characterize the 5-HT receptor subtype(s) in taste receptor cells.
View this table:
TABLE 1.
Comparison of pharmacological profiles and effector pathways for selected agonists/antagonists of
5-HT receptor subtypes
,5-cyclic monophosphate (cAMP). To investigate whether cAMP was involved in the serotonergic modulation of ICa in taste receptor cells, we focally applied 8cpt-cAMP, a membrane permeant analogue of cAMP. The majority of cells (16 of 22) responded with an increase in ICa (Fig. 5). Inhibition of ICa was never observed with 8cpt-cAMP. This result suggests that the increase in ICa could be mediated by upregulation of cAMP. It also rules out the 5-HT1B receptor because that receptor has only been reported to decrease cAMP. If elevation of cAMP stimulates ICa, its action on the Ca2+ channel may be via a cAMP-dependent kinase that would phosphorylate the channel, or it may directly activate the channels. To test whether cAMP-dependent kinases were involved in the modulation of ICa by 5-HT, we treated isolated cells with H-89 (20 µM) for 30 min before recording. H-89 is a selective inhibitor of cyclic-nucleotide-dependent kinases at this concentration (Chijiwas et al. 1990). In cells treated with H-89, 5-HT either reduced ICa (8 of 13; Fig. 6A) or had no effect (Fig. 6B); that is, 5-HT never potentiatedICa in H-89-treated cells. These results are consistent with5-HT-mediated stimulation of adenylyl cyclase, resulting in activation of a cAMP-dependent kinase and phosphorylation of Ca2+ channels leading to potentiation of ICa. The data also suggest that the inhibitory effect of 5-HT on ICa is not mediated through cAMP.
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FIG. 5.
Membrane-permeable analogue of cAMP, 8cpt-cAMP, potentiates ICa in taste receptor cells. Example of potentiation of ICa by 8cpt-cAMP is shown. Dark line above graph: time course of application of 8cpt-cAMP. In 70% of tested cells, 8cpt-cAMP increased ICa. In the other 30% of taste receptor cells, no response to 8cpt-cAMP was observed.
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FIG. 6.
H-89, a selective inhibitor of protein kinase A, affects modulation of ICa by 5-HT. Cells were treated 
30 min before recording with 20 µM H-89 in APS. H-89 was included in all bath solutions. A: even after treatment with H-89, taste receptor cells showed a reduction in ICa in response to 5-HT. B: in some of the taste receptor cells treated with H-89, 5-HT did not elicit any change in ICa.
; Frazer et al. 1990; Penington et al. 1991). We tested for this possibility by treating isolated taste buds for 12-24 h with PTX (500 ng/ml) in APS at 4°C. Of the PTX-treated cells, a few had no response to 5-HT (6 of 22; Fig. 7A), whereas the majority of cells responded to 5-HT with a potentiation of ICa (16 of 22, Fig. 7B). These results suggest that the inhibitory action of 5-HT on ICa in taste receptor cells is mediated by a PTX-sensitive G protein. In the PTX-treated cells, 5-HT never caused inhibition of ICa. It was also noted that although the magnitude of ICa varied from cell to cell, in general ICa was greater in the PTX-treated taste receptor cells than in the controls.
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FIG. 7.
Effect of pertussis toxin (PTX) on the ability of 5-HT to modulate ICa. Intact taste buds were treated with 500 ng/ml PTX in APS for 12-24 h at 4°C. Control taste buds were treated the same way, except no PTX was added to the APS. A: 30% of the PTX-treated taste receptor cells showed no response to 5-HT. B: 70% of PTX-treated taste receptor cells responded with an enhancement in ICa. PTX treatment completely blocked the reduction in ICa normally observed in response to 5-HT.
). Both DOG and PDBr potentiated ICa (data not shown), suggesting that activation of PLC is not the pathway that mediates the inhibition of ICa.
). H-7 is a nonselective blocker of protein kinases, particularly protein kinase A, PKC, and protein kinase G. Inclusion of H-7 in all bath solutions (50 µM) and in the patch pipette (200 µM) blocked all of the inhibitory effects of 5-HT on ICa (n = 11). Although not investigated systematically, treatment with either H-89 or H-7 seemed to decrease the total amount of ICa, suggesting that phosphorylation is required for calcium channel function in taste receptor cells. Collectively, these results suggest that the inhibition of ICa by5-HT involves a PTX-sensitive G protein and a kinase sensitive to H-7 but not H-89; however, the full nature of this pathway is not yet known.
DISCUSSION
Abstract
Introduction
Methods
Results
Discussion
References
and Bigiani et al. (1996). McPheeters et al. (1994) reported that both dark cells and a small subset of light cells exhibited ICa. The question of which taste receptor cell type(s) 5-HT is acting on remains to be answered.
; Humphrey et al. 1993; Matthes et al. 1993; Ruat et al. 1993a,b). In the present study, the results obtained by applying agonists and antagonists seem to rule out all but the 5-HT1A and 5-HT1B receptors as modulating ICa in Necturus taste cells. Furthermore, results obtained by analyzing the effector systems apparently rule out 5-HT1B receptors mediating the potentiation of ICa. 5-HT1B receptors decrease cAMP by inhibiting AC. The potentiation of ICa by 5-HT in taste receptor cells operates via an increase in cAMP, not a decrease, so 5-HT1B receptors cannot be mediating this response. Therefore it seems that 5-HT1A would have to be mediating this response, according to the pharmacological profile. The comparison of the effector system for known 5-HT1A receptors with that regulating the potentiation of ICa by 5-HT in taste cells should support this hypothesis. Unfortunately, there is some confusion about the effector system for 5-HT1A receptors. In some tissues 5-HT1A receptors activate AC (Barbaccia et al. 1983; Hoyer and Schoeffter 1991; Lucas et al. 1993; Markstein et al. 1986; Shenker et al. 1985; Taiwo et al. 1992). In other tissues 5-HT1A receptors inhibit AC (Clarke et al. 1987; DeVivo and Maayani 1988). Thus several reviews of 5-HT receptor subtypes have 5HT1A linked with inhibition and activation of AC (DeVivo and Maayani 1988; Frazer et al. 1990; Hoyer and Schoeffter 1991). Expression of the cloned 5-HT1A receptor in different cell types has shown that 5-HT1A receptors can activate several different second-messenger systems in the same cell (Fargin et al. 1989, 1991; Liu and Albert 1991; Raymond et al. 1992, i.e., Boess and Martin 1994), although activation of AC has not yet been reported. Thus it seems possible that a 5-HT1A receptor modulates the potentiation of ICa in taste receptor cells, as our results suggest.
, where 5-HT activated a G protein directly coupled to the Ca2+ channel. Thus, in Necturus taste receptor cells, the second-messenger pathway responsible for the ability of 5-HT to reduce ICa appears to involve a 5-HT receptor coupled to a PTX-sensitive G protein that leads to activation of an unknown protein kinase.
; Corsi et al. 1991; Sanchez-Armass et al. 1991; Sumner et al. 1989). Either possibility, that of two different receptors or one receptor linked to two different second-messenger pathways, seems equally plausible in Necturus taste cells.
reported that, when taste receptor cells are constantly stimulated, bath application of 5-HT slowly hyperpolarizes the cells and increases their input resistance. Merkel-like basal cells, which contain 5-HT, may be stimulated to release the monoamine during chemostimulation of taste buds, and this could modify synaptic transmission at receptor cell synapses. Alternatively, efferent input to Merkel-like basal cells might stimulate 5-HT release. In the presence of 5-HT, one subset of taste receptor cells might release more neurotransmitter, whereas a second subset of taste receptor cells would release less. Such an effect could modulate the ability to discriminate certain taste stimuli.
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ACKNOWLEDGEMENTS |
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The authors thank Drs. Albertino Bigiani, Vincent Dionne, and Heather Eisthen for critical reading of the manuscript.
This work was supported by National Institute of Deafness and Other Communications Disorders Grants 5R01 DC-00374 and 5P01 DC-00244 to S. D. Roper, and DC-00766 and DC-00244 to S. C. Kinnamon.
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FOOTNOTES |
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Address for reprint requests: R. J. Delay, Boston University Marine Program, Marine Biological Laboratory, Woods Hole, MA 02543.
Received 28 October 1996; accepted in final form 3 January 1997.
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REFERENCES |
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Abstract
Introduction
Methods
Results
Discussion
References
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