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Previous Article | Next Article
The Journal of Neuroscience, November 1, 2000, 20(21):7978-7985
In Situ Ca2+ Imaging Reveals Neurotransmitter Receptors for Glutamate in Taste Receptor Cells
Alejandro Caicedo1, 3, M. Samir Jafri1, and Stephen D. Roper1, 2 1 Department of Physiology and Biophysics and 2 Program in Neuroscience, University of Miami School of Medicine, Miami, Florida 33136, and 3 Laboratorio de Biofísica, Centro Internacional de Física, AA 49480 Bogotá, Colombia
ABSTRACT
TOP
ABSTRACT
INTRODUCTION
The neurotransmitters at synapses in taste buds are not yet known with confidence. Here we report a new calcium-imaging technique for taste buds that allowed us to test for the presence of glutamate receptors (GluRs) in living isolated tissue preparations. Taste cells of rat foliate papillae were loaded with calcium green dextran (CaGD). Lingual slices containing CaGD-labeled taste cells were imaged with a scanning confocal microscope and superfused with glutamate (30 µM to 1 mM), kainate (30 and 100 µM), AMPA (30 and 100 µM), or NMDA (100 µM). Responses were observed in 26% of the cells that were tested with 300 µM glutamate. Responses to glutamate were localized to the basal processes and cell bodies, which are synaptic regions of taste cells. Glutamate responses were dose-dependent and were induced by concentrations as low as 30 µM. The non-NMDA receptor antagonists CNQX and GYKI 52466 reversibly blocked responses to glutamate. Kainate, but not AMPA, also elicited Ca2+ responses. NMDA stimulated increases in [Ca2+]i when the bath medium was modified to optimize for NMDA receptor activation. The subset of cells that responded to glutamate was either NMDA-unresponsive (54%) or NMDA-responsive (46%), suggesting that there are presumably two populations of glutamate-sensitive taste cells
one with NMDA receptors and the other without NMDA receptors. The function of GluRs in taste buds is not yet known, but the data suggest that glutamate is a neurotransmitter there. GluRs in taste cells might be presynaptic autoreceptors or postsynaptic receptors at afferent or efferent synapses.
Key words: calcium imaging; taste bud; gustatory system; glutamate receptors; tongue; foliate papilla; kainate; NMDA; calcium green dextran
INTRODUCTION
Taste cells form synapses with axons of primary gustatory neurons and possibly with other cells in the mammalian taste bud. Taste cells also may receive efferent connections. However, the identity of neurotransmitters at these synapses in taste buds remains a key unanswered question in chemosensory neurobiology.
Glutamate is the major excitatory neurotransmitter in the CNS and in certain peripheral sensory organs (e.g., cochlea and retina). Glutamate also may be a neurotransmitter in taste buds. Chaudhari et al. (1996)
identified ionotropic GluRs (iGluRs; NMDAR1, NMDAR2, KA2, and
1) in lingual epithelium from foliate and vallate papillae in rats, implicating glutamatergic synaptic mechanisms in that tissue. Furthermore, primary gustatory neurons express iGluR subunits (Caicedo et al., 1999
To address these questions, we have developed a new Ca2+ microfluorometric technique to measure changes in intracellular [Ca2+] induced by the activation of GluRs in taste cells in situ. This technique capitalizes on the ability of GluR activation to elicit changes in [Ca2+]i in taste cells (Hayashi et al., 1996
Our data show that a subset of taste cells responds to glutamate. The pharmacological profile of the responses to glutamate suggests that iGluRs of the non-NMDA and NMDA types are involved. These experiments provide the first demonstration of functional neurotransmitter receptors in taste cells in a semi-intact preparation.
MATERIALS AND METHODS
All experimental protocols were approved by the University of Miami Care and Use Committee.
CaGD injection and preparation of slices. Tongues were obtained from 67 young adult Sprague Dawley rats (150-200 gm) of both sexes. Rats were killed in a closed chamber containing CO2, followed by cervical dislocation. Tongues were removed quickly and immersed in cold, oxygenated Tyrode's solution (in mM: 135 NaCl, 5 KCl, 8 CaCl2, 1 MgCl2, 10 HEPES, 10 glucose, 10 Na-pyruvate, and 5 NaHCO3, pH 7.4, 320-330 mOsm). Blocks of tissue (~5 × 5 × 5 mm) containing foliate papillae were removed from the tongue. CaGD (molecular weight 3000, KD = 259 nM; Molecular Probes, Eugene, OR) was injected iontophoretically (5 mM in H2O;
3.5 µA; 10 min) through a glass micropipette (20 µm tip) into the foliate papillae (cf. Krimm and Hill, 1998
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Figure 1. Example of Ca2+ microfluorometric recordings, illustrating how data were processed in this study. A, Confocal image of a taste bud loaded with calcium green dextran (CaGD). The cell bodies of taste cells selected for measurements are encircled (a-d). B, Raw data from recordings of CaGD fluorescence from these four taste cells showing a response to KCl depolarization superimposed on a gradual decline in fluorescence over time (bleaching). The lowest trace (d) illustrates how an exponential fit was used to correct for this bleaching. The single exponential curve was fit to the first 120 sec and the last 30 sec of the recording. C, The exponential curve in the bottom trace in B (d) was subtracted from the recorded signal to correct for bleaching, and the fluorescence was expressed as F/F. Scale bar, 10 µm.
The mechanisms of CaGD uptake into taste cells are unknown. We have used a protocol that is used widely for the injection of tracer substances in the brain and has been used specifically in taste buds (Krimm and Hill, 1998
Drug application. All chemicals were bath-applied. Switching between solutions was achieved with electronically controlled small-volume solenoid valves (Lee Company, Westbrook, CT). Complete bath exchange was accomplished in ~20 sec when the tissue was in place. All experiments were performed at room temperature. Glutamate agonists were applied at
5 min intervals to avoid receptor desensitization. Antagonists (CNQX and GYKI 52466) were allowed to equilibrate with the receptors for 5 min before stimulation with an agonist. Antagonists were used at ~10 times their published IC50 values (Donevan and Rogawski, 1993
The latencies of the responses were determined by the perfusion rate (2-3 ml/min) and the depth of the imaged cell within the slice. Slightly longer latencies in responses were observed for cells embedded deeper in the slice. Response latencies for a given cell were constant for sequential stimuli. We corrected for the differences in latencies when comparing responses between cells and when averaging responses (see below).
L-Glutamate, kainate, and GYKI 52466 were purchased from Sigma; NMDA, AMPA, and CNQX were obtained from Tocris (Ballwin, MO).
Confocal microscopy. CaGD-loaded cells were excited at 488 nm by using an argon laser attached to an Olympus Fluoview scanning confocal microscope. Foliate papillae were viewed with a 40× water immersion objective. Images of single taste buds were magnified 5× digitally. We acquired images without offset correction, additional gain, or filtering. We used a large confocal aperture (200-300 µm) to collect fluorescence from approximately the whole-cell thickness in a single image. This minimized artifacts associated with movement in the z-plane. To restrict photobleaching and phototoxicity, we reduced the laser intensity to 6% by a neutral density filter. Confocal images were collected at 5 sec intervals and processed with Fluoview software.
Fluorometric Ca2+ measurements. CaGD has a high affinity for Ca2+ (KD ~300 nM), making it possible to measure small changes in [Ca2+]i. We measured the mean intensity of CaGD fluorescence in cell bodies, apical processes, and/or basal processes of individual taste cells by selecting a region 110% the area of the target cell or process and then measuring fluorescence changes every 5 sec. Changes in CaGD fluorescence over time were analyzed by Fluoview software. We recorded resting fluorescence levels for 2 min before applying stimuli (Fig. 1). Then stimuli were applied for 1 min and were followed by a 2 min washout. We corrected for fluorescence bleaching by fitting a single exponential curve to the resting fluorescence of each trace that was recorded before stimulation and for a 30 sec interval beginning 1.5 min after the stimulation (Fig. 1). We expressed the fluorometric signals as relative fluorescence change
To compare the responses between taste cells, we recorded from taste cells with similar resting fluorescence levels. In general, we recorded from cells with intermediate levels of CaGD loading. Taste cells heavily loaded with CaGD did not respond to stimulation and showed signs of phototoxicity (constantly increasing fluorescence and cell membrane blebbing).
Data analysis. Our criteria for accepting Ca2+ responses for analysis were (1) that responses could be elicited
RESULTS
CaGD loading in taste cells
Iontophoretic injection of CaGD into foliate papillae loaded up to 15 taste cells per taste bud with CaGD (Fig. 2A,B). However, not all taste buds were loaded. The nonsensory epithelium surrounding the taste buds showed little CaGD loading, suggesting that the outermost layers of the epithelium were relatively impermeable to CaGD and that the access of CaGD to taste buds was limited to the taste pore (see below). Consequently, there was little background fluorescence, and single taste cells could be imaged readily. Most if not all CaGD-loaded taste cells contacted the taste pore (Fig. 2A-C), suggesting that CaGD entered taste cells through their apical tips. CaGD-loaded taste cells were distinctly fluorescent at rest, and levels of loading differed from cell to cell (see Fig. 2B,C). CaGD filled the cytoplasm of the cells, making cell processes clearly distinguishable in many instances. Most cells had ovoid cell bodies and long, thin processes extending to the apical and basal ends of the taste bud (Fig. 2C). Other CaGD-loaded cells had multiple processes and less-defined cell bodies. This is in agreement with the notion that different taste cell types (e.g., light cells, dark cells) contact the taste pore (Lindemann, 1996
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Figure 2. Foliate taste bud cells can be loaded with CaGD and visualized in slices of lingual epithelium. This figure shows confocal images of tissue slices (100 µm thick) from a foliate papilla that had been injected iontophoretically with CaGD, as described in Materials and Methods. CaGD is present in some taste buds and as an adhering layer to the superficial epithelium. A, Superimposed fluorescence and Nomarski differential interference contrast image. B, Fluorescent image alone from a different preparation. C, A higher magnification of the boxed region in B shows that five taste cells are loaded with CaGD. Apical processes extend to and converge at the taste pore. D, Ca2+ response (
Responses to depolarization
We first tested whether we could elicit Ca2+ responses in taste cells by depolarizing cells with Tyrode's solution containing 50 mM K+ (equimolar substitution of NaCl with KCl). According to the Nernst equation, a change of the extracellular [K+] from 5 to 50 mM (10-fold) might be expected to depolarize taste cells by ~60 mV. KCl depolarization increased CaGD fluorescence in 45% of the taste cells (50 of 110; Table 1) that were examined in the presence of 2 mM Ca2+ in the bath. The average peak
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Table 1. Proportions of taste cells responding to KCl depolarization and glutamate receptor agonists
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Figure 3. Ca2+ responses to KCl depolarization depend on extracellular Ca2+. A, Ca2+ responses elicited by depolarization (elevated K+, 50 mM) were larger in 8 mM [Ca2+]o than in 2 mM [Ca2+]o. B, Mean Ca2+ responses from cells bathed in 8 mM [Ca2+]o were significantly larger than in cells bathed in 2 mM [Ca2+]o (*Student's t test, p < 0.01). KCl responses were reversibly eliminated when Ca2+ was omitted from the bath. Numbers in parentheses equal the numbers of cells; error bars indicate SEM.
In cells that did respond to KCl depolarization, elevating Ca2+ in the bath to 8 mM significantly increased depolarization-induced responses (mean peak
Responses to glutamate
To test whether taste cells responded to glutamate, we superfused slices with Tyrode's solution containing glutamate (30 µM-1 mM) and measured changes in CaGD fluorescence. Between 26 and 35% of the cells that were examined responded to glutamate, under normal physiological conditions (when NMDA receptors would not be expected to be stimulated optimally; see below). The proportion of cells that responded to glutamate increased with increasing glutamate concentration (Table 1). Peak
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Figure 4. Ca2+ response to glutamate (1 mM) in a taste cell. The cell body (bottom) and the apical process (top) were selected for measurements (circles in the top left panel). In the cell body the peak amplitude of the response was 18%
Glutamate could be eliciting Ca2+ responses directly by stimulating Ca2+-permeable iGluRs, indirectly by depolarizing taste cells and activating VGCC, by inducing Ca2+ release from intracellular stores, or by a combination of the three. To begin to discriminate among these alternatives, we used the next experiment to test whether both glutamate and KCl stimulation could evoke Ca2+ responses in any given taste cell. Eighteen percent of the cells responded to both glutamate and KCl depolarization (18 of 98; Fig. 5Aa,B). Most cells, however, responded only to depolarization (39%, 38 of 98; Fig. 5Ab,B). Importantly, a small number of taste cells responded only to glutamate (9%, 9 of 98; Fig. 5Ac,B). Of the cells that responded to glutamate, two-thirds also responded to KCl depolarization and one-third did not respond (Table 1). (34% of the cells in this experiment did not respond either to glutamate or to KCl.) These results show that, at least in certain taste cells (9%), glutamate elicited responses that might not be attributed to KCl depolarization and Ca2+ influx through VGCCs.
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Figure 5. Ca2+ responses to glutamate (1 mM) in KCl depolarization-sensitive and KCl depolarization-insensitive taste cells. A, Representative traces from three different taste cells stimulated sequentially with 1 mM glutamate (glu) and 50 mM KCl (K+). B, Summary of data from 82 cells, showing incidence of responses to glutamate and KCl (glu + K+) as in a, KCl alone (K+) as in b, glutamate alone (glu) as in c, and cells that did not respond either to KCl or glutamate (none).
In the next experiment we assessed whether glutamate-induced Ca2+ responses were localized to regions of the taste cell where synapses are found. The majority of taste cell synapses in rodent taste buds occurs on the cell body and basal processes (Kinnamon et al., 1985
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Figure 6. Ca2+ responses to glutamate are localized to basal processes and cell bodies. A, Representative responses from one cell to 1 mM glutamate (glu) and 50 mM KCl (K+). This cell responded only to KCl depolarization; Ca2+ transients were recorded in the apical process, cell body, and basal process. B, Results from another cell that responded only to 1 mM glutamate and not to KCl depolarization. Note that responses to glutamate were restricted to the basal process and cell body in this cell.
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Figure 7. Quantification and statistical analysis of results such as those illustrated in Figure 6. Taste cells were selected for this analysis according to the criteria described in Results. All basal processes (6 of 6) and 82% of the cell bodies responded to 300 µM glutamate (shaded bars), but only 28% (2 of 7) of the apical processes responded. The differences in the proportions of the responses between the apical process and the other cell regions were significant (Fisher Exact Test; *p < 0.05 for the difference between the apical process and the cell body and p < 0.01 for the difference between the apical process and the basal process). By contrast, KCl depolarization elicited Ca2+ transients in all compartments (filled bars).
We further tested whether responses to depolarization were localized similarly to one or another region of taste cells. KCl-evoked Ca2+ responses in all three regions were similar (Figs. 6A, 7). All basal processes (4 of 4), 90% of the cell bodies (9 of 10), and 88% of the apical processes (8 of 9) showed Ca2+ transients in response to KCl depolarization. The differences between these proportions were not significant.
Collectively, data from these experiments suggest that the GluRs responsible for Ca2+ responses are mainly on the cell body and basal processes of taste cells and that responses were produced by Ca2+ influx through iGluRs. That is, the observed compartmentalization of Ca2+ responses would not be expected if Ca2+ influx were secondary to cell depolarization, unless, of course, iGluR-induced depolarization was restricted spatially (e.g., decrements caused by changing surface-to-volume ratios). This is unlikely in such small, electrotonically compact cells as taste cells.
Pharmacological characterization of the responses to glutamate
To test further whether Ca2+ responses were elicited by activating GluRs, we examined glutamate concentration-response relationships and pharmacological specificity. Ca2+ responses elicited by glutamate were concentration-dependent in the range from 30 µM to 1 mM (Fig. 8). At concentrations
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Figure 8. Ca2+ responses to glutamate are concentration-dependent. A, Peak amplitudes increased with increasing glutamate (glu) concentrations (from 30 µM to 1 mM). Traces from four different cells are superimposed and aligned at the initiation of the rising phase. B, Summary of concentration-response data for several experiments. Dotted line is the maximum
To examine desensitization of the glutamate receptors, we tested cyclothiazide, an AMPA receptor-specific blocker of desensitization. However, the application of cyclothiazide (10 µM) alone induced large changes in [Ca2+]i. An accurate characterization of GluRs in the presence of cyclothiazide thus was not possible, and we did not continue with these experiments.
Application of the non-NMDA receptor agonist kainate (30 µM, n = 9; Fig. 9A, Table 1) elicited responses that were similar to those obtained with glutamate. The responses to 30 µM kainate had a mean amplitude of 5.8% ± 1.3 (range from 3.8 to 10.9%) and showed a sharp peak, followed by a rapid recovery. All of the kainate-responsive cells also responded to glutamate, and most glutamate-responsive cells responded to kainate (83%, 5 of 6 cells). The AMPA receptor-specific agonist AMPA (30 µM), applied to cells that responded to kainate and glutamate (n = 4) as well as to other cells (n = 17), did not induce changes in [Ca2+]i. Last, NMDA (100 µM) stimulated increases in [Ca2+]i in 25% of taste cells (15 of 61) in a separate series of experiments when the bath medium was modified to optimize for NMDA receptor activation (Mg2+-free, 100 µM glycine; Table 1). Calcium responses elicited by NMDA usually were prolonged and had plateaus with a sustained amplitude (mean
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Figure 9. Taste cells responding to glutamate can be subdivided into NMDA-unresponsive and NMDA-responsive populations. A, B, Taste cells responded to kainate or to NMDA. Ca2+ responses to kainate (30 µM) were different from those to NMDA (100 µM with 100 µM glycine and 0 mM Mg2+). The response to kainate (A) was transient and recovered while kainate was still present. In another cell, NMDA induced a long-lasting response (B). C, Glutamate responses in NMDA-responsive cells were different from those in NMDA-unresponsive cells. NMDA-unresponsive cells (dark traces) showed large transient responses to glutamate (glu; 300 µM) compared with glutamate responses in NMDA-responsive cells (light traces). D, Normalized and averaged glutamate (300 µM) responses in NMDA-unresponsive cells (dark trace; n = 4 cells) and in NMDA-responsive cells (light trace; n = 4 cells). E, Glutamate responses in an NMDA-unresponsive cell were reversibly antagonized by the non-NMDA receptor antagonist CNQX (10 µM). CNQX was applied 5 min before and during stimulation with glutamate (glu; 300 µM). F, In an NMDA-responsive cell the glutamate responses (with 100 µM glycine and without Mg2+) were reversibly blocked by the NMDA receptor antagonist D-AP5 (50 µM).
Taste cells responding to glutamate under conditions favorable for NMDA receptor activation could be subdivided into NMDA-unresponsive (54%, 7 of 13 cells) and NMDA-responsive cells (46%, 6 of 13 cells; see Table 1). Responses to glutamate (300 µM) in NMDA-responsive cells were different from those of NMDA-unresponsive cells (Fig. 9C,D). Responses to glutamate of NMDA-unresponsive cells under these conditions were similar to those recorded in normal Tyrode's solution (sharp peak with a mean
The non-NMDA receptor antagonist CNQX (10 µM) reversibly abolished responses to glutamate (300 µM; 3 of 3 cells; Fig. 9E). Similar results were obtained with the structurally unrelated non-NMDA antagonist GYKI 52466 (10 µM; n = 3). Responses to NMDA and glutamate in NMDA-responsive cells could be reversibly blocked with the NMDA-specific antagonist D-AP5 (50 µM; n = 2 of 2 cells; Fig. 9F).
Collectively, these data suggest that there are at least two populations of glutamate-sensitive taste cells
DISCUSSION
We have developed a new preparation of rat taste buds and a new Ca2+-imaging approach that enables us to record the activation of neurotransmitter receptors in taste buds in situ. The principal finding in this report is that a population of taste cells expresses functional glutamate receptors (GluRs), especially on their cell bodies and basal processes. The concentration-response relations and pharmacological characterization of the responses to glutamate indicate that ionotropic GluRs (iGluRs), similar to synaptic iGluRs in the brain, are present in taste cells. Both NMDA- and non-NMDA-type GluRs were observed. Taste epithelium indeed expresses neuronal kainate and NMDA receptor subunits (Chaudhari et al., 1996
The present results are in agreement with our previous study that used glutamate-stimulated Co2+ uptake (Caicedo et al., 2000
Our studies reveal that non-NMDA iGluRs are present on taste cells. These receptors were activated by glutamate and kainate and were characterized by transient Ca2+ responses that declined even during the agonist application. The transient Ca2+ responses induced by kainate and glutamate in taste cells suggest that GluRs in taste cells desensitize rapidly, although other explanations are possible. In other tissues, kainate receptors, but not AMPA receptors, rapidly desensitize on exposure to kainate (Lerma et al., 1997
In addition, our results indicate that taste cells also express NMDA receptors. NMDA responses were prolonged and lasted the duration of agonist application. This may reflect a relative lack of receptor desensitization for NMDA receptors in taste buds, although other explanations are possible. Our results are consistent with the possibility that a population of taste cells expresses non-NMDA receptors and another population expresses NMDA receptors. Whether some taste cells express both NMDA and non-NMDA receptors remains a possibility.
In attempts to study glutamate as a taste stimulus, responses to glutamate, NMDA, and a metabotropic GluR agonist L-AP4 in isolated taste buds have been reported previously with Ca2+ imaging or patch-clamp recordings (Hayashi et al., 1996
Although we did not attempt to investigate Ca2+ mechanisms per se in taste cells, we can make some inferences from our results. In some cases the cells that responded to glutamate did not respond to KCl depolarization. This implies that these cells lack potassium channels, VGCCs, or both. Therefore, in these cells at least, the glutamate-induced Ca2+ responses resulted from Ca2+ entry through iGluRs. Alternatively, iGluRs also might interact with G-proteins, leading to activation of second messenger cascades and of intracellular Ca2+ release mechanisms, as has been described for kainate receptors (Rodriguez-Moreno and Lerma, 1998
Responses to glutamate are localized to synaptic regions
We were able to measure changes in [Ca2+]i in different compartments of taste cells. Responses to glutamate were localized to the basal processes and the cell bodies. We conclude that iGluRs are present at higher densities in the basal regions of taste cells. This preferential localization of iGluRs in the basal process and the cell bodies matches the distribution of synapses on murine taste cells (Kinnamon et al., 1985
Functional considerations
Glutamate receptors in taste cells might be presynaptic receptors (autoreceptors) at synapses between taste cells and sensory axons (Fig. 10). In this view, taste cells would release glutamate as a neurotransmitter to activate postsynaptic primary sensory axons. Primary gustatory neurons express GluRs (Caicedo et al., 1999
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Figure 10. Schematic drawings of the structure and putative synaptic connections of a taste bud. A, Fifty to 100 taste cells are grouped in a taste bud (only eight taste cells are shown). Taste receptor cells have apical processes that extend to and converge at the taste pore in the apical region. On their basal processes and cell bodies the taste cells form synaptic contacts with primary afferent fibers. B, Taste cells form synapses with primary sensory axons (a). Taste cells also may synapse with other taste cells within the taste buds (b). Furthermore, taste cells may receive efferent connections (c). The box shown in B is enlarged at the right (a, c). The GluRs reported in this study may function at each of these sites (see Discussion).
GluRs also might be postsynaptic receptors at efferent synapses between axons and taste cells (Fig. 10). Efferent synaptic regulation plays an important role in shaping incoming information in other sensory organs (e.g., cochlea). Efferent function of sensory neurons is well documented (for review, see Maggi, 1991
FOOTNOTES Received May 3, 2000; revised Aug. 17, 2000; accepted Aug. 17, 2000.
This work was supported by National Institutes of Health/National Institute on Deafness and Other Communication Disorders Grants 2 R01 DC00374 and 1P01 DC00244 (to S.D.R.).
Correspondence should be addressed to Dr. Alejandro Caicedo, Department of Physiology and Biophysics, University of Miami School of Medicine, P.O. Box 016430, Miami, FL 33101. E-mail: acaicedo{at}chroma.med.miami.edu.
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