J Physiol Volume 513, Number 3, 639-646, December 15, 1998
The Journal of Physiology (1998), 513.3, pp. 639-646
© Copyright 1998 The Physiological Society
Heterogeneity of homomeric GluR5 kainate receptor desensitization expressed in HEK293 cells
Geoffrey T. Swanson and Stephen F. Heinemann
Molecular Neurobiology Laboratory, The Salk Institute, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA
Received 7 September 1998; accepted after revision 28 October 1998.
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ABSTRACT |
- Kainate receptors with pharmacological properties similar to those of the GluR5 subunit have been shown to modulate inhibitory synaptic transmission in the CA1 region of the hippocampus. The kinetic properties of currents gated by GluR5 receptors have not been examined in detail. Here we describe several biophysical features of recombinant GluR5 receptors expressed in HEK293 cells.
- We found that homomeric GluR5 receptors can exhibit striking inter-cell variability in channel kinetics in response to the agonists kainate and glutamate. Desensitization rates in response to kainate varied between individual cells by nearly 1000-fold (range, 1·5 ms to 1·5 s), while glutamate desensitization rates differed by 9-fold (range, 1·0 to 9·0 ms).
- The time course of recovery from desensitization in response to glutamate also showed inter-cell variation. The majority of glutamate currents in GluR5-expressing cells recovered from desensitization with two widely separated exponential components: 50 ± 10 ms and 5·1 ± 1·0 s (contributing 37·6 % and 62·4 % of the sum of the exponential fits, respectively). In contrast, currents with the fastest desensitization kinetics had a recovery time course of 4·8 ± 0·3 s.
- Kainate receptors in murine dorsal root ganglion neurons are likely to be composed of homomeric GluR5 subunits. These receptor currents recovered from glutamate desensitization with a biexponential time course of 36 ± 4 ms and 4·7 ± 0·7 s.
- These results suggest that aspects of GluR5 kainate receptor function are modulated by intracellular mechanism(s). At synapses such mechanisms could regulate the frequency- response relationship of synaptic kainate receptors by altering their rate of entry into and recovery from desensitization.
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INTRODUCTION |
Kainate receptor subunits assemble to form a family of ionotropic glutamate receptors whose contribution to mammalian synaptic transmission has only recently begun to be understood (reviewed by Lerma, 1997). Evidence for synaptic kainate receptors has relied on the development of antagonists that selectively block AMPA receptors (Bleakman et al. 1996; Lerma, 1997), which are responsible for the fast-decaying current at the majority of excitatory synapses. Using GYKI 53655, an AMPA receptor-selective antagonist, kainate receptors were shown to underlie a slowly activating synaptic current observed at high stimulation frequencies in hippocampal CA3 pyramidal neurons (Castillo et al. 1997; Vignes & Collingridge, 1997). Also, pharmacological studies suggest GluR5 subunits contribute to kainate receptors that modulate inhibitory synaptic transmission to CA1 pyramidal neurons (Clarke et al. 1997; Rodriguez-Moreno et al. 1997) and participate in pain transmission in dorsal root ganglion neurons (Agrawal & Evans, 1986; Huettner, 1990).
One confusing issue arising from the recent descriptions of native kainate receptor currents in CA3 pyramidal neurons is the requirement for high-frequency stimulation. These synaptic receptors were proposed to incorporate the GluR6 subunit, because gene ablation of this subunit eliminated the CA3 kainate receptor synaptic current (Mulle et al. 1998). Recombinant GluR6 kainate receptors exhibit a particularly slow recovery from desensitization, in the order of 2 s (Heckmann et al. 1996; Traynelis & Wahl, 1997), and therefore seem ill-suited to respond to the stimulation frequencies of 30-200 Hz used to stimulate CA3 kainate receptors (Castillo et al. 1997; Vignes & Collingridge, 1997; Mulle et al. 1998). One possible explanation was that the activated kainate receptors were located perisynaptically and therefore relied on 'spillover' of glutamate from the synapse. This seemed unlikely because glutamate uptake blockers did not change the time course of the synaptic current decay (Castillo et al. 1997; Vignes & Collingridge, 1997). Other possibilities may account for the ability of these synaptic kainate receptors to follow high frequency stimulation: for example, native kainate receptors might have different kinetics from the recombinant receptors studied to date, or different kainate receptor subunit combinations may alter the receptor kinetics to allow faster recovery of the current. Indeed, a recent report presented pharmacological evidence that implicated GluR5-containing receptors in the generation of the CA3 synaptic current, a result seemingly at odds with that from the GluR6 knockout study (Vignes et al. 1997; Mulle et al. 1998).
We have examined the current kinetics of recombinant GluR5 receptors to determine if this channel exhibits properties distinct from GluR6 receptors. Desensitization kinetics for GluR5 receptor currents evoked by kainate, a high-affinity agonist, have been reported previously to be variable (Swanson et al. 1997). In this report, we analyse that variability in some detail, and find that many of the channel kinetic parameters, including the desensitization rate in response to glutamate, are significantly different between individual transfected cells. In addition, we demonstrate that GluR5 receptors can recover from glutamate-induced desensitization much faster than GluR6 receptors. Based on the properties of these recombinant receptors, we suggest that desensitization kinetics of native receptors containing the GluR5 subunit may be highly mutable, and may activate at significantly higher frequencies than have been described previously for other kainate receptors.
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METHODS |
HEK293 cells were maintained and calcium phosphate-transfected as described previously (Swanson et al. 1997). Between 0·5 and 1 µg of rat GluR5 cDNA and 0·2 µg human CD8 antigen cDNA were transfected per glass coverslip in 24-well dishes for 5-12 h at 37°C and 5 % CO2. We used the unedited (glutamine-containing) GluR5a isoform cDNA generously provided by Peter Seeburg (Max Planck Institute for Medical Research, Heidelberg, Germany). Electrophysiological recordings were made 2-3 days after transfection. Coverslips were incubated with polystyrene beads coated with anti-CD8 antibody (Dynal Inc., Lake Success, NY, USA) before transferring them to the recording bath chamber. Patch clamp recordings were made as described in Swanson et al. (1997). The internal solution was composed of (mM): 110 CsF, 30 CsCl, 4 NaCl, 0·5 CaCl2, 10 Hepes and 5 EGTA (adjusted to pH 7·3 with CsOH). The external bath solution contained (mM): 150 NaCl, 2·8 KCl, 2 CaCl2, 1·0 MgCl2 and 10 Hepes (adjusted to pH 7·3 with NaOH). The fast application system used in this study was described previously (Swanson et al. 1997). Transfected HEK293 cells were lifted from the coverslip to facilitate rapid solution exchange. Data were acquired directly to a computer and were analysed off-line using fitting routines contained in pCLAMP software (Axon Instruments). L-Glutamate was purchased from Sigma; kainate was from Tocris.
For preparation of dissociated dorsal root ganglion neurons, mice between the ages of E17 and P7 were rapidly decapitated and the spines were transferred to 10 mM Hepes-buffered saline solution. Dorsal root ganglia were removed after bisection of the spinal column and removal of the spinal cord. Ganglia were incubated in 20 units ml-1 papain in Hepes-buffered saline solution with 1 mM CaCl2 and 0·5 mM EDTA. Ganglia were washed twice in culture media identical to those used to grow the HEK293 cells and triturated with a flame-polished glass pipette. Dissociated neurons were plated on poly-D-lysine/collagen-coated glass coverslips and allowed to recover for 4-6 h in a 37°C incubator with 5 % CO2. Electrophysiological recording was performed as described for the transfected HEK293 cells.
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RESULTS |
Currents mediated by homomeric GluR5 receptors exhibited marked variability in desensitization rates between individual transfected HEK293 cells (Fig. 1, and see Fig. 1 in Swanson et al. 1997). Responses to 1 s applications of kainate (1 mM) in different cells had widely varying desensitization time courses (Fig. 1, left column). To facilitate comparison of channel kinetic properties, and to determine whether variable kinetics were correlated across cells, we assigned each responding cell to one of three categories depending on their time course of desensitization in response to kainate (Fig. 1 and Table 1). 'Slow' (S-type) cells had a slowly desensitizing time course that was fitted to a single exponential component with a desensitizing time constant (
des) of 548 ± 61 ms (mean ± S.E.M., n = 24 cells). 'Intermediate' (I-type) cells had both a fast ( < 100 ms) and a slow component (
300 ms) to their desensitization, and the slower desensitizing component dominated the current decay (n = 5). 'Fast' (F-type) cells had a double exponential time course of desensitization with the faster being predominant: des,fast = 2·4 ± 0·2 ms and des,slow = 131 ± 51 (84·9 % and 15·1 %, respectively, S.E.M. 3·6 %; n = 9). The majority of cells tested, 63·2 %, were of the S-type, while 23·7 % were of the F-type (38 cells in total). Variations in the rates of kainate current desensitization were recorded within a batch of expressing cells from a single transfection, as well as between cells from separate transfections. Table 1 summarizes the measured kinetic parameters from S- and F-type responses.
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Figure 1. Heterogeneity of GluR5 receptor responses
A, representative kainate (left panel) and glutamate (right panel) responses from a slowly desensitizing S-type GluR5 receptor expressed in an HEK293 cell. B, representative responses from a GluR5-expressing cell exhibiting intermediate (I-type) desensitization kinetics. C, representative responses from a fast desensitizing F-type GluR5 receptor response in an HEK293 cell. Kainate (1 mM) applications marked by the bar were for 1 s; glutamate (10 mM) was applied for 100 ms. The holding potential was -70 mV in all recordings. The calibration bars are: x-axis, 600 ms (kainate) and 40 ms (glutamate); y-axis, 160 pA (top panel), 200 pA (middle panel) and 300 pA (bottom panel).
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Table 1. Kinetics of GluR5 receptor responses exhibiting S- or F-type properties
| Glutamate | Kainate |
| S-type | F-type | S-type | F-type |
| Rise time (ms) | 1·26 ± 0·10 | 0·85 ± 0·10 | 8·7 ± 1·7 | 1·3 ± 0·10 |
| Peak current (pA) | 262 ± 39 | 1012 ± 278 | 201 ± 28 | 368 ± 96 |
| Desensitization (%) | 96·2 ± 0·8 | 99·0 ± 0·3 | 73·9 ± 2·1 | 93·9 ± 1·7 |
| des,fast (ms) | 5·1 ± 0·3 | 1·6 ± 0·2 | - | 2·4 ± 0·2 |
| | | | (84·9 ± 3·6 %) |
| des,slow (ms) | - | - | 548 ± 61 | 131 ± 51 |
| | | | (15·1 ± 3·6 %) |
| rec,fast (ms) | 0·05 ± 0·01 | - | - | - |
| (37·6 ± 3·5 %) |
| rec,slow (s) | 5·1 ± 1·0 | 4·8 ± 0·3 | - | - |
| (62·4 ± 3·5 %) |
| Number of cells | 24 | 9 | 24 | 9 |
Summary of measured kinetic parameters for GluR5 kainate receptor responses expressed in HEK293 cells. Responses were categorized as either slow (S-type) or fast (F-type) according to the kinetics of their response to kainate as described in the text. The kainate desensitization rates for S-type responses were taken from the initial application after patch formation to avoid problems of interpretation introduced by time-dependent increases in desensitization rates. The percentage desensitization in response to kainate was measured at the end of the 1 s application. The percentage contributions for each exponential component to the multi-exponential time course are given in parentheses below the mean ± S.E.M.
A subset of S-type responses showed a time-dependent increase in the rate of desensitization (Fig. 2A). In the example shown, at 1 min after whole-cell patch formation the des of the single fitted exponential was 446 ms, which decreased to 286 ms after 10 min. Since the increased desensitization was not observed for all kainate responses, and proceeded to different degrees in different cells, we did not attempt to characterize the change quantitatively. In those responses that did show an increasing desensitization rate, a fast desensitizing component similar to that seen in I-type or F-type cells was often observed (Fig. 2B). These results suggest that the time-dependent increase and the inter-cell variability in desensitization may arise from a common mechanism of intracellular modulation of the kainate receptor function, although S-type responses never exhibited more than a minor fast desensitizing component after an extended recording time.
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Figure 2. Time-dependent increase in kainate receptor desensitization
A, an example of a slowly desensitizing GluR5 kainate receptor response whose rate of desensitization increased with time of recording. Two responses were averaged to produce the traces shown. The response at 10 min after initiation of whole-cell patch clamp was normalized to the initial response. Kainate (1 mM) was applied for 1 s. B, an expanded view of the initial portion of the responses shown in A. Note that the response at 10 min had a fast desensitizing component that was absent in the initial response.
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The type of desensitization observed upon application of kainate - S- or F-type - correlated with the glutamate desensitization rate (Fig. 1, right column). In cells where both agonists were tested, S- and F-type cells had slowly and rapidly desensitizing responses, respectively, to 100 ms applications of 10 mM glutamate: des,fast = 1·6 ± 0·2 ms (n = 9); des,slow = 5·1 ± 0·3 ms (n = 24, P < 0·01, Student's unpaired t test; Fig. 3A). The glutamate desensitization rate in different cells ranged from 1·0 to 9·0 ms. This variability in GluR5 desensitization rates is similar in range to that reported previously for glutamate desensitization of homomeric GluR6 receptors expressed in HEK293 cells (Bufler et al. 1997). Unlike GluR6, however, GluR5 des values were not normally distributed, but rather showed two preferred states that corresponded to our categorization of F- and S-type responses (Fig. 3B).
S- and F-type responses also exhibited correlated differences in other channel properties (summarized in Table 1). The peak amplitudes of the glutamate currents in the two types of cells were significantly different: 1012 ± 278 pA for F- and 262 ± 39 pA for S-type cells (P < 0·05). Also, currents activated by glutamate had a 10-90 % rise time of 0·85 ± 0·10 ms in F-type cells as compared with 1·26 ± 0·10 ms in S-type cells (ranges, 0·5-1·4 ms and 0·7-2·6 ms, respectively; P < 0·05; Fig. 3A). Because of the very rapid rise time of the currents, this kinetic parameter is particularly sensitive to introduced artifacts such as variability in application speed between cells as well as differences in series resistance and cell capacitance. We can rule out the latter as possible sources of error because the rise time of S- and F-type currents did not correlate with either series resistance (S-type, 12·9 ± 0·9 M
; F-type, 11·2 ± 1·1 M; R = 0·31) or cell capacitance (S-type, 7·7 ± 0·5 pF; F-type, 6·8 ± 0·6 pF; R = 0·19). While sub-optimal application speeds for a subset of cells is difficult to rule out post hoc, the correlation between rapid rise-times and the desensitization and recovery rates, which are not limited by the application speed under our recording conditions, suggests that this is not a significant source of error with respect to the difference in rise times. Thus, these data suggest that GluR5 receptors expressed in HEK293 cells exist in two kinetic modes differentiated by multiple aspects of their kinetic response to different agonists.
The time course of recovery of GluR5 kainate receptors from glutamate desensitization was also heterogeneous. Recovery from a 100 ms application of glutamate was measured by varying the interval between a control and test response. Surprisingly, we found that cells expressing S-type responses had glutamate currents that recovered with two widely separated exponential components of 50 ± 10 ms and 5·1 ± 1·0 s, comprising 37·6 % and 62·4 % of the recovery time course, respectively (S.E.M. 3·5 %, n = 6; Fig. 4A and D). In contrast, F-type responses recovered with only a single exponential component that had a time course similar to the slower component in S-type responses: 4·8 ± 0·3 s (n = 5; Fig. 4B and D). Thus, in the S-type mode, GluR5 kainate receptors recover from desensitization with a time course that is significantly faster than that of GluR6 kainate receptors.
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Figure 4. Recovery from desensitization for S- and F-type GluR5 and DRG kainate receptor responses
A, recovery from desensitization induced by glutamate for an S-type cell. The test currents shown on the right were evoked at varying intervals after an initial control glutamate current. Note that nearly 50 % of the initial peak current is evoked by a test application after a 100 ms interval. B, recovery from desensitization induced by glutamate for an F-type cell. The test current at 100 ms was negligible. C, recovery from desensitization induced by glutamate in a DRG neuron acutely dissociated from an E17 mouse. As with the S-type GluR5 response, a substantial peak current was evoked after an interval of 100 ms. All glutamate (10 mM) applications were for 100 ms. D, representative time courses of recovery from desensitization induced by application of 10 mM glutamate for S- and F-type GluR5 and DRG kainate receptor responses. Data from S-type GluR5 ( , continuous line) and DRG ( , dotted line) glutamate responses were fitted with two exponential components with time constants of 47 ms and 4·4 s (S-type GluR5) and 33 ms and 5·5 s (DRG); the F-type GluR5 time course ( , dashed line) was fitted with a single exponential with a time constant of 4·8 s. The calibration bars are: x-axis, 25 ms; y-axis, 140 pA (A and B) and 70 pA (C).
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In order to determine which kinetic mode, S- or F-type, more accurately reflects the behaviour of native GluR5 receptors, we analysed kainate receptor currents in dorsal root ganglion (DRG) neurons. It is known from previous studies that kainate receptors in DRG neurons are composed predominantly of homomeric GluR5 subunits (Huettner, 1990; Sommer et al. 1992; Partin et al. 1993; Swanson et al. 1996, 1998). Accordingly, we measured the rate of recovery from glutamate-induced desensitization in acutely isolated mouse DRG neurons to determine which type of response from a native receptor most closely resembled that from recombinant GluR5 receptors (Fig. 4C and D). As shown in the figure, glutamate currents in DRG neurons had a biexponential time course of recovery from desensitization similar to that observed with S-type recombinant GluR5 receptors. In these neurons, the mean rec,fast was 36 ± 4 ms and the rec,slow was 4·7 ± 0·7 s (25·3 and 74·7 % of the sum of the fitted exponentials, respectively, n = 3). These data, and those reported previously (Huettner, 1990; Swanson et al. 1996, 1998), suggest that the kinetic properties of the DRG kainate receptor are mirrored by a subset of homomeric recombinant GluR5 receptor.
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DISCUSSION |
We have shown that GluR5 receptors can exhibit at least two distinct modes of channel gating in response to activation by glutamate and kainate. The two kinetic profiles of the receptor have strikingly dissimilar activation, desensitization and resensitization properties. Since the ratio of the peak current amplitudes activated by these agonists was significantly different (Table 1), it is also likely that the probability of channel opening in response to either kainate or glutamate (or both) is distinct in the S-type and F-type responses. While not characterized extensively, our observation that desensitization rates increase with recording time may be important if it defines the source of the kinetic variability as intracellular (as opposed to, for example, intercellular differences in the degree of N-glycosylation). The time dependency of the desensitization rate is similar to that observed with glycine-independent desensitization of NMDA receptors (McBain & Mayer, 1994). The latter arises from intracellular mechanisms, since it is sensitive to intracellular calcium and calcineurin inhibitors (Tong & Jahr, 1994). The GluR5a subunit used in this study has a relatively short carboxy-terminal domain with a single consensus site for serine phosphorylation, and phosphorylation-dependent alterations in GluR5 channel kinetics have not been reported.
Intracellular mechanisms similar to those that produce S- and F-type GluR5 receptors could play an important role in determining the frequency of activation of synaptic kainate receptors by affecting their recovery from desensitization. Desensitization of neuronal AMPA receptors has been shown to proceed even after brief (1 ms) applications of glutamate (Raman & Trussell, 1995; Angulo et al. 1997). Thus, even when the activation of a glutamate receptor is terminated by deactivation (i.e. removal of glutamate) rather than desensitization, the receptor follows a time course of re-activation determined by the rate of recovery from desensitization. The slow recovery from desensitization has been considered to be one channel property that distinguishes kainate from AMPA receptors, which recover from glutamate application with a much faster time course of tens to hundreds of milliseconds (e.g. Trussell & Fischbach, 1989; Lomeli et al. 1994). Kainate receptors in cultured hippocampal neurons, as well as recombinant GluR6 kainate receptors, have a time course of recovery in the order of seconds, similar to that observed for GluR5 receptors in the F-type kinetic mode in this report (Heckmann et al. 1996; Traynelis & Wahl, 1997; Wilding & Huettner, 1997). However, our observation that DRG kainate receptors can partially re-activate with a relatively rapid time course indicates that the time course of recovery of desensitization cannot be used to unequivocally differentiate native AMPA and kainate receptors.
The recent development of AMPA receptor-selective antagonists, GluR5-selective pharmacological compounds, and kainate receptor knockout mice has contributed to an increased understanding of the role played by kainate receptors in synaptic transmission. Nevertheless, even in hippocampal neurons, where much of the effort has been focused, controversy exists as to the physiological function and subunit makeup of native kainate receptors. In CA3 neurons, high-frequency stimulation of mossy fibre afferents revealed a postsynaptic current mediated by a GluR6-containing kainate receptor (Castillo et al. 1997; Vignes & Collingridge, 1997; Mulle et al. 1998); this result was somewhat surprising given the consistently slow recovery from desensitization exhibited by native and recombinant GluR6-containing receptors (Heckmann et al. 1996; Traynelis & Wahl, 1997; Wilding & Huettner, 1997). Our observation that S-type mode GluR5 kainate receptors have the potential to respond to relatively high frequencies of stimulation, producing 20 % of the initial peak response at activation frequencies of up to 30 Hz, is intriguing in the light of a recent pharmacological study of the kainate current at the CA3 synapse. This study provided evidence for the participation of GluR5-containing receptors in the synaptic and whole-cell kainate receptor currents in these neurons (Vignes et al. 1997). One possible interpretation that accounts for both sets of observations in CA3 neurons is the existence of receptors assembled from both GluR5 and GluR6 subunits. These neuronal receptors could have GluR5 pharmacology and kinetics, and contain the GluR6 subunit as a critical and necessary component of the receptor channel. It is clear that despite recent progress, much remains to be learned about the participation of kainate receptors in neuronal physiology.
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Acknowledgements
The authors would like to thank Peter Seeburg for the GluR5-2a cDNA and Brian Seed for the CD8 cDNA. We also thank Anis Contractor, Andrea Ghetti and Tim Green for critical reading of the manuscript, and Quynh-Chi Phan for technical assistance. This work was supported by an NRSA fellowship (#1 F32 GM 18717-01) to G. T. S., a National Institute for Neurological Diseases and Stroke grant (#2 RO1 NS 28709-06) to S. F. H. and a McKnight Endowment Fund for Neuroscience grant to S. F. H.
Corresponding author
G. T. Swanson: Molecular Neurobiology Laboratory, The Salk Institute, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
Email: swanson{at}salk.edu
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Top
Introduction
) and rapidly desensitizing (F-type, 
