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MS 8846 Received 12 October 1998; accepted after revision 25 January 1999.
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ABSTRACT |
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 TopAbstract IntroductionMethodsResultsDiscussionReferences |
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INTRODUCTION |
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Metabotropic GABA (GABAB) receptors play key roles in synaptic transmission throughout the nervous system, regulating functions as diverse as muscle tone and long term potentiation (Getova et al. 1997). Two GABAB receptor mechanisms of action have been described, both inhibitory: calcium channel suppression and potassium channel activation (Misgeld et al. 1995). These mechanisms explain GABAB receptor suppression of synaptic transmission. Paradoxically, GABAB receptors sometimes increase synaptic efficacy rather than diminish it. For example, Brenowitz et al. (1998) found that presynaptic GABAB receptors in auditory nerve fibres increased synaptic signals when a high frequency stimulus protocol was employed. In the retina, GABAB receptors mediate an enhancement in fast EPSPs in amacrine and ganglion cells (Bai & Slaughter, 1989). These effects are not consistent with a purely inhibitory mechanism of action.
Baclofen, a GABA analogue containing a chlorinated phenol ring, has become the prototypical agonist for the GABAB receptor (Bowery et al. 1980). As in many other neurons, retinal ganglion cells possess baclofen-sensitive GABAB receptors that suppress N-type calcium channels (Zhang et al. 1997). However, in isolated ganglion cells the affinity of the GABAB receptor mediating this response is reduced (Shen & Slaughter, 1997). Under these conditions, a facilitatory GABAB receptor effect was unmasked. The facilitatory effect may be mediated by a discrete baclofen-sensitive GABAB receptor since it acts through a different second messenger pathway and has a distinct pharmacology. This action may explain the increase in synaptic strength that is sometimes associated with baclofen.
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METHODS |
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The preparation used in all experiments was the freshly dissociated retina of the tiger salamander (Ambystoma tigrinum). Procedures used were in accordance with the guidelines of the National Institutes of Health and the University Animal Care Center. The animal was stunned, decapitated and double-pithed. The eye was removed. The retina was isolated and treated with papain-containing Ringer solution at 22°C for 45-60 min (12 U ml-1 papain; Worthington Biochemicals). The retina was then triturated in calcium-free Ringer solution and the isolated cells were fixed to lectin-coated glass coverslips. The cells were maintained in a 17°C incubator. Experiments were performed within a few hours after the dissociation procedure.
Neurons were voltage clamped using the whole-cell recording method. Low resistance electrodes (< 5 M
) were filled with (mM): 106 potassium gluconate, 5 NaCl, 2 MgCl2, 5 EGTA, 4 ATP, 20 phosphocreatine, 50 U ml-1 creatine phosphokinase, and 5 Hepes, buffered to pH 7·4 with KOH. Recordings were made with a List EPC-9 amplifier controlled by a Macintosh Quadra computer running HEKA Pulse software. Analog signals were filtered at 5 kHz. Leak subtraction was not utilized and access resistance (6-12 M) was monitored but not compensated.
Under control conditions, the cells were superfused with oxygenated Ringer solution containing (mM): 111 NaCl, 2·5 KCl, 1·8 CaCl2, 1 MgCl2, 10 dextrose, and 5 Hepes, buffered to pH 7·8 with HCl. After a whole-cell recording had been obtained and a voltage clamp protocol had been used to establish the types of voltage-sensitive channel present, the Ringer solution was changed to one containing 10 mM BaCl2 and 40 mM TEA-Cl, in equimolar replacement of some of the NaCl and all of the CaCl2. TTX (1 µM) was added to block sodium channels. Cells with large voltage-activated sodium currents were selected for study. This criterion excluded second-order neurons and biased the study towards ganglion cells, although some amacrine cells might have been included.
Baclofen, nifedipine, protein kinase C 19-36 fragment (PKC (19-36)), GF-109203x, RP-cyclic AMP (Rp-cAMP), 3-aminopropyl-(methyl)phosphinic acid dihydrochloride (APMPA), picrotoxin, staurosporine and 1-(5-isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride (H-7) were obtained from Research Biochemicals International. GDP
S and 
-conotoxin GVIA were purchased from Sigma. CGP35348 and CGP55845 were gifts from Dr W. Fröestl, Novartis Pharma AG, Basel, Switzerland. All drugs were dissolved in Ringer solution directly, except for nifedipine and GF-109203x, which were dissolved in DMSO and then diluted in Ringer solution to their final concentration. The final concentration of DMSO was less than 0·01 %. This concentration of DMSO was tested alone and had no apparent effects in our experiments.
Both voltage ramps and steps were used to evoke currents through high-voltage-activated calcium channels. In these experiments the currents were carried by barium ions and therefore are referred to as IBa,HVA. These currents were blocked by 50 µM cadmium. Cumulative data are expressed as means ± S.E.M. (n, number of neurons). Details of this methodology have been described previously (Shen & Slaughter, 1998).
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RESULTS |
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Previous studies in ganglion cells in the salamander retinal slice preparation demonstrated that baclofen suppressed -conotoxin GVIA-sensitive, high-voltage-activated calcium currents (Zhang et al. 1997). Similar observations were made in isolated neurons from the salamander retina, but higher concentrations of baclofen were required (Shen & Slaughter, 1997). Because the GABAB receptor linked to the N-type calcium channel was less sensitive to baclofen, it was possible to detect another action of baclofen that enhanced calcium channel current. A voltage-activated calcium channel current, IBa,HVA, was isolated as described in Methods. This current was blocked by 50 µM cadmium, a calcium channel blocker (Fig. 1A). As illustrated in Fig. 1B and C, IBa,HVA was elicited with either a ramp (-40 to +50 mV in 50 ms) or a single step from -70 to +10 mV. Although application of 300 µM baclofen suppressed this inward current (Fig. 1B), application of 500 nM baclofen enhanced the current (Fig. 1C). The peak of the enhanced current elicited by the ramp was not shifted along the voltage axis and the rise time of the current evoked by the voltage step was similar to that of the control trace. This contrasts with the effects of 300 µM baclofen, which reduced IBa,HVA, shifted the peak current to more positive voltages, and slowed the rise time of the step response (Zhang et al. 1997). While the inhibitory effect of baclofen was observed in each cell tested, the facilitatory effect was not always observed. In experiments on 98 neurons, 500 nM baclofen enhanced the inward current by more than 5 % in 42 cells, by less than 5 % in 35 cells, and had no apparent effect on 21 cells. We arbitrarily set a criterion response of > 5 %, concluding that only 43 % of the cells showed a facilitatory response. The mean facilitation in those 42 cells was 16 ± 4 %. The facilitatory effect was reversible, but recovery after removal of baclofen was slower than recovery from the inhibitory effect. Application of GABA (1 µM) duplicated the effects of 500 nM baclofen if the ionotropic GABA receptors were blocked by the addition of 100 µM picrotoxin (Fig. 1D). This was examined in 11 cells, of which five showed a criterion response, with a mean facilitation of 16 ± 3 %.
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Calcium channel currents were isolated by external application of TTX, barium and TEA. A, inward currents elicited in a cell under control conditions and in the presence of 50 µM external cadmium, a calcium channel blocker. B, inward currents produced by ramp and step protocols under control conditions (continuous trace) and after application of 300 µM baclofen (interrupted trace). C, effect of 500 nM baclofen, using the protocol in B. D, inward currents produced by a single voltage step from -70 to +10 mV under control conditions (continuous trace) or in the presence of 1 µM GABA and 100 µM picrotoxin, a blocker of ionotropic GABA receptor currents. The holding potential was -70 mV. Ramps were from -40 to +50 or +60 mV in 50 ms, steps were 30 ms in duration from -70 to 0 or +10 mV, except in A where a series of steps ranged from -30 to +40 mV in 10 mV increments. | ||
The facilitatory and inhibitory effects of baclofen could be observed in the same cell. In the neuron shown in Fig. 2A, 200 nM baclofen increased the inward current while 300 µM baclofen suppressed it. Two common observations were that facilitatory effects had a slower onset and smaller amplitude, compared with inhibitory effects. Similar experiments were performed on five cells to generate dose-response curves (Fig. 2B). Nanomolar concentrations of baclofen increased IBa,HVA. A maximal enhancement was observed near 500 nM baclofen. Higher baclofen concentrations produced less enhancement and above 1 µM began to suppress the inward current relative to control. This suggests that both facilitatory and inhibitory effects balance out at around 1-10 µM baclofen. On the basis of these data we will refer to facilitatory and inhibitory GABAB receptor responses.
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A, 200 nM baclofen increased inward current but 300 µM baclofen reduced inward current. The inward current was monitored with a 30 ms step to +10 mV given every 10 s ( | ||
The inhibitory GABAB receptor response acts to suppress -conotoxin GVIA-sensitive, putative N-type calcium channels (Zhang et al. 1997). The facilitatory response was not altered by this toxin (data not shown) but was blocked by dihydropyridines. The effects of nifedipine on both inhibitory and facilitatory responses are shown in Fig. 3. Voltage steps from -70 to +10 mV elicited inward currents. IBa,HVA was enhanced after application of 500 nM baclofen (Fig. 3A). Baclofen was then removed and the cell was treated with 25 µM nifedipine, which reduced the inward current. Nifedipine occluded the effect of reapplied baclofen. There was a slight effect of 500 nM baclofen during the initial rising phase of IBa,HVA. This may represent a small effect of baclofen on the inhibitory GABAB receptor, but this phenomenon was not examined. The action of nifedipine on the facilitatory response contrasts with the inconsequential influence of dihydropyridines on the inhibitory response (Fig. 3B). A high concentration of baclofen suppressed IBa,HVA. After recovery, 25 µM nifedipine was applied. This caused a reduction in the inward current but 300 µM baclofen, in the presence of nifedipine, still reduced IBa,HVA. These results indicate that facilitatory and inhibitory GABAB receptor responses affected different types of calcium channel.
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A, control inward current was evoked by a step to +10 mV, then 500 nM baclofen was applied. Baclofen was removed and after recovery nifedipine was applied. Baclofen was then applied in the presence of nifedipine. B, a similar experiment was performed using 300 µM baclofen. | ||
The inhibitory GABAB receptor action in retinal ganglion cells is removed by a strong depolarizing prepulse (Zhang et al. 1997), a characteristic of direct, G-protein-mediated responses (Hille, 1994). In contrast, a depolarizing prepulse did not suppress the facilitatory response. This difference is illustrated by the protocol in Fig. 4A. IBa,HVA was evoked by a 30 ms step from -70 to +10 mV, and then again by a step to +10 mV after a 100 ms conditioning prepulse to +100 mV. Under control conditions the inward currents were similar in amplitude before and after the prepulse. In the presence of 100 µM baclofen the inward current was suppressed in the first step, but was similar to control levels after the prepulse. This prepulse sensitivity is probably the result of a voltage-sensitive binding of a G-protein to the calcium channel (Campbell et al. 1995; Dolphin, 1998). When 500 nM baclofen was applied, it enhanced the inward current before and after the prepulse. This experiment suggests that the inhibitory GABAB receptor response was mediated by a direct G-protein interaction with the N-type calcium channel while the facilitatory GABAB receptor response was mediated by a more circuitous second messenger cascade. This would be consistent with the slower time course of the facilitatory response noted in Fig. 2. Evidence that the facilitatory response was G-protein mediated was provided by the consistent block of facilitation (n = 6) when GDPS was included in the recording pipette (Fig. 4B). Previous results indicated that GDPS blocked the inhibitory response (Zhang et al. 1997).
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S
A, inward current was elicited by a step to +10 mV, either from a holding potential of -70 mV (left) or after a prepulse to +100 mV (right). The same voltage protocol was repeated in the presence of 500 nM baclofen and 100 µM baclofen. B, a neuron was dialysed with 1 mM GDP | ||
Broad-spectrum kinase inhibitors were employed as a first step in determining the second messenger pathway of the facilitatory response. Both staurosporine and H-7 suppressed the facilitatory GABAB receptor response (data not shown). Therefore, specific inhibitors of the protein kinase A (PKA) and C pathways were tested (Fig. 5). Rp-cAMP, a PKA inhibitor, produced a modest suppression of facilitation. Since this antagonist was included in the pipette solution, results were compared with a different set of control cells. Under control conditions 500 nM baclofen produced a 16 ± 4 % enhancement in IBa,HVA, while in the presence of Rp-cAMP the enhancement was 7 ± 2 %. The actions of PKC inhibitors were greater. IBa,HVA was augmented by only 0·7 ± 0·7 % by 500 nM baclofen when the PKC inhibitory subunit, PKC (19-36), was included in the pipette. When the antagonist GF-109203x was present, the augmentation produced by 500 nM baclofen was 1·3 ± 0·6 %. This suggests that PKC plays an essential role in mediating the facilitatory baclofen response.
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Neurons were treated with GF-109203x or PKC (19-36) subunit (both PKC antagonists) or Rp-cAMP (a PKA antagonist). The peak inward current was then measured before and during application of 500 nM baclofen. The histogram plots the current in the presence of baclofen relative to the control current. Rp-cAMP (50 µM) and PKC (19-36) (2 µM) were added to the pipette and dialysed into the cell. GF-109203x (1 µM) was superfused on the cell before and during application of baclofen. Control is the effect of baclofen in the absence of inhibitors. | ||
In another approach to compare the facilitatory and inhibitory GABAB receptor responses, their pharmacology was examined. The inhibitory response could be activated by APMPA, which is a potent agonist at the GABAB receptor. APMPA was more efficacious than baclofen in retina (G. Awatramani & M. M. Slaughter, personal communication). This was not true for the facilitatory response, where baclofen was more effective (Fig. 6A and B). In tests on 18 neurons, 500 nM baclofen increased IBa,HVA by 18 ± 5 %, while 500 nM APMPA increased this current by 8 ± 2 % (Fig. 6B). Since APMPA is a potent agonist for the inhibitory response, it is possible that 500 nM APMPA produced as large a facilitatory response as baclofen, but that the facilitation was masked by a concomitant inhibitory response. To test this possibility, the effects of baclofen, APMPA, and APMPA in the presence of nifedipine were compared in 14 cells. Results for a single cell and cumulative data are shown in Fig. 6C and D, respectively. Overall, 500 nM APMPA facilitated the current by 8 ± 1 %, compared with the baclofen-induced facilitation of 17 ± 4 %. However, when L-type channels were blocked by 30 µM nifedipine, 500 nM APMPA had little effect on the remaining calcium channel current. Nifedipine alone suppressed the inward current by 34 ± 4 %; APMPA plus nifedipine reduced the current by 36 ± 4 %. The difference between the facilitatory effects of baclofen and APMPA was statistically significant (P < 0·01, Student's t test), but the difference between nifedipine alone and nifedipine plus APMPA was not significant (Student's t test and Wilcoxon signed-rank test). This indicates that 500 nM APMPA did not suppress a significant amount of the N-type current in these isolated neurons, and confirms that APMPA was less effective than baclofen on the facilitatory response.
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A, IBa,HVA was measured by stepping a neuron from -70 to +10 mV under control conditions, in the presence of 500 nM baclofen, or in the presence of 500 nM APMPA. B, histogram of the responses from 18 neurons using the protocol in A. The increase in peak current was relative to control. C shows, in a single cell, the inward current elicited as in A. The effects of 500 nM baclofen and 500 nM APMPA were compared. Nifedipine was then applied and the effect of APMPA was tested in the presence of nifedipine. D, cumulative data were collected using the protocol in C, although the full set of variables could not be tested in every cell. | ||
Similarly, antagonists that produced a near complete block of the inhibitory response were less effective on the facilitatory response. We found that 1 mM CGP35348 and 100 µM CGP55845 were very effective in blocking the inhibitory GABAB receptor response (Zhang et al. 1997). However, neither fully blocked the facilitatory response to 500 nM baclofen (Fig. 7A). When the effect of 500 nM baclofen was tested on the same cells before and during treatment with 1 mM CGP35348, the antagonist only suppressed 33 % of the response (n = 18). Similarly, 100 µM CGP55845 blocked 64 % of the facilitatory response (n = 10). A further test of the preferential activity of these antagonists was to use them in combination with a high concentration of baclofen. Normally, 100 µM baclofen produced a suppression of IBa,HVA (e.g. Fig. 4). However, in the presence of CGP35348, 100 µM baclofen caused an enhancement of IBa,HVA (Fig. 7B). This is consistent with 100 µM baclofen producing a concomitant facilitation and inhibition. Usually 100 µM baclofen only appeared to produce inhibition because the total current suppressed (in excess of 35 %) overwhelmed the total current enhanced (approximately 15 %).
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A, histogram of the change in IBa,HVA (relative to control) resulting from application of 500 nM baclofen before and during treatment with CGP35348 (1 mM) or CGP55845 (100 µM). B, IBa,HVA was evoked by a step from -70 to +10 mV under control conditions, with 1 mM CGP35348 (Control and CGP35348 traces are superimposed), or with 100 µM baclofen in the presence of 1 mM CGP35348 (interrupted trace). | ||
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DISCUSSION |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The facilitatory GABAB receptor response
These experiments indicate that a GABAB receptor with relatively high affinity serves to enhance current through L-type calcium channels. This response is G-protein mediated and requires activation of a protein kinase pathway. Potent agonists and antagonists of the inhibitory GABAB receptor response are less effective on the facilitatory response. The different second messenger pathways and pharmacology of the inhibitory and facilitatory GABAB receptor responses suggest that two baclofen-sensitive metabotropic GABA receptors coexist in retinal ganglion cells. This adds to a surfeit of GABA receptors that have already been identified in amphibian retinal ganglion cells. The list includes the ionotropic GABAA and GABAC receptors plus two metabotropic GABAB receptors that are sensitive to baclofen and another that is selectively activated by cis -aminocrotonic acid (Zhang & Slaughter, 1995; Zhang et al. 1997).
In this study the facilitatory baclofen-sensitive receptor was easily identified because the inhibitory action of baclofen was not evident until micromolar baclofen concentrations were used. This distinction is artificial and results from a reduced affinity of the receptor mediating the inhibitory effect. We have found that the inhibitory action of baclofen required 10- to 100-fold higher concentrations in isolated cells in culture compared with neurons in situ, either in tissue slice or intact retina (Shen & Slaughter, 1997). Nevertheless, while this phenomenon simplified studies on the facilitatory GABAB receptor, it does not imply that the two metabotropic GABA receptors have widely differing affinities under normal conditions.
This is the first demonstration of a direct facilitatory action produced by GABAB receptors. There is a report demonstrating rebound facilitation of high-voltage-activated calcium current when baclofen was removed (Fujikawa et al. 1997). During baclofen application calcium current was suppressed. This rebound effect was also PKC sensitive and may represent the same phenomenon described in this paper if one assumes that the inhibitory response recovered quickly, leaving only the facilitatory action. There is also a report demonstrating that baclofen, acting through a nifedipine-sensitive pathway, can increase the internal calcium concentration in chromaffin cells. This may be another example of GABAB receptor-mediated calcium channel facilitation (Parramon et al. 1995).
Baclofen-sensitive metabotropic GABA receptors
The relative effectiveness of a few GABAB receptor agonists and antagonists suggests that the inhibitory and facilitatory actions of baclofen are mediated by different receptors. However, there are no generally accepted standards by which to distinguish GABAB receptor subtypes. Two GABAB receptors have been cloned. They differ in their N-terminal domains, the putative region of ligand binding, but their pharmacology is indistinguishable (Kaupmann et al. 1997). Several studies have suggested the existence of GABAB receptor subtypes based on pharmacological specificity (Bonanno & Raiteri, 1993) or physiological distinctions (Bowery et al. 1990; Bonanno & Raiteri, 1992). However, further studies will be required to determine whether the facilitatory response is due to a unique GABAB receptor or is simply the same receptor coupled to a singular transduction cascade.
Metabotropic GABA receptors regulate different calcium channels
Each of the three metabotropic GABA receptors found in amphibian retinal ganglion cells has a different effect on high-voltage-activated calcium channels. The inhibitory baclofen-sensitive GABAB receptor suppresses N-type calcium channels, the facilitatory baclofen-sensitive GABAB receptor augments L-type channels, while the cis-aminocrotonic acid-sensitive GABAB receptor inhibits L-type calcium channels.
Although baclofen-sensitive GABAB receptors both enhance and inhibit high-voltage-activated calcium channels, their actions probably do not negate each other since they affect different channels. Based on the onset of action, N-type channel inhibition occurs rapidly and can be relieved by spike activity (Pfrieger et al. 1994; Zhou et al. 1997). In contrast, the L-type channel facilitation occurs slowly but is independent of prior electrical activity. Therefore, modulation of N-type channels will affect the earlier components of a compound calcium current. The effect on calcium influx may have ramifications on potassium channels since calcium-dependent potassium channels represent a prominent conductance in ganglion cells (Lipton & Tauck, 1987). This would influence retinal encoding because potassium currents alter the pattern of spike activity in retinal neurons (Eliasof et al. 1987; Lukasiewicz & Werblin, 1988).
Calcium channel facilitation
There are several mechanisms of calcium channel facilitation (Dolphin, 1996). L-type channel facilitation can result from a strong conditioning depolarization (such as a naturally occurring action potential or an artificial prepulse) that recruits 'silent channels' (Artalejo et al. 1990). Alternatively, L-type channels can be facilitated by protein kinases. L-type calcium channels possess several consensus PKA and PKC phosphorylation sites and physiological studies have demonstrated channel facilitation by both enzymes (McDonald et al. 1994). Based on the partial suppressive effect of Rp-cAMP, the PKA system may play a role in GABAB receptor facilitation in retinal ganglion cells. However, the PKC system appears more important since PKC (19-36) and GF-109203x almost completely inhibited baclofen-induced facilitation.
L-type channel facilitation in the hippocampus combines voltage- and kinase-dependent mechanisms (Kavalali et al. 1997). In retinal ganglion cells, L-type channel facilitation is only kinase dependent but it is complemented by a voltage-dependent facilitation (relief of GABAB receptor-mediated inhibition) of N-type calcium channels. Therefore, both mechanisms coexist in retina as they do in hippocampus. This may relate to a need for two temporal spans of facilitation, a fast acting, voltage-dependent mechanism and a slow acting, kinase-dependent pathway.
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This work was supported by grant EY05725 from the National Eye Institute. We thank Dr W. Fröestl, Novartis Pharma AG, Basel, Switzerland, for generously donating CGP35348 and CGP55845.
Corresponding author
W. Shen: Department of Physiology and Biophysics, State University of New York, 124 Sherman Hall, Buffalo, NY 14214, USA.
Email: wenshen{at}acsu.buffalo.edu
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 L.-N. Cui, E. Coderre, and L. P. Renaud GABAB presynaptically modulates suprachiasmatic input to hypothalamic paraventricular magnocellular neurons Am J Physiol Regulatory Integrative Comp Physiol, May 1, 2000; 278(5): R1210 - R1216. [Abstract] [Full Text] [PDF]
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 Z.-H. Pan Differential Expression of High- and Two Types of Low-Voltage-Activated Calcium Currents in Rod and Cone Bipolar Cells of the Rat Retina J Neurophysiol, January 1, 2000; 83(1): 513 - 527. [Abstract] [Full Text] [PDF]
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). B, the inward currents were measured during voltage steps from -70 to +10 mV while different concentrations of baclofen were applied. Results were normalized to the control current.