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REPORT
Section of Neurobiology, Physiology, and Behavior, University of California, Davis, California 95616
Submitted 19 May 2004; accepted in final form 22 June 2004
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ABSTRACT |
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INTRODUCTION |
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reported that D1-type dopamine receptor and PKA activation reduce INa without changing the rates of fast or slow inactivation from closed or open states. In striatal neurons, Schiffman et al. (1998) showed that INa can be reduced by the PKA-phosphorylated form of the dopamine- and cAMP-regulated phosphoprotein, DARPP-32. In prefrontal cortical neurons, Carr et al. (2003) found that PKA activation reduces INa by accelerating the entry of fast-inactivated Na+ channels into a slow-inactivated state.
The ability to reduce INa by different means suggests several possible functional consequences. For example, increasing the rate of slow inactivation should accelerate losses of excitability during sustained or repeated excitatory inputs because slow inactivation accumulates during sustained and repeated depolarizations (Brismar 1977; Chandler and Meves 1970; Ellerkmann et al. 2001; Fleidervisch et al. 1996; Martina and Jonas 1997; Mickus et al. 1999; Rudy 1975; Toib et al. 1998). Unlike fast inactivation, where entry and recovery are both rapid, recovery from slow inactivation is slow, at least in part, and entry can be fast or slow (e.g., Rudy 1978, 1981). Does this imply that, in cells where entry into inactivation is slow, PKA activation could modulate spikes only after several spikes fired? This is of interest because some neurons transmit information with relatively few spikes (Kara and Reid 2003; Lisman 1997; Reinagel et al. 1999; Usrey et al. 1998), and one would wonder if PKA activation modulates INa in ways that affect these spikes. To investigate this possibility, we tested the effect of a D1-type dopamine receptor agonist and PKA activators on the inactivation of INa in retinal ganglion cells. These cells are well suited for this purpose because D1-type dopamine receptor activation reduces spike generation in them even after blocking their voltage-gated Ca2+ current (Vaquero et al. 2001) and because they generate brief spike volleys in response to various inputs (Balasubramanian and Berry 2002; Barlow et al. 1971; Berry et al. 1997; Sakuranaga et al. 1987).
Parts of this study have been published previously in a meeting abstract (Hayashida and Ishida 2003).
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METHODS |
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), anti-dopamine receptor antibodies bind to them (Mora-Ferrer et al. 1999), and dopaminergic cells synapse onto them (Yazulla and Zucker 1988). However, dopamine receptors are also found in bipolar cells that synapse onto ganglion cells (Hedden and Dowling 1978). Therefore to ensure that effects were mediated by receptors in ganglion cells, all experiments were performed on isolated ganglion cells. Cells were isolated mechanically without exposure to enzymes (Hayashida et al. 2004), identified by methods described previously (Ishida and Cohen 1988), and used within 24 h of plating. All animal care and experimental protocols were approved by the Animal Use and Care Administrative Advisory Committee of the University of California, Davis.
Because an anti-D1-type dopamine receptor antiserum stains ganglion cell somata (Mora-Ferrer et al. 1999); cAMP levels in these somata can be elevated and lowered by a D1-type receptor agonist and antagonist, respectively (Vaquero et al. 2001); and the dendritic arbor, axon, and gap junctions of intact ganglion cells would prevent a space-clamp sufficient for the voltage-clamp measurements attempted here, recordings were made from isolated somata having no neurites or no more than a few short neurites. Because ganglion cells respond to D1-type dopamine receptor agonists in perforated-, but not ruptured-, patch mode (Vaquero et al. 2001), measurements were made only in perforated-patch mode (Horn and Marty 1988) using amphotericin B as the perforating agent (for details, see Hayashida et al. 2004). Currents and voltages were measured, with a discontinuous single-electrode voltage-clamp amplifier (npi electronic, SEC-05LX; Tamm, Germany), from cells in an extracellular solution that con-tained (in mM) 140 NaCl, 3.5 KCl, 3.4 MgCl2, 0.1 CaCl2, 10 D-glucose, and 5 HEPES; pH adjusted to 7.4 with NaOH. The Na+ concentration was matched to cyprinid plasma levels (Houston and Madden 1968) and was not lowered to reduce series resistance errors for two reasons. One was to avoid the possibility that lowering extracellular Na+ levels alters the rates of entry into slow inactivation and recovery from fast inactivation as found in other cells (Kuo and Liao 2000; Townsend and Horn 1997). The second is that the membrane potentials measured during the currents reported here differed from the command potentials by less than a few millivolts (Figs. 1–3) [see Hayashida et al. (2004) for details of the supercharging pulses, capacitance neutralization, feedback gain, switching frequency and other amplifier settings]. The lowered Ca2+ and elevated Mg2+ concentrations in this external solution blocked voltage-gated Ca2+ current (Vaquero et al. 2001) and thus precluded effects of Ca2+ influx on Na+ channel phosphorylation (Kondratyuk and Rossie 1997) and changes in whole cell current due to Ca2+ current modulation (Liu and Lasater 1994).
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). To ensure that the effects observed were due to changes in INa rather than changes in K+ current, K+-free solutions were also used. The K+-free extracellular solution contained (in mM) 110 NaCl, 3 CsCl, 30 tetraethylammonium-Cl, 2.4 MgCl2, 0.1 CaCl2, 10 D-glucose, and 5 HEPES; pH adjusted to 7.4 with CsOH. The K+-free recording electrode solution contained (in mM) 140 CsOH, 15 NaCl, 2.6 MgCl2, 0.34 CaCl2, 1 EGTA, and 10 HEPES; pH was adjusted to 7.4 with MSA. We noticed no significant difference between the effects on INa obtained with K+-containing and K+-free solutions and therefore pooled the data obtained with these solutions in this report. The osmolality of the extracellular and recording electrode solutions were 280 and 260 mmol/kg, respectively. The extracellular solution was grounded via an agar bridge, and recordings were made at room temperature (23°C). Pharmacological agents were either bath-applied or superfused over cells with a U-tube, and to avoid any chance that effects measured in a given cell were contaminated by effects lingering from prior applications, test agents were introduced only once into a given dish. Chemicals were obtained from Sigma (St. Louis, MO), with the following exceptions: CaCl2 (BDH Laboratory Supplies, Poole, UK); CsCl and CsOH (ICN Biomedical, Aurora, OH); 8-bromo-cAMP, dimethylsulfoxide, tetraethylammonium-Cl, and tetrodotoxin (Calbiochem, La Jolla, CA); Pluronic F-127 (Molecular Probes, Eugene, OR); and 5,6-dichloro-1-
-D-ribofuranosylbenzimidazole-3',5'-cyclic monophosphorothioate, Sp-isomer (Sp-5,6-DCl-cBIMPS; Biolog Life Science Institute, Bremen, Germany). The output signals from the amplifier were analog-filtered (5–20 kHz, 2-pole Bessel) and digitally sampled (10–50 kHz). To reduce noise, the recorded signals were digitally filtered off-line (4 kHz, 8-pole Bessel). In some instances, linear leakage and membrane capacitive currents were subtracted off-line by using scaled, averaged current traces elicited by small voltage jumps. The membrane potentials reported here were corrected for liquid junction potentials that arose from differences between the extracellular and recording electrode solutions. pCLAMP software (v. 8.1.01, Axon Instruments; Union City, CA) was used for voltage protocol generation and data acquisition. SigmaPlot (version 5.0.5; SPSS, Chicago, IL) and Matlab (version 6.5.1.199709 [EC] Release13; The MathWorks, Natick, MA) were used for data analyses.
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RESULTS |
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) and because studies of other preparations found that PKA effects on INa are attenuated at more negative voltages (Cantrell et al. 1999; Carr et al. 2003; Gershon et al. 1992; Li et al. 1993; Schubert et al. 1989).
SKF-38393 reduced whole cell INa amplitude without altering the activation range or current kinetics. Figure 1A shows the amplitude and kinetics of INa activated by depolarizations to –7 mV before and during application of 28 µM SKF-38393. Currents were activated, at most, once per 5 s to allow the current to recover fully from inactivation induced by the test pulses (see control values in Fig. 1). By 
10 min after the agonist application began, the amplitude of the INa peak fell by 38% (from 7.9 to 4.9 nA) and remained at this level for 10 min thereafter (i.e., for the remainder of this recording). SKF-38393 (12–30 µM) produced similar results in all of the cells tested, reducing the peak INa amplitude by 24 ± 3% (mean ± SE, n = 13) within the first 7–10 min of agonist application. During the same time, the voltage dependence of activation (Fig. 2, B and C), the time required for INa to reach peak amplitude ("time-to-peak;" Fig. 2D), and the time to decay to half-peak amplitude ("half decay; " Fig. 2E), did not change by statistically significant amounts.
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10% of the peak amplitude) was reduced by 35 ± 6% (n = 4) of the control. (Thus when the peak of the INa measured in SKF-38393 was normalized to that in the control, there was no significant difference between the current amplitudes measured at this 2-ms time point, as noted in the following text in regard to Fig. 3.) We did not routinely attempt to quantify reductions of the small amounts of INa that flow at later times during longer test depolarizations because the voltage-clamp current noise obscured its amplitude.8-bromo-cAMP and Sp-5,6-DCl-cBIMPS also reduced INa amplitude (Fig. 1, C–F), without altering the current time-to-peak or half-decay time (data not shown). Like SKF-38393, neither agent suppressed INa completely; 8-bromo-cAMP (170–350 µM) and Sp-5,6-DCl-cBIMPS (40 µM) reduced the peak INa by 31 ± 2% (n = 3) and 43 ± 4% (n = 3), respectively, of the control amplitude. The time course of the response to 8-bromo-cAMP was as slow as that to SKF-38393 (Fig. 1C). The response to cBIMPS was faster but still required 1–2 min to reach steady state (Fig. 1E).
To test the effect of modulation on the availability of INa during subthreshold depolarizations, we modified the voltages used to study gradual entry into inactivation in other cells (Brismar 1977; Chandler and Meves 1970; Martina and Jonas 1997; Rudy 1975) so that our protocols incorporated measured values of resting potential, the voltage that ganglion cells depolarize to before generating a spike, the voltage that ganglion cells repolarize to between spikes, and the voltage that activates the maximum Na+ conductance in these cells (see Hayashida et al. 2004; Hidaka and Ishida 1998; Vaquero et al. 2001). Thus entry into inactivation was assessed by depolarizing cells from a holding potential of –72 mV to a conditioning potential of –52 mV for different amounts of time and testing INa by a depolarization to –7 mV. After each test depolarization, cells were returned to the holding potential for 15 s before starting the next episode of depolarization. At these intervals, the INa amplitudes activated without conditioning depolarizations were constant (data not shown), and the loss of INa during one conditioning depolarization was unlikely to contribute to the loss during subsequent conditioning depolarizations.
Figure 3 plots the membrane potential measured during this protocol (Fig. 3A), the clamp current elicited by eight test depolarizations to –7 mV in the control solution (Fig. 3B), and the clamp current elicited in the same cell by the same test depolarizations 15–19 min after beginning the application of 13 µM SKF-38393 (Fig. 3C). For clarity, only the current activated by the conditioning depolarizations; the rising phase, peak, and most of the decline of current activated by each test depolarization; and the corresponding traces of membrane potential are shown. The INa amplitude declined as the conditioning depolarization duration increased (Fig. 3B). Because this decline continued when the conditioning depolarization was increased from 2 to 100 ms, the loss of current was more gradual than "fast" inactivation at –52 mV (Hodgkin and Huxley 1952), as gradual as "slow inactivation" in some preparations (Martina and Jonas 1997; Mickus et al. 1999), and less gradual than "ultra-slow inactivation" (Fox 1976). Consistent with the measurements of slow inactivation in various cells (Howe and Ritchie 1992; Rudy 1975), the current kinetics during test depolarizations did not change in any conspicuous way despite this fall in amplitude.
SKF-38393 accelerated this fall in INa amplitude (Fig. 3, C and D), consistent with the possibility that D1-type dopamine receptor activation increased the rate at which Na+ channels became unavailable for activation. To show the time dependence of this effect, the lines connecting each control INa peak in Fig. 3B were superimposed over the SKF-38393 data in Fig. 3C after normalizing the amplitudes of the currents activated without conditioning depolarizations. This shows that INa inactivated in the presence of SKF-38393 as quickly as the control current did for the first few milliseconds at –52 mV. Then as the conditioning depolarization exceeded 10 ms, the current in SKF-38393 declined faster than the control. The plot of normalized current amplitudes from all cells tested this way (n = 4) shows this as a statistically significant difference between the control and modulated current, when the duration of the conditioning depolarization reached 30 and 100 ms (Fig. 3D; P < 0.05, Student's t-test, unpaired).
After cells dwelled for >30 ms at –52 mV, the acceleration of inactivation accounted for a substantial fraction of the total reduction in current. As noted in the preceding text, the mean raw current amplitudes (control vs. SKF-38393) differed by 24% when activated by depolarizations from –72 mV. When these depolarizations were preceded by 100-ms conditioning depolarizations to –52 mV, the currents differed by 34% (for the cells represented in Fig. 3D; e.g., Fig. 3, B and C). The acceleration of inactivation at –52 mV thus accounted for roughly one-third [i.e., (34–24%)/(34%)] of the reduction in current by SKF at this time point. The lines drawn through the data in Fig. 3D suggest that this fraction might be larger after longer times at –52 mV.
Because –72 mV is more negative than the INa activation threshold in retinal ganglion cells of the species used here (Hayashida et al. 2004; Hidaka and Ishida 1998), the reduction of INa at this potential in Figs. 1 and 3 are consistent with the possibility that D1-type dopamine receptor and PKA activation facilitate "closed-state inactivation", i.e., a kinetic transition from a closed state to an inactivated state (Armstrong and Bezanilla 1977). The current amplitude in SFK-38393 was not restored to the control amplitude by 100-ms conditioning hyperpolarizations to –87 mV (data not shown). Our results are therefore consistent with the possibility that SKF-38393 facilitates entry of retinal ganglion cell Na+ channels into at least one "slow" inactivated state that requires longer times for recovery. For two reasons, we did not attempt to measure the rate of entry into or recovery from this process or the voltage sensitivity of this process. First, recovery from slow inactivation can continue for as long as several minutes at negative voltages (Fox 1976), whereas ganglion cells do not hyperpolarize for such prolonged times in response to light flashes or fluctuating stimuli (e.g., Saito 1983; Sakuranaga et al. 1987). Second, complete recovery generally requires that the channels be hyperpolarized below –100 mV (e.g., Brismar 1977; Chandler and Meves 1970; Rudy 1981), whereas ganglion cells do not traverse such negative voltages during their responses to light (e.g., Zaghloul et al. 2003).
Finally, we tested the recovery from open-state inactivation because this is likely to contribute to losses of excitability during repetitive spiking (Ruff 1996). In the two-pulse protocol used for this, cells were depolarized for 2-ms from the holding potential to –7 mV to activate and inactivate INa; returned to the holding potential for various amounts of time; and depolarized again to –7 mV to test the amount of INa available for activation (cf. Fleidervisch et al. 1996; Mickus et al. 1999; Rudy 1981). Cells were kept at the holding potential for 6 s after each test depolarization before starting the next episode so that the amplitude of INa activated by each conditioning depolarization was constant, and the loss of current during one conditioning depolarization was unlikely to contribute to the rate of recovery after subsequent conditioning depolarizations. The data in Fig. 3, E–I, are formatted as in Fig. 3, A–D. E–G plot the recordings of membrane potential, control INa, and INa in SKF-38393 (20 µM, 13–17 min after beginning the application) from a single cell; the lines connecting the current peaks in F are superimposed over the data in G (after normalizing the currents elicited by the conditioning pulses); and H and I show the values collected from all cells (n = 5) studied this way.
Two results emerge from these plots. First, we find that INa recovers almost completely from inactivation within 1 s. This is neither as fast as recovery from fast inactivation, nor as slow as the slow recovery that occurs over seconds in other cells at voltages similar to the ones we have made our measurements at (e.g., Fig. 9 of Howe and Ritchie 1992; see also Figs. 6 and 8 of Mickus et al. 1999). Although we did not test the effect of longer conditioning depolarizations to –7 mV, a study of cat retinal ganglion cells reported recovery rates that are no slower than the values we find after depolarizations to –5 mV for as long as 1 s (Kaneda and Kaneko 1991). Slower recovery has been found in salamander retinal ganglion cells after 500-ms depolarizations to –20 mV (Kim and Rieke 2003). However, the external Na+ concentration was substantially lower than in our recordings and the cat study, leaving the extent of the difference among these results, if any, unclear (Kuo and Liao 2000; Townsend and Horn 1997). Second, we find that SKF-38393 slowed the rate of recovery from inactivation induced by brief depolarizations and that there is less current available for activation in the SKF-38393-containing solution compared with the control values, for 2–1,000 ms after the conditioning depolarization. The slower recovery in SKF-38393 was especially apparent within the first 30 ms after the conditioning pulse in the raw data (Fig. 3G). The difference in recovery rates was estimated by fitting the normalized amplitudes by the sum of two exponential time functions (Fig. 3H). The fast and slow time constants obtained from these fits are 3.6 and 360 ms for recovery in SKF-38393 (red curve) versus 2.7 and 240 ms for the control data (black curve). (Thus the fast and slow rate constants in SKF-38393 were 24 and 35% smaller than the corresponding control values.) The log-log plot in Fig. 3I allows the recovery process over a wide range of time, as well as the difference between the currents during the first 30 ms after the conditioning depolarization, to be seen more clearly. Although the current amplitudes at 0 ms are not plotted (because the scale is logarithmic), they overlap (Fig. 3, G and H), and therefore the difference in amplitudes observed at the subsequent time points shows that SKF-38393 slows the recovery rate. For example, the current recovers 80% of its amplitude within 10 ms after the conditioning depolarization in the control solution, whereas this amount of recovery does not occur until 20–30 ms after the conditioning depolarization in the presence of SKF (see the blue arrows and the times marked a and b in Fig. 3I).
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DISCUSSION |
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The effects we show here are consistent with previous demonstrations that PKA activation reduces INa amplitude without marked changes in kinetics or activation range and that the voltage-sensitivity of steady-state inactivation measured with brief conditioning voltages shifts leftward slightly (Cantrell et al. 1999; Gershon et al. 1992; Li et al. 1992; Maurice et al. 2001; Schiffmann et al. 1995; Smith and Goldin 1997). Because changes in whole cell current amplitude generally reflect changes in channel gating voltage sensitivity (rather than single-channel conductance), one possible interpretation of our data is that activating either D1-type dopamine receptors or PKA in retinal ganglion cells reduces the number of Na+ channels available for activation at the resting potential, does not markedly change the probability that the remaining Na+ channels open or close during depolarizations from the resting potential, and produces a time-dependent reduction in the number of Na+ channels available for activation during subthreshold depolarizations.
SKF-38393, 8-bromo-cAMP, and Sp-5,6-DCl-cBIMPS reduced INa by 10–50% of the control amplitude. Previous studies have reported similar reductions of INa by PKA activation in other preparations (e.g., Cantrell et al. 1999; Gershon et al. 1992; Li et al. 1992), and to our knowledge, PKA activation has never been reported to abolish INa totally. This would be expected to alter individual spikes and volleys of spikes in several ways. The simplest would resemble effects of losing inward current by slow inactivation, namely a decrease in spike rate of rise (Narahashi 1964) and a decrease in spike amplitude (e.g., Colbert et al. 1997). How these effects contribute to retinal ganglion cell function remains to be seen. On the other hand, SKF-38393 reduced the INa elicited by small as well as large depolarizations (Fig. 2, A and B), implying that dopamine could raise spike threshold (by increasing the amount of inward current necessary to counterbalance outward currents). This is consistent with the inhibition of spikes in ganglion cells of the species studied here (Hayashida and Ishida 2003; Vaquero et al. 2001) and in other species (e.g., Straschill and Perwein 1969). A corollary of selectively reducing INa is that in cells where INa does not contribute significantly to the resting conductance, dopamine could inhibit spikes without changing resting potential (e.g., Schiffmann et al. 1995; Stanzione et al. 1984; Vaquero et al. 2001).
In addition to raising spike threshold by reducing INa without changing the activation range, our results are consistent with the possibility that dopamine fosters accumulation of inactivation, i.e., that it increased the rate of inactivation at subthreshold potentials, and slowed recovery from inactivation after brief depolarizations. Previous studies reported qualitatively and quantitatively different effects of dopamine receptor and PKA activation on INa. Although we find that SKF-38393 slowed the recovery from inactivation during the first 2–1,000 ms after a brief conditioning depolarization, Schiffmann et al. (1995) found that dopamine reduced INa without altering the rate of recovery from inactivation, Carr et al. (2003) found no significant effect of PKA activation on the rate of recovery from inactivation, and Wicher (2001) showed that PKA activation slowed the recovery of INa from fast, rather than slow, inactivation. Furthermore, while our results show that SKF-38393 increased the amount by which INa inactivates if cells dwell at –52 mV for as little as 30 ms and for 2 ms at –7 mV, Cantrell et al. (1999) reported that PKA activation did not affect the amount of current inactivated by conditioning depolarizations to either –40 or 0 mV, and Carr et al. (2003) found no effect of PKA activation until conditioning depolarizations to –20 mV exceeded 1 s. Is it possible that PKA modulates different rates (fast, slow, and very slow) of INa inactivation because these differentially influence the spiking behavior of different cells? This is not yet known for ganglion cells at least in part because the extent that other currents are modulated by dopamine and the possibility that dopamine modulates much slower INa inactivation remain to be examined. However, the duration of spike bursts in these cells (e.g., 5 spikes at 100–200 Hz) (Berry et al. 1997) is similar to the time at which dopamine receptor activation begins to enhance inactivation, viz. after cells spend more than 10–30 ms at –52 mV (Fig. 3, A–D). Cells spiking at 100–200 Hz may also be primed to lose INa because dopamine receptor activation markedly slows recovery from inactivation during the first 5–10 ms after single brief depolarizations (see Fig. 3, E–I). Slower losses of INa might, by contrast, delay the truncation of spiking (e.g., compare Figs. 5 and 9 of Carr et al. 2003).
Our results show that this inhibition is slow both in onset and time to reach steady state. The INa amplitude did not fall within the first several seconds of applying SKF-38393, 8-bromo-cAMP, and Sp-5,6-DCl-cBIMPS, and the steady-state response to these agents was reached 2–10 min thereafter. This is not a peculiarity of retinal ganglion cell Na+ channels as the response of Na+ channels in at least some preparations to SKF-38393, PKA activation (Li et al. 1993; Schiffmann et al. 1995; Smith and Goldin 1997; Zhang et al. 1998), and protein kinase C activation (Numann et al. 1991; Sigel and Baur 1988), as well as the effect of dopamine on other channels in other retinal neurons (e.g., Piccolino et al. 1984), have all been found to follow similarly slow time courses. This does not necessarily pose a functional disadvantage: while the response reaches steady state too slowly to signal moment-to-moment changes in distributions of light falling on the retina in situ, this would be compatible with the gradual changes in light sensitivity mediated by dopamine released endogenously under natural conditions (e.g., Manglapus et al. 1999).
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GRANTS |
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Address for reprint requests and other correspondence: A. Ishida, Section of Neurobiology, Physiology, and Behavior, University of California, One Shields Ave., Davis, CA 95616-8519 (E-mail: atishida{at}ucdavis.edu).
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ABSTRACT
INTRODUCTION
, peak INa amplitude during each test depolarization. 
, time from onset of test depolarization to INa peak. 
, time for INa to decline from peak to half the peak amplitude. Dashed vertical lines, time at which each ligand application began. In each pair of panels (A and B; C and D; E and F), the current traces labeled a–c were recorded at the times indicated by these letters in the corresponding amplitude plots. Leak and capacitive currents were subtracted off-line. Each pair of panels presents data from a different cell. Recordings were made with K+-free external and electrode solutions in A and B, and with K+-containing solutions in C–F.
fast] + b[1 – exp(–t/