Activation of Ca2+-dependent K+ channels by cyanide in guinea pig adrenal chromaffin cells

M. Inoue and I. Imanaga

Department of Physiology, School of Medicine, Fukuoka University, Fukuoka 814-01, Japan

    ABSTRACT
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Abstract
Introduction
Methods
Results
Discussion
References

The effects of cyanide (CN) on whole cell current measured with the perforated-patch method were studied in adrenal medullary cells. Application of CN produced initially inward and then outward currents at -52 mV or more negative. As the membrane potential was hyperpolarized, amplitude and latency of the outward current (Io) by CN became small and long, respectively. A decrease in the external Na+ concentration did not affect the latency for CN-induced Io but enhanced the amplitude markedly. The CN Io reversed polarity at -85 mV, close to the Nernst potential for K+, and was suppressed by the K+ channel blockers curare and apamin but not by glibenclamide, suggesting that Io is due to the activation of Ca2+-dependent K+ channels. Consistent with this notion, the Ca2+-mobilizing agents, muscarine and caffeine, also produced Io. Exposure to CN in a Ca2+-deficient medium for 4 min abolished caffeine- or muscarine-induced Io without development of Io, and addition of Ca2+ to the CN-containing solution induced Io. We conclude that exposure to CN produces Ca2+-dependent K+ currents in an external Ca2+-dependent manner, probably via facilitation of Ca2+ influx.

ATP; calcium pump; store sites; small-conductance calcium-dependent potassium channel; mitochondria

    INTRODUCTION
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Abstract
Introduction
Methods
Results
Discussion
References

HYPOXIA OR METABOLIC INHIBITION induces cell death through increases in intracellular concentrations of Ca2+ ([Ca2+]i) and subsequent activation of Ca2+-dependent enzymes, such as protease (25). Thus much attention has been directed to mechanisms related to Ca2+ increase. Application of cyanide (CN) to cultured human skin epidermoid A-431 cells induced an increase in Ca2+ concentration, and the underlying mechanism was Ca2+ influx via the Na+/Ca2+ exchange system (18). By contrast, in glomus cells of the rabbit carotid body, hypoxia- and CN-induced Ca2+ elevation was due to Ca2+ release from mitochondria (2) or to Ca2+ influx across voltage-dependent Ca2+ channels resulting from suppression of voltage-dependent K+ channels and the subsequent depolarization (22). It is also known that hypoxia in hippocampal neurons (1) and cerebellar Purkinje cells (17) appears to mobilize Ca2+ from inositol trisphosphate (IP3)-sensitive store sites, the underlying mechanism being a reduction in NADH (17). To elucidate the mechanism for Ca2+ elevation evoked by hypoxia or mitochondrial inhibition, we evaluated effects of CN on whole cell currents in dissociated adrenal chromaffin cells. Such mechanisms may be involved in anoxia-induced secretion of catecholamines from the adrenal medulla (4), a release that is vital for survival (6). Furthermore, chromaffin cells originate from the neural crest, as do peripheral neurons, and transform to neurons in the presence of nerve growth factor (28). Thus findings obtained with chromaffin cells would pave the way for treatment of neuronal disorders and lead to a better understanding of neuron death and the consequent brain damage (5).

    METHODS
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Introduction
Methods
Results
Discussion
References

Whole cell recordings. Adrenal medullae from female guinea pigs were treated with collagenase to obtain dissociated chromaffin cells, as described elsewhere (14). The whole cell current was recorded using the perforated-patch method to diminish washout of cellular components (10, 12). Dissociated chromaffin cells were left for a few minutes to facilitate attachment to the bottom of the bath before being constantly perfused with standard saline at a rate of ~1 ml/min. The standard saline contained (in mM) 137 NaCl, 5.4 KCl, 1.8 CaCl2, 0.5 MgCl2, 0.53 NaH2PO4, 5 D-glucose, 5 N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES), and 2.6 NaOH. To study the effects of CN, the standard solution was exchanged with CN solution in which 5 mM NaCl was replaced with 5 mM NaCN and the glucose was removed unless otherwise noted. In Ca2+-free solutions, 3.6 mM Mg2+ was substituted for 1.8 mM Ca2+. The pH of all external solutions was adjusted to 7.4. The current was recorded using an Axopatch 200A amplifier and then fed into a brush recorder after low-pass filtering at 5 Hz and into a videocassette recorder after digitizing by an analog-to-digital converter. The pipette solution contained (in mM) 120 potassium isethionate, 20 KCl, 10 NaCl, 10 HEPES, and 2.6 KOH. The pH of the pipette solution was adjusted to 7.2. When current-voltage (I-V) relationships were investigated, the pulse protocol consisting of a 50-ms negative pulse, 300-ms interval, and a 50-ms positive pulse was applied 10 times in 10-mV steps from a holding potential. At the same time, currents were stored on a diskette of a computer at a sampling interval of 0.1 ms after filtering at 3 kHz. The series resistance (20-30 MOmega ) was not compensated, and resulting voltage errors did not generally exceed 5 mV in the I-V curves. On the day of experiment, nystatin was added to the pipette solution at a final concentration of 100 µg/ml. The membrane potential was corrected for a liquid junction potential of -12 mV between the nystatin solution and the standard saline. All experiments were carried out at 23-25°C. Data were expressed as means ± SD unless otherwise noted, and the Student's t-test was used to determine statistical significance.

Chemicals. Sources of chemicals are as follows: (±)-muscarine chloride, curare, and nystatin (Sigma); apamin and charybdotoxin (Peptide Institute, Japan); glibenclamide (Research Biochemicals International); collagenase (Yakult, Japan); NaCN (Hayashi Pure Chemical Industries, Japan).

    RESULTS
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Abstract
Introduction
Methods
Results
Discussion
References

Activation of Ca2+-dependent K+ channels by CN. Because chromaffin cells have Ca2+-dependent K+ channels (13, 20, 23), an increase in [Ca2+]i could be detected as an increase in outward current (Io) at membrane potentials positive to the equilibrium potential for K+ (-84 mV, under present conditions). Figure 1A shows that exposure to CN produced a gradual increase in Io at -52 mV. The current began to develop with a latency of ~1 min and reached a maximum of 37.0 ± 29.7 pA (n = 16) at 3.7 ± 1.1 min (n = 16). The size of Io evoked by CN was not noticeably affected by addition of 10 mM glucose (n = 3). To elucidate ionic mechanisms without substantial contamination by the CN-induced inhibition of an inwardly rectifying K+ current (16), I-V relationships were examined 4 and 6 min after the application of CN. The I-V relationship examined at the maximum (b in Fig. 1, A and B) crossed a control (a) at -82 mV (-85.3 ± 5.1 mV, n = 6), close to the Nernst potential for K+. To clarify voltage dependence of CN-induced Io, CN-sensitive currents (Fig. 1D) were obtained by subtracting currents in response to pulses before (a) from those during exposure to CN (b). The CN-sensitive current (Fig. 1C) changed polarity at -82 mV, and the conductance decreased with hyperpolarization. This CN-induced Io was enhanced markedly by a decrease in Na+ concentration (135 mM N-methyl-D-glucamine in place of Na+). The I-V relationship examined in the Na+-deficient CN solution crossed those in standard saline and CN solution at the same membrane potential of -82 mV (Fig. 1B; reversal potential for CN-sensitive current enhanced by decrease in [Na+], -84.3 ± 1.0 mV, n = 4, Fig. 1, C and Db). Restoration of physiological Na+ in the presence of CN induced a transient Io increase.


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Fig. 1.   Ionic mechanism for cyanide (CN)-induced outward current (Io). A: chart record of a whole cell current at -52 mV. Standard saline was replaced with standard CN solution (CN; 5 mM) or Na+-deficient CN solution [CN Na(-)] during indicated periods (see METHODS). In CN Na(-), 135 mM Na+ was replaced equimolarly with N-methyl-D-glucamine. Upward and downward deflections were truncated currents in response to -100-mV pulse of 50 ms or to pulse protocol. Pulse protocol consisting of 50-ms negative pulse, 300-ms interval, and 50-ms positive pulse was applied in 10-mV steps 10 times. B: current-voltage (I-V) relationships examined in saline (a in A, open circle ), CN solution (b, down-triangle), and Na+-deficient CN solution (c, square ). C: CN-induced I-V relationships in presence of 140 mV (down-triangle) and 5 mM Na+ (square ). CN-induced currents were obtained by subtracting currents in response to pulses in saline from those in standard CN solution and Na+-deficient CN solution. D: families of CN-sensitive currents in 140 (a) and 5 mM Na+ (b). Amplitudes of current were measured at end of pulse. Arrows in this and following figures represent 0-current level.

To determine the K+ channel type involved in CN-induced Io, the effects of K+ channel blockers were studied. In Fig. 2A, bath application of CN induced an inward current without a noticeable delay and 4.5 min later began to induce Io at -67 mV. This Io was reversibly blocked by bath application of 0.1 mM curare, an agent known to block a small-conductance Ca2+-dependent K+ channel (SK channel; Ref. 3, 23, 24). The I-V relationships before and during application of curare crossed at -82 mV (Fig. 2B; -83.0 ± 3.6 mV, n = 3), and the extent of suppression was 71.4% (73.8 ± 25.1%, n = 3). Apamin at 0.1 µM, another SK channel blocker (3), also inhibited the Io by 33.3% (Fig. 2C; 39.5 ± 22.2%, n = 4), and the reversal potential for apamin-sensitive currents was -87.0 mV (-86.3 ± 3.3 mV, n = 4). In contrast, the current was not suppressed either by 0.1 µM charybdotoxin (n = 4), a blocker of a large-conductance Ca2+-dependent K+ channel (BK channel, Ref. 20; 21) or 10 µM glibenclamide (n = 3), a blocker of an ATP-sensitive K+ channel (26). Figure 2D demonstrates that -82 mV was the reversal potential for K+ channels in this cell: addition of 1 mM Ba2+ to the perfusate abolished an inwardly rectifying K+ channel (11).


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Fig. 2.   Suppression of CN-induced Io by Ca2+-dependent K+ channel blockers. A: chart record of a whole cell current at -67 mV. CN, 0.1 mM curare (Cur), 0.1 µM apamin (Apa), or 1 mM Ba2+ (Ba) was applied during indicated period. B: I-V relationships during (open circle ) and after (bullet ) application of curare in presence of CN (b in A). C: I-V relationship before (open circle ) and during (bullet ) apamin (c in A). D: I-V relationship during (open circle ) and after (bullet ) Ba2+. I-V relationships were examined, as explained for Fig. 1.

Source of Ca2+ involved in channel activation. The foregoing results suggest that the CN-induced Io is due to activation of Ca2+-dependent K+ channels but not of ATP-sensitive channels. We reported that guinea pig chromaffin cells have intracellular store sites sensitive to caffeine and putatively to IP3 (15). Thus Ca2+ in these store sites is possibly involved in the generation of Io by CN, as was noted on a hyperpolarizing response to anoxia in hippocampal neurons (1). Application of 10 mM caffeine later than 2 min of CN exposure failed to induce Io (Fig. 3A). This event may not be due to involvement of stored Ca2+ in the CN-induced Io. Caffeine applied at ~1 min of the exposure, a time when Io had already developed in response to CN, evoked Io for a longer period. Similar results were observed in two other cells. One possibility to account for the failure of caffeine to induce Io at 2 min or later would be depletion of Ca2+ from store sites, and this depletion probably results from a decrease in Ca2+ pump activity due to diminution in cellular ATP contents. This notion was supported by the finding that restoration of the caffeine response after termination of CN exposure required longer intervals than that in the absence of CN. In four of five cells, application of caffeine 2-4 min after termination of CN exposure, which lasted for >4 min, failed to evoke Io (Fig. 3B), whereas an interval of 2-3 min was sufficient for reproduction of caffeine Io in all seven cells (13, 15). In addition, as CN exposure was lengthened, longer intervals after washout of CN were required for reproduction of Io. In Fig. 3B (open squares), caffeine applied 4.4 min after the washout induced Io in the case of 3.5-min treatment but not in that of 10.6 min. The results suggest that CN exposure for >4 min apparently depletes Ca2+ from store sites and that depleted Ca2+ are probably not involved in the generation of Io by CN.


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Fig. 3.   Effects of CN on Io response to caffeine. A: chart records of a whole cell current. Holding potential, -52 mV. CN and/or 10 mM caffeine (Caf) were applied during indicated periods (single and double bars, respectively). Top and bottom, continuous record. B: times of caffeine application after washout of CN are plotted against duration of CN treatment. Open and filled symbols indicate success and failure of 10 mM caffeine to induce an Io, respectively. Same symbols mean same cells. Straight line shows rough discrimination between failure and success.

We then investigated effects of Ca2+ removal on CN-induced Io at -52 mV (Fig. 4). Administration of CN in the absence of external Ca2+ did not produce Io and abolished Io in response to 6 µM muscarine (n = 3, Fig. 4A) and to 10 mM caffeine applied at 4 min (n = 8, Fig. 4B), indicating that CN depleted Ca2+ in store sites without producing Io. The subsequent addition of 1.8 mM Ca2+ to the Ca2+-free CN solution, however, resulted in a gradual development of Io without a latency (n = 6), and the evoked current diminished after washout of Ca2+ slowly with a half time (T1/2) of 27 ± 8 s (n = 6). This slow decline may not be due to sequestration of Ca2+ into intracellular store sites because the uptake was suppressed during exposure to CN (Fig.3).


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Fig. 4.   Dependence of CN-induced Io on external, but not internal, Ca2+. A and B: chart records of a whole cell current at -52 mV. Different cells. Removal of Ca2+ [Ca(-)] and application of CN were indicated by 1st and 2nd lines below each chart record, respectively. Application of 10 mM caffeine (single bar) or 6 µM muscarine (M, double bar) was shown by 3rd lines. First 2 Ios evoked by caffeine in B were out of scale.

Mechanism for CN-induced increase in [Ca2+]i. There are several possibilities to account for the CN-induced increase in [Ca2+]i. One is the reversed mode of Na+/Ca2+ exchange due to accumulation of Na+ at the inner surface of the membrane. To explore this possibility, effects of ouabain, a Na+-K+-adenosinetriphosphatase (ATPase) inhibitor, were examined. Application of 20 µM ouabain for up to 4 min did not induce Io at -67 mV, whereas in the same cells CN consistently produced it (n = 3). Moreover, a decrease in Na+ concentration from 140 to 5 mM enhanced Io in response to CN. Figure 5A shows that, at -52 mV, bath application of CN induced an inward current without a noticeable delay and then apparently began to produce Io at 72 s. When a Na+-deficient CN solution was perfused, the inward current did not develop (n = 5) and the Io began to develop with a latency of 30 s (70 ± 34 s, n = 5), which did not differ from that (56 ± 35 s, n = 6) in the presence of standard Na+. After a switch to saline, the Io was transiently enhanced and then diminished. On the other hand, after Io had developed in the CN solution, the decrease in [Na+] of the CN solution led to a time-dependent enhancement of the Io without a noticeable delay (n = 3). The restoration of standard Na+ concentration in the CN solution resulted in a decrease in Io with T1/2 of 23 ± 9 s (n = 6). These results indicate that Na+ loading is not a prerequisite for the generation of Io by CN.


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Fig. 5.   Effects of a decrease in Na+ concentration on CN-induced Io. A-C: chart records of a whole cell current at -52 mV. Same cell. Standard saline was replaced with standard CN solution (CN) or Na+-deficient CN solution [CN Na(-)] during indicated periods. In CN Na(-), 135 mM Na+ was equimolarly replaced with N-methyl-D-glucamine. Downward deflections in C were truncated currents in response to -100-mV pulse of 50 ms.

In some experiments, application of CN initially induced an inward, then an outward current (e.g., Figs. 2 and 5), and this inward current was abolished by replacement of Na+ with N-methyl-D-glucamine. Thus another possibility is that Ca2+ flowing through a cation channel mediates production of the Io. If this is indeed the case, then the cation channel involved in the inward current should be activated for the generation of Io. We thus examined effects of CN at hyperpolarized membrane potentials, since the amplitude of Io is expected to decrease at such potentials with a decrease in the driving force for K+ and the voltage dependence of Ca2+-dependent K+ channels. Figure 6A shows that as the membrane potential was hyperpolarized, production of an inward current was dominant. At -77 mV, CN induced the inward current alone over a period of 4 min. Similar results were observed in all 3 cells held at -77 mV and in 12 of 16 cells at -67 mV but not in 3 cells at -57 mV nor in 6 cells at -52 mV. In Fig. 6B, the incidence and latency of the development of Io during >= 4 min of exposure to CN were plotted against various membrane potentials. The results suggest that the apparent absence of an inward current at depolarized membrane potentials is due to masking by the concomitant generation of Io. Thus cation channels responsible for the inward current are probably being activated for the generation of Io.


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Fig. 6.   Voltage dependence of inward current and Io in response to CN. A: chart records of a whole cell current at -57, -67, and -77 mV. CN was applied during indicated periods. Same cell. B: latency (down-triangle) and incidence (open circle ) of development of Io are plotted against membrane potentials. Latencies of <4 min were calculated. Number of cells examined was 3 at -77, 16 (4, latencies <4 min) at -67, 3 at -57, and 6 at -52 mV.

    DISCUSSION
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Abstract
Introduction
Methods
Results
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References

Involvement of Ca2+-dependent K+ channels. In various types of cells, exposure to hypoxia or mitochondrial inhibitors led to an increase in [Ca2+]i. In rabbit glomus cells (2) and mouse sensory neurons (7, 8), such an increase was thought to be due to release of Ca2+ from mitochondria, whereas in hippocampal neurons (1) Ca2+ was mobilized from IP3-sensitive store sites. In chromaffin cells, application of CN reversibly induced an increase in Io with a latency that depended on a membrane potential. This generation of Io was apparently not affected by the addition of glucose, but the suppression of glycolysis with 2-deoxyglucose and iodoacetate resulted in a gradual development of Io (16). These results indicate that the production of Io by CN could be ascribed to depletion of cellular ATP due to chemical hypoxia. The CN-induced Io reversed polarity at membrane potentials close to the equilibrium potential for K+ and was suppressed by the SK channel blockers apamin and curare but not by the ATP-sensitive K+ channel blocker glibenclamide. In addition, CN Io at -55 mV diminished rapidly within 10 s of intracellular access with a 5 mM ethylene glycol-bis(beta -aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA)-containing pipette solution, regardless of whether the pipette solution contained ATP (16). These results indicate that exposure to CN induced a Ca2+-dependent K+ current but not an ATP-sensitive current. Application of 0.1 mM curare and 0.1 µM apamin suppressed the current at -67 mV by 74 and 40%, respectively, whereas 0.1 µM charybdotoxin, a BK channel blocker, had no suppressing action. Thus SK channels may be involved in the current at -67 mV or more negative, but latency for the production of Io was markedly shortened at more positive membrane potentials. This finding suggests that BK channels may also be responsible for the current at such membrane potentials, since activation of BK channels, but not SK channels, was enhanced by depolarizations (19), and the presence of the channel was noted in rat (23) and bovine chromaffin cells (20).

The SK channel was suggested to contribute to resting membrane potential in rat chromaffin cells (23). Although the present experiment demonstrated the presence, it would not be a major one in the formation of resting membrane potential in the guinea pig. As shown in Figs. 1 and 2, membrane conductance examined using the perforated-patch method exhibited an inward-going rectification between -50 and -130 mV, and at more negative potentials, the conductance diminished. These properties of membrane conductance were similar to those noted under conditions in which intracellular Ca2+ was strongly chelated with 5 mM EGTA, and the inward rectification under these conditions was ascribed to openings of inwardly rectifying K+ channels (11). Consistent with this notion, addition of 1 mM Ba2+ to saline abolished the rectification (Fig. 2), whereas it suppressed about half the CN-induced Io at -67 mV.

Putative mechanism for CN-induced outward current. The present result indicates that >= 4-min exposure to CN depletes Ca2+ from caffeine- and muscarine-sensitive store sites. However, Ca2+ originating from the store sites was not involved in activation of Ca2+-dependent K+ channels at -52 mV or more negative. First, exposure to Ca2+-free CN solution did not induce Io, whereas it abolished the response to caffeine or muscarine. Second, Io developed in response to CN even before the subsequent application of caffeine evoked the current for a longer duration. Finally and most importantly, generation of the Io entirely depended on external Ca2+. Addition of Ca2+ to Ca2+-free CN solution produced the Io without a delay after exposure to CN for 3-6 min, whereas application of CN in the presence of Ca2+ began to produce Io with a delay of ~1 min at -52 mV. This difference in latency could be explained by impairment of Ca2+ sequestration and/or extrusion during CN treatment. When CN was applied in the presence of external Ca2+, Ca2+ flowing into the cell may be extruded or sequestered into store sites during the latent period. In contrast, when Ca2+-handling mechanisms were blocked by CN, Ca2+ flowing into the cell would quickly accumulate above a concentration sufficient for openings of Ca2+-dependent K+ channels. In fact, the Ca2+ pump in store sites was suppressed during exposure to CN (Fig. 3). This suppression is probably due to a decrease of cellular ATP content, since addition of 5 mM glucose to CN solution restored in part the response to caffeine (unpublished observations). This impairment of ATP-driven extrusion and sequestration mechanisms alone could not account for CN-induced Io. First, larger amounts of Io were evoked by application of caffeine within 2 min of CN exposure, at which time Io had already developed substantially. This result suggests that, during the early period, at least Ca2+ pump activity in store sites is not impaired. The larger generation of Io may be due to block of mitochondrial uptake of Ca2+, as was noted in rat chromaffin cells (9) and sensory neurons (29). Second, application of cyclopiazonic acid, a specific inhibitor of the Ca2+ pump in store sites (27), did not induce Io at -52 mV (15). Thus inhibition of at least the Ca2+ sequestration mechanism may not produce an increase in Ca2+ concentratio sufficient for openings of Ca2+-dependent K+ channels. On the basis of these results, Ca2+ influx seems to be enhanced during CN exposure.

There are at least two possibilities to account for the CN-induced Ca2+ influx. One possibility is the reversed mode of Na+/Ca2+ exchange. A decrease in ATP contents would be expected to result in suppression of Na+-K+-ATPase and the subsequent accumulation of Na+ beneath the plasma membrane. This accumulation might be sufficient for Na+/Ca2+ exchange to function in the reverse mode. However, this possibility is questionable. First, application of 20 µM ouabain for 4 min did not produce Io, whereas that of CN consistently did so in the same cells. Second, Io did not develop when extracellular Na+ concentration decreased from 140 to 5 mM (unpublished observations). Furthermore, application of CN under Na+-deficient conditions produced Io with a latency comparable to that for the current evoked under standard conditions. This result suggests that Na+ loading is not a prerequisite for the CN-induced Io and that Ca2+-ATPase in the plasma membrane is mainly responsible for Ca2+ extrusion and Na+/Ca2+ exchange contributes little in intact cells and during the latent period (cf. Ref. 29). In contrast, under metabolically suppressed conditions, Ca2+ may be extruded mainly by Na+/Ca2+ exchange. Thus the suppression or reversed operation of Na+/Ca2+ exchange by replacement of Na+ with N-methyl-D-glucamine enhanced the CN-induced Io with no substantial delay.

The second possibility regarding an increase in Ca2+ concentration is a Ca2+ influx through Ca2+-permeable channels. Application of CN initially produced inward and then outward currents at membrane potentials more positive than -67 mV, whereas at a more negative potential it generated an inward current alone during the entire period. These results suggest that, at depolarized membrane potentials, the inward current may be masked by concomitant generation of Io. The inward current elicited at -52 mV was apparently abolished by substitution of N-methyl-D-glucamine for 135 mM Na+ in CN solution, suggesting that the current is due to activation of Na+-permeable channels. This CN-activated cation channel might have a substantial permeability to Ca2+. To determine whether the second possibility is tenable, [Ca2+]i has to be measured under voltage clamp conditions and compared with amplitudes of CN-induced inward currents.

    ACKNOWLEDGEMENTS

This study was supported by a Grant-in-Aid from the Ministry of Education, Science, Sports, and Culture of Japan.

    FOOTNOTES

Address reprint requests to M. Inoue.

Received 20 February 1997; accepted in final form 3 September 1997.

    REFERENCES
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Abstract
Introduction
Methods
Results
Discussion
References

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AJP Cell Physiol 274(1):C105-C111
0363-6143/98 $5.00 Copyright © 1998 the American Physiological Society




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