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1Department of Neuroscience and Oral Physiology, Osaka University Graduate School of Dentistry; 2Division for Interdisciplinary Dentistry, Osaka University Dental Hospital, Osaka; 3The Research Institute of Personalized Health Science and 4Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Hokkaido; and 5Department of Morphological Brain Science, Graduate School of Medicine, Kyoto University, Kyoto, Japan
Submitted 23 September 2007; accepted in final form 18 February 2008
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ABSTRACT |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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), S-nitroso-N-acetylpenicillamine (SNAP) or 8-bromoguanosine-3',5'-cyclomonophosphate (8-Br-cGMP) induced a membrane hyperpolarization in the presumed basal forebrain cholinergic (BFC) neurons by activating K+ currents that usually displayed Goldman–Hodgkin–Katz (GHK) rectification, most likely the leak K+ current. However, it has been reported that nitric oxide (NO) increased membrane excitability in striatal medium spiny neurons, presumably by inhibition of leak K+ channels (West and Grace 2004). It has also been reported that long-term activation of the NO–cGMP–protein kinase G (PKG) pathway in injured motoneurons resulted in an inhibition of a pH-sensitive leak K+ current, suggesting an involvement of NO in inhibiting TWIK-related acid-sensitive K+ (TASK) current (Gonzalez-Forero et al. 2007). Thus activation of the NO–cGMP pathway may have differential effects on neuronal excitability among different brain regions. In the present study, we examined whether the presumed BFC neurons express any pH-sensitive K+ current and whether 8-Br-cGMP can modulate the activity of such pH-sensitive K+ current. We found that the presumed BFC neurons displayed a pH-sensitive K+ current similar to TASK1 current in response to changes in the external pH and that 8-Br-cGMP dramatically enhanced the K+ current only at pH 7.3, leaving it almost unchanged at pH 6.3 and 8.3.
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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). Electrophysiological recording
Details of the whole cell patch-clamp recording method were also described in an earlier study (Kang et al. 2007). The composition of extracellular solution was the same as previously reported (in mM): 124 NaCl, 1.8 KCl, 2.5 CaCl2, 1.3 MgCl2, 26 NaHCO3, 1.2 KH2PO4, and 10 glucose. When changing the external pH, 26 mM NaHCO3 in the extracellular solution was substituted with 10 mM HEPES and 12 mM NaCl, and pH was adjusted using NaOH (Talley et al. 2000). The composition of the internal solution was the same as the modified internal solution previously reported (in mM): 123 K-gluconate, 8 KCl, 20 NaCl, 2 MgCl2, 0.5 ATP-Na2, 0.3 GTP-Na3, 10 HEPES, and 0.1 EGTA; the pH was adjusted to 7.3 with KOH. All recordings were obtained in the presence of tetrodotoxin (1 µM). Under the voltage-clamp condition, the baseline current at the holding potential of –70 mV was continuously measured except during the depolarizing ramp (–130 to –40 mV, 1-s duration) and step (to –90 mV, 0.1-s duration) pulses applied alternately every 10 s. The conductance was measured using linear regression across the linear part of the current–voltage (I–V) plot (–70 to –95 mV) in response to the ramp pulses.
Drug application
8-Br-cGMP, a membrane-permeable cGMP analog (Sigma–Aldrich, St. Louis, MO), and BaCl2 (Wako Pure Chemicals, Osaka, Japan) were dissolved in distilled water for preparing respective stock solutions. They were bath-applied at a dilution >1:1,000 to give a final concentration of 0.2 mM (8-Br-cGMP) and 0.1 mM (BaCl2).
Data analysis
Numerical data were expressed as means ± SD. The statistical significance was assessed using paired or unpaired Student's t-test, or using ANOVA followed by Fisher's PLSD (protected least-significant difference) post hoc test.
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RESULTS |
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Given that the leak K+ current was mediated by the activity of TASK channels, the leak K+ current in the presumed BFC neurons would be sensitive to changes in the external pH. This possibility was investigated under the voltage-clamp condition at a holding potential of –70 mV. The external pH was changed after the baseline current reached the respective steady levels that remained constant for 
30 s at respective pH values (Fig. 1A). Following changes of external pH from 8.3 to 6.3, the baseline current decreased from a positive value to a minimum level (Fig. 1, A and Cb). To isolate pH-sensitive components, the amplitude of the baseline current (Ix) was scaled between 0 and 1 and defined as the scaled baseline current (S-Ix) as follows: S-Ix = (Ix – IpH6.3)/(IpH8.3 – IpH6.3), where x is the pH of the external solution. The amplitudes of S-I at pH 6.3, 7.3, and 8.3 were 0, 0.34 ± 0.05, and 1, respectively (Fig. 1B, n = 5).
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; Kim et al. 1998; Leonoudakis et al. 1998). In the next experiments, we examined whether this pH-sensitive current is sensitive to Ba2+. Ba2+ sensitivity of pH-sensitive currents in the presumed BFC neurons
After the current responses to the ramp pulse were obtained at pH 7.3 and 8.3 (Fig. 2 Aa, black and gray traces, respectively), 100 µM Ba2+ was added in the extracellular solution maintained at pH 8.3. Ba2+ substantially reduced the current response at pH 8.3 (Fig. 2Ab, gray trace). Thereafter, when pH was decreased from 8.3 to 7.3 in the presence of Ba2+, the current response remained almost unchanged (Fig. 2Ab, compare gray and black traces). Ba2+-sensitive currents at pH 8.3 and 7.3 (Fig. 2Ba) were obtained by subtracting currents obtained after application of Ba2+ (Fig. 2Ab) from those obtained before application of Ba2+ (Fig. 2Aa) and their I–V relationships were revealed to be inwardly rectified (Fig. 2Bb). The pH-sensitive currents were also obtained by subtracting the current responses obtained at pH 7.3 from those at pH 8.3, before and after application of Ba2+ (Fig. 2Ca, black and gray traces). As revealed in the I–V relationship, the pH-sensitive current in the absence of Ba2+ was slightly outwardly rectified (Fig. 2Cb, black trace), whereas in the presence of Ba2+ there was little pH-sensitive current over the voltage range from –130 to –40 mV (Fig. 2Cb, gray trace). In six presumed BFC neurons, when the possible conductance decrease following decreasing pH from 8.3 to 7.3 was measured in the presence of Ba2+, the conductance changed from 6.4 ± 1.6 to 6.1 ± 1.8 nS by –0.2 ± 0.6 nS. There was no significant (P > 0.4) decrease in the conductance in the presence of Ba2+, contrasting to large conductance decreases observed in the absence of Ba2+ following the same decrease in the external pH (–7.0 ± 4.4 nS, n = 5, P < 0.04).
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Differential effects of 8-Br-cGMP on the leak K+ current between pH 6.3 and pH 7.3
8-Br-cGMP (0.2 mM) was applied at pH 7.3 after examining the control current responses to the ramp pulse at pH 8.3, 7.3, and 6.3 (Fig. 3, A and B). Following application of 8-Br-cGMP at pH 7.3, both the baseline current and the conductance increased considerably, exceeding their original values at pH 7.3, as revealed in the continuous recording (Fig. 3, A and B, a and b; compare *1 and *3) and by the superimposed traces of current responses (Fig. 3Ca). The 8-Br-cGMP–induced current can be obtained by subtraction of the current response (Fig. 3B, *1) at pH 7.3 before application of 8-Br-cGMP from that (Fig. 3B, *3) at pH 7.3 during application of 8-Br-cGMP (Fig. 3Cb, *3 – *1, gray trace). By contrast, there was nearly no difference in the current responses at pH 6.3 obtained before and after 8-Br-cGMP application (Fig. 3Ba; compare *2 and *4), as revealed by the current obtained by subtraction of *2 from *4 (Fig. 3Cb, *4 – *2, black trace). In agreement with this observation, neither the baseline current nor the ramp response was affected significantly (Fig. 3D, a and b) when 8-Br-cGMP was applied at pH 6.3. Thus 8-Br-cGMP increased the pH-sensitive leak K+ current at pH 7.3, but failed to increase at pH 6.3.
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To further examine the sensitivity of 8-Br-cGMP–induced current to external pH changes, current responses were recorded at various external pH values before, during, and after application of 8-Br-cGMP. Since even the brief application of 8-Br-cGMP caused a long-lasting hyperpolarization (half-duration, 29 ± 12 min, n = 5) in the presumed BFC neurons (see Figs. 2B, 4B, and 5 in Kang et al. 2007 and see also Fig. 6 in this paper), effects of pH changes on the 8-Br-cGMP–induced current can be safely examined at least for 20–30 min after the removal of 8-Br-cGMP. Therefore 8-Br-cGMP was applied only once in this experiment. The external pH was changed only after the baseline current reached a steady level that remained constant for 30 s.
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) and inwardly rectifying K+ (Kir) channels (Farkas et al. 1994) in response to the ramp command pulse, the I–V relationship would neither be linear nor display GHK rectification (Fig. 4Ca, *2). When the leak K+ conductance was increased by 8-Br-cGMP or by raising pH, the space clamp would become less stringent, resulting in less activation of voltage-dependent currents (Fig. 4Ca, *4). Since 8-Br-cGMP–induced K+ currents can be isolated only by the subtraction method following application of 8-Br-cGMP in native BFC neurons (Fig. 4C, a and b), the I–V relationship (Fig. 4Cb, gray trace) may be less accurate, especially at very depolarized or hyperpolarized membrane potentials due to the larger contamination by Kv and Kir currents, respectively, in the control condition (Fig. 4Ca, *2). External pH-dependent effects of 8-Br-cGMP on leak K+ currents
Summary data of the external pH-dependent effects of 8-Br-cGMP are shown in Fig. 5. Bath application of 8-Br-cGMP increased the conductance of the leak K+ current measured between –70 and –95 mV in a manner dependent on the external pH. The conductance obtained after application of 8-Br-cGMP at pH 7.3 was 2.24 ± 0.43-fold larger than the control (Fig. 5A, P < 0.02, n = 6). However, those at pH 8.3 and 6.3 were only 1.10 ± 0.09-fold (P > 0.05, n = 6) and 1.03 ± 0.03-fold (P > 0.1, n = 6) larger than their controls, respectively (Fig. 5A). Using these values of normalized conductances and the scaled conductances in the control condition (Fig. 1D), the possible scaled conductances of 8-Br-cGMP–induced leak K+ currents at the respective pH levels were calculated. The scaled conductances at pH 6.3, 7.3, and 8.3 following application of 8-Br-cGMP were 0, 0.90, and 1, respectively (Fig. 5B, hollow columns). As represented by solid (control) and hollow (8-Br-cGMP) columns (Fig. 5B), the pH profile of scaled conductances was dramatically changed by 8-Br-cGMP. Although the modified pH profile was not necessarily obtained following pH changes in the same neurons, it is likely that 8-Br-cGMP changed the pH sensitivity of the leak K+ current, from the one similar to that of TASK1 to the other rather similar to that of TASK3 current (Berg et al. 2004; Kang et al. 2004). Indeed, after 8-Br-cGMP application, the K+ current obtained by pH decrease from 7.3 to 6.3 was larger than that obtained by pH decrease from pH 8.3 to 7.3 (n = 3, Fig. 4), contrary to the case seen in the control condition (Fig. 1). In the next experiment, Ba2+ sensitivity of 8-Br-cGMP–induced current was examined.
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In the presence of Ba2+, 0.2 mM 8-Br-cGMP was bath applied for 5–6 min under the voltage-clamp condition (Fig. 6, A and B). There were no significant differences in either the baseline current level (P > 0.9) or the conductance (P > 0.8) between the current responses obtained before (9 ± 33 pA and 3.9 ± 1.2 nS, respectively) and 5–6 min after application of 8-Br-cGMP (10 ± 23 pA and 4.0 ± 1.2 nS, respectively) in five presumed BFC neurons examined (Fig. 6B, compare *1 and *2; see also Fig. 6D, a and b). Nevertheless, following the simultaneous washout of Ba2+ and 8-Br-cGMP, the baseline current level was significantly (P < 0.001) shifted outwardly from 10 ± 23 to 88 ± 24 pA by 78 ± 27 pA (n = 5) when measured from the original baseline current level, and the conductance was also significantly (P < 0.002) increased from 4.0 ± 1.2 to 7.2 ± 2.5 nS by 3.2 ± 1.5 nS (n = 5) (Fig. 6B, compare *2 and *3; see also Fig. 6D, a and b). Consistent with the I–V relationship shown in Fig. 2Bb, the Ba2+-sensitive component of 8-Br-cGMP–induced current obtained by subtraction of the current response at the time point of *1 from that at *3 in Fig. 6B displayed slight inward rectification (Fig. 6C, *3 – *1). By contrast, 8-Br-cGMP induced no marked current at potentials examined by the ramp pulse in the presence of Ba2+, as revealed by subtraction of the current response at the time point of *1 from that at *2 in Fig. 6B (Fig. 6C, *2 – *1). The long-lasting nature and Ba2+ sensitivity to 8-Br-cGMP–induced conductance increase were confirmed by the second brief application of Ba2+ (Fig. 6, A and B). These observations clearly indicate that 100 µM Ba2+ completely antagonized the action of 8-Br-cGMP. Thus 8-Br-cGMP–induced K+ current was almost completely blocked at any potential examined, by lowering external pH to 6.3 as well as by bath application of 100 µM Ba2+, as was the case with the pH-sensitive current expressed in the presumed BFC neurons. Therefore the 8-Br-cGMP–induced K+ current is likely to be mediated by a pH- and Ba2+-sensitive leak K+ current expressed in the presumed BFC neurons.
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DISCUSSION |
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Among the 2P-domain K+ channels, TASK channels (Duprat et al. 1997; Talley et al. 2000) are the most likely candidates for the leak K+ channels. Indeed, the presumed BFC neurons displayed pH-sensitive currents in the present study (Figs. 1–5), and the external pH decrease from 8.3 to 7.3 caused significantly larger changes in the conductance than did the pH decrease from 7.3 to 6.3 (Fig. 1). Therefore the presumed BFC neurons express K+ channels similar to TASK1 channels in the recombinant systems (Duprat et al. 1997; Kim et al. 1998; Leonoudakis et al. 1998).
As reported in the previous studies using in situ hybridization, many neurons in nuclei of medial septum/diagonal band (MS/DB) expressed a moderate to abundant amount of mRNA of TASK1 channels (Karschin et al. 2001; Talley et al. 2001), whereas there were only few cells in MS/DB that abundantly express mRNA of TASK3 channels (Karschin et al. 2001). Our electrophysiological findings are in good agreement with these histological observations. Given the expression of TASK1 channels in the BFC neurons as reported histologically, TASK1 currents should be reflected, at least partly, in our electrophysiological observations.
Contamination of GHK rectification with voltage-dependent Kir and Kv currents
The 8-Br-cGMP–induced K+ current was invariably and completely inhibited by the external acidification to pH 6.3, regardless of whether it displayed a clear GHK rectification (Figs. 3–5). This clearly indicates the acid sensitivity of 8-Br-cGMP–induced K+ currents in the presumed BFC neurons, which displayed pH-sensitive leak K+ current similar to TASK1 currents in its pH sensitivity. However, the 8-Br-cGMP–induced K+ currents did not necessarily display GHK rectification, unlike TASK1 current. This is because the 8-Br-cGMP–induced K+ current was often contaminated with Kv and Kir currents at very depolarized or hyperpolarized membrane potentials, respectively. When the leak K+ conductance was increased by 8-Br-cGMP or by raising pH, the space clamp would become less stringent, resulting in less activation of voltage-dependent currents (Figs. 2Aa, 3Ca, and 4Ca, gray traces). Then, the I–V relationship of the 8-Br-cGMP–induced or pH-sensitive current isolated by the subtraction method in native neurons (Fig. 2Cb, black trace; Figs. 3Cb and 4Cb, gray traces) may be less accurate, especially at very depolarized or hyperpolarized membrane potentials due to the contamination with Kv and Kir currents, respectively (Figs. 2Aa, 3Ca, and 4Ca, black traces). Thus the apparent inconsistency with GHK rectification does not necessarily exclude the possibility of involvement of leak K+ or TASK current in 8-Br-cGMP–induced pH-sensitive K+ current.
Modulation of pH-sensitive leak K+ current by cGMP in the presumed BFC neurons
In the absence of 8-Br-cGMP, the conductance increase was significantly larger following raising pH from 7.3 to 8.3 than raising pH from 6.3 to 7.3 (Fig. 1). On the contrary, after the application of 8-Br-cGMP, the conductance increase was significantly larger following raising pH from 6.3 to 7.3 than raising pH from 7.3 to 8.3, as was confirmed in three neurons tested (Fig. 4). This suggests that 8-Br-cGMP may have changed the pH sensitivity of the leak K+ current, from the one similar to that of TASK1 to the other rather similar to that of TASK3 current, as seen in the pH profiles of the scaled conductances obtained in the control condition and after 8-Br-cGMP application (Fig. 5B, solid and hollow columns, respectively).
Similar upregulations of TWIK-related K+ channel 1 (TREK1) and TWIK-related alkaline pH-activated K+ channel (TALK) channels by cGMP have been reported in nonneuronal cells; the NO–cGMP pathway acts to open TREK1 in smooth muscles (Koh et al. 2001) and TALK in the acinar cell of the exocrine pancreas (Duprat et al. 2005). However, since TREK1 and TALK channels are much less sensitive to the acidification to pH 6.3 (Duprat et al. 2005; Patel and Honore 2001), it is unlikely that these channels are responsible for the acid-sensitive 8-Br-cGMP–induced K+ current in the presumed BFC neurons.
Many neuromodulators closing leak K+ channels including TASK1 channels have been reported in a variety of neurons in the thalamus and cortex (McCormick 1992), cerebellum (Abudara et al. 2002; Millar et al. 2000), and brain stem (Talley et al. 2000). By contrast, the endogenous neuromodulators opening leak K+ channels in neurons remained unknown, although the volatile general anesthetics have been found to open TASK1 channels in neurons of the locus coeruleus (Sirois et al. 2000) and TASK1/3 channels in neurons of the raphe nucleus (Washburn et al. 2002). The present study demonstrates for the first time in neurons that cGMP activates leak K+ channels in the presumed BFC neurons, although we did not identify the detailed subtype of the acid-sensitive leak K+ channel. This identification would be a very important issue in a future study.
Ba2+ sensitivity of the pH-sensitive K+ current
Ba2+ sensitivities of cloned rTASK (Leonoudakis et al. 1998) or TASK1 (Millar et al. 2000) channels appeared to be lower (IC50 = 0.35 mM) than those of the pH-sensitive current or 8-Br-cGMP–induced responses seen in the present study (Figs. 2 and 6). However, Ba2+ sensitivity was increased by replacing some amino acids of the channel proteins with histidine in TASK1 channels, although its acid sensitivity was reduced (O'Connell et al. 2005). Then, it may be possible that native wild-type TASK1 channels are more sensitive to Ba2+ than recombinant TASK1 channels in expression systems, given the unknown posttranslational modification of TASK1 channels, partly similar to replacement of the amino acids. Indeed, a similar high Ba2+ sensitivity of TASK1/3 channels has been reported in thalamocortical neurons, in which no pH-sensitive K+ current remained in the presence of 150 µM Ba2+ (Meuth et al. 2003), as seen in the present study (Figs. 2 and 6).
Ba2+-sensitive currents or Ba2+-sensitive components of 8-Br-cGMP–induced currents obtained by the subtraction method did not display GHK rectification. Instead, these usually displayed an inward rectification (Figs. 2B and 6C). However, this is completely consistent with the previous report, in which the voltage-dependent blockade of TASK1 channels by Ba2+ became apparent as [Ba2+]o is increased (O'Connell et al. 2005). As the membrane potential was hyperpolarized, the attraction of positively charged blocking ions to the channel pore would increase, resulting in an increase in the degree of channel block (Hille 2001). Then, the "inward rectification" of Ba2+-sensitive K+ current is not due to the rectification of the channel itself, and has nothing to do with the inwardly rectifying nature of Kir channels mediated by intracellular Mg2+ (Matsuda et al. 1987) and polyamine (Ficker et al. 1994; Lopatin et al. 1994). Therefore the apparent inwardly rectifying nature of Ba2+-sensitive current does not necessarily mean the involvement of Kir channels in generating the inward rectification, as were the cases with recombinant TASK1 channels (O'Connell et al. 2005) and TASK1/3 channels in thalamocortical neurons (Meuth et al. 2003).
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FOOTNOTES |
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The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Address for reprint requests and other correspondence: Y. Kang, Department of Neuroscience and Oral Physiology, Osaka University Graduate School of Dentistry, 1-8, Yamadaoka, Suita, Osaka 565-0871, Japan (E-mail: kang{at}dent.osaka-u.ac.jp)
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REFERENCES |
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pH7.3 = [(