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The main goal of this study was to investigate the effect of H2S on ion currents and membrane potentials of Helix pomatia U-cells. H2S is generally known as a very toxic gas but the relatively high levels of 50-160 µmol/l H2S in mammalian brain tissue (Savage & Gould, 1990; L R Goodwin et al., 1989; Marcus W. Warenycia et al., 1989) and the physiological functions of H2S like synaptic modulation, vasorelaxation and neuroprotection (reviewed by Åowicka & BeÅ‚towski, 2007 and Mancardi et al., 2009) suggest an important role as gaseous signaling molecule. As reviewed in Wang (2002) it is hypothesized that H2S is the third gasotransmitter beside CO and NO. H2S acts on many targets including ion channels such as potassium and calcium channels (Kawabata et al., 2007; W. Yang et al., 2005; Zhao & Rui Wang, 2002; Zhao et al., 2001; Sitdikova et al., 2010). The research on physiological effects of H2S on ion channels increases our knowledge about the function of gasotransmitters in invertebrates and vertebrates.
In the present study NaHS was used as a H2S donor and applied extracellularly to the ganglia. NaHS was usually used at a concentration of 100 µM in the experiments, whereas at a physiological pH of 7.4 approximately one third of H2S is present in the undissociated form and the remaining two third exist in HS- (R J Reiffenstein et al., 1992). The concentration of about 30 µmol/l H2S, which is effectively in the solution, is even below the range of 50-160 µmol/l detected in mammalian brain tissue (Savage & Gould, 1990; L R Goodwin et al., 1989; Marcus W. Warenycia et al., 1989) and similar to the reported plasma levels of 34 µmol/l H2S in mice and 44 µmol/l H2S in humans (Li et al., 2005). The influence of 100 µM Na+ on the electrophysiological experiments is negligible, because the bath solution for controls contains 80 mmol/l of Na+. NaHS also doesn't influence the pH of the bath solution at concentrations of <1mmol/l NaHS (Hideo Kimura et al., 2005).
In the present study an increase in the potassium outward currents after extracellular application of 100 µM NaHS was found. This effect was smaller in Ca2+-free solution. NaHS shifted the I-V curve of potassium outward currents to the left on the voltage axis. 100 µM NaHS significantly (p<0.05) decreased the calcium inward current and changed the activation and inactivation kinetics of Ca2+ channels. Ï„ of activation kinetic was significantly (p<0.05) decreased and Ï„ of inactivation kinetics was increased by NaHS.
100 µM NaHS acted on firing cells in many ways and changed the action potential time course in current clamp experiments. The membrane potential was depolarized significantly (p<0.05) and the action potential amplitude was significantly (p<0.05) decreased. The action potential rise slope and maximum rise slope as well as decay slope and maximum decay slope are decreased under NaHS condition (all differences are significant except rise slope). Action potential rise time and decay time are significantly (p<0.05) increased compared to control conditions. The action potential half-width, which is a measurement of the action potential duration at half of the amplitude, is prolonged by NaHS.
One of the most conspicuous effects of 100 µmol/l NaHS in the experiments was the increase of potassium outward currents in voltage clamp experiments, with a half maximum concentration of 49.81 ± 7.41 µmol/l NaHS. This shows that H2S induces effects on the outward currents even below the observed physiological relevant concentration of 50-160 µmol/l (Savage & Gould, 1990; L R Goodwin et al., 1989; Marcus W. Warenycia et al., 1989). The relatively steep dose-response curve illustrates the narrow range of the physiological H2S effect. At concentrations of 1 mmol/l the effect of H2S on the outward current was already reduced to 70 ± 7.81 % of the full effect. In experiments on hippocampal slices in rats, endogenous H2S levels of 50-160 µmol/l have been shown to facilitate the long term potentiation (LTP). But H2S concentrations of 320 and 640 µmol/l suppressed field EPSPs and population spikes and no effect was observed (Abe & H Kimura, 1996). Furthermore, lethal H2S concentration in the brain of rats is only 2-fold (!) higher than endogenous levels of H2S (Marcus W. Warenycia et al., 1989). A small range of H2S effect on formation of memory was also observed in the snail Lymnaea stagnalis. Exposure to 75 and 100 µmol/l showed an effect on learning and memory formation, whereas 50 µmol/l H2S showed no effect (Rosenegger et al., 2004).
H2S shifts the I-V curve of outward currents to the left, which indicates that ion channels activate at lower membrane potentials. The I-V relationship shows that outward currents at physiological membrane potentials (V = < +50 mV) are increased by H2S. In patch clamp and whole cell experiments it has been demonstrated that the outward current in U-cells flows mainly through BK-type Ca2+ activated K+ channels (Gola et al., 1990). The observed increase of K+ outward current below +50 mV caused by H2S matches with the range where the BK-type current is predominant, making the BK-type channels a possible target of H2S. A fast activating and inactivating potassium outward current also referred to as transient outward K+-current (IK(A)) has been discovered in invertebrate and vertebrate cells (Connor & C F Stevens, 1971; Rogawski, 1985; Y. Nakajima et al., 1986) and was found in medium sized Helix neurons (Erwin Neher, 1971; Kiss et al., 2002). However IK(A) has not been reported to be prominent in U-cells. The presence of the IK(A) and delayed outward current are indicated by an initial rapid rise in the outward current, which results in a change from a fast to a slow rise. Experiments on U-cells where different depolarizing pulses were delivered (+20 to +120 mV) (data not shown) reveal a very small change in the time course of the outward currents compared to other cells in Helix pomatia. This suggests that this current component makes only a minor contribution to the total current. In experiments conducted by Lux and Hofmeier (1982) these fast activating currents were determined by the amplitude of the current at the point of the maximum change in the current time course. The measured current values at this point contribute less than 7% to the total outward current during a depolarizing pulse. Furthermore a fast outward current was found in U-cells and was attributed to voltage dependent K+-channels (KV channels). But in U-cells the KV component was only detectable at large depolarizations, and in the physiological range at voltages lower than +40 mV this component contributed less than 10 % to the net outward current. It was found that KV channels played a limited role in U-cells (Crest & Gola, 1993) and the outward current in U-cells consists almost exclusively of Ca2+ mediated K+ outward current (H D Lux & Hofmeier, 1982). These findings strongly suggest that BK-type channels are involved in the increased outward current caused by H2S.
Intracellular buffering of Ca2+ by dibromo-BAPTA abolished the N-shape in the IV curve of outward currents and the H2S evoked increase of outward currents below +50 mV. These facts also suggest that BK-type channels play a role in the outward current increasing effect of H2S. A recent patch clamp study carried out by Sitdikova et al. (2010) supports this assumption. H2S enhanced the activity of BK channels in rat pituitary tumor cells by increasing the channel open probability.
As shown in the I-V curve the outward currents above +120 mV are as well increased by H2S. The increase of outward currents above +120 mV was not abolished after injection of dibromo-BAPTA, which buffered intracellular Ca2+. But the increased activation of the BK-type channels could account for this effect above +120 mV as well. It was found that the activation of hSlo (BK channel in human cells) becomes independent below intracellular Ca2+ concentration of 100 nmol/l and activates at +200 mV (Vergara et al., 1998). It is possible that BK-type channels in Helix pomatia above +120 mV activate in the absence of intracellular Ca2+ and are involved in the increasing effect of H2S on the outward current above +120 mV. H2S could also increase the KV current component above +120 mV. Further experiments are required to investigate which current components are responsible for the increased outward current above +120 mV.
Using CP 339818 hydrochloride, a Kv1.3 and Kv1.4 K+ channel blocker, reduced the K+ outward current only in some cells. In these cells H2S still increased the outward currents, which leads to the assumption that the effect of H2S is not carried by KV channels to a large extent. But in some cells H2S had no effect after perfusion with CP 339818 hydrochloride. In cells where CP 339818 hydrochloride had a small or no effect the increase of the outward current after NaHS application was relatively high. This could have different reasons: (1) CP 339818 hydrochloride didn't block KV channels completely and therefore NaHS could activate these channels which would cause the increase in outward current. (2) Cells which were not or to a small extent affected by CP 339818 hydrochloride had a relatively small number of KV-channels and large number of BK-type channels and the latter would cause the increase in outward current after NaHS application. The fact that KV channels contribute only 10 % to the outward current at voltages below +40 mV (Crest & Gola, 1993), rather suggests the second possibility.
In voltage clamp experiments Ca2+-free solution reduced the total outward current, which suggests that Ca2+ activated K+ currents are reduced in Ca2+ free medium. This assumption is strengthened by the finding that Ca2+-free bath solution suppresses Ca2+ activated K+ current in U-cells (H D Lux & Hofmeier, 1982). In calcium free solution H2S increases the outward currents only to 124 %, whereas in control bath solution (containing Ca2+) H2S increases the outward current to 178 %. Thus, the increasing effect of H2S on the outward currents is reduced to 31 % compared to the effect in normal bath solution. Therefore suggesting that reduced Ca2+-activated K+-currents cause a strong decrease of the H2S effect, indicating an important role of BK-type channels in the effect of H2S.
These results may raise the question why the outward current wasn't completely blocked by Ca2+-free solution. Since a small amount of the outward current in U-cells is ascribed to the KV current, the remaining outward current could be ascribed to the KV current, which does not particularly depend on extracellular Ca2+ (Heyer & H D Lux, 1976). Given that H2S increased the remaining current component in Ca2+ free condition, the increased outward current could then be ascribed partly to an increase of the KV current component. Furthermore, a nominally Ca2+ free solution still contains some Ca2+ (H D Lux & Hofmeier, 1982), maybe preventing a complete blocking of Ca2+ activated K+ current. Further experiments are necessary to find out to which extent BK-type channels and KV channels are involved in the effect of H2S.
In patch clamp studies on Helix U-cells it was found that Ca2+-activated K+-channels have to be colocalized with Ca2+ channels to be involved in firing of nerve cells. Furthermore the Ca2+-activated K+-channels did not open if related Ca2+ channels were prevented from opening (Gola & Crest, 1993). These results indicate a strong functional relationship between Ca2+-activated K+-channels and Ca2+-channels. Therefore one could assume that a possible increase of Ca2+-inward current caused by H2S, which would consequently lead to enhanced activation of Ca2+ activated K+ channels, could lead to an increased outward current.
But experiments of the present study in Na+-free solution containing the K+-channel blockers TEA and 4-AP, showed a decrease of the HVA Ca2+ inward current in H2S conditions. The decrease of HVA Ca2+-current by 15 % rules out the hypothesis that an increase in Ca2+ inward current is responsible for the increased K+ outward current. Though the I-V curve shows an increase of the HVA Ca2+-current at 0 mV in H2S condition, it is assumed that this effect is not responsible for the measured increase of outward current. In voltage clamp experiments the cells were usually depolarized to +20 mV, and at this potential the HVA Ca2+-current was decreased by H2S as it is shown in the I-V curve of HVA Ca2+-currents. An inhibitory effect of H2S on L-type Ca2+ channels was also found in cardiomyocytes of rats (Sun et al., 2008). In this study it was observed that the recovery from depolarization-induced inactivation was inhibited by NaHS. No shift of the HVA Ca2+-current I-V curve was found after NaHS treatment in our study, which is in line with the findings of Sun et al. (2008). This suggests that the voltage dependence of HVA Ca2+ channels was not modified by an interaction with H2S.
A study carried out on astrocytes showed that H2S induces Ca2+ waves mainly through an increase of Ca2+ influx (NAGAI et al., 2004). This finding seems to be contradictory to the discovered decrease of HVA Ca2+ channels in the present study. However the type of Ca2+ channel, which was affected by H2S in astrocytes was not determined. Therefore it can be assumed that in mammalian astrocytes a different type of Ca2+ channel was affected by H2S than in the mollusk U-cell of Helix pomatia. Exposure of cerebellar granule neurons to H2S for two hours raises cytosolic Ca2+ through activation of L-type Ca2+ channels (García-Bereguiaín et al., 2008). But in mollusks L-type like Ca2+ channels were found to have different properties (conductance, sensitivity to blockers, activation) (Kits & Mansvelder, 1996), and it can be assumed that H2S affects Ca2+ channels in Helix pomatia in a different way.
By applying curve fitting to the HVA Ca2+ inward current it was found that H2S decreases the activation time of the current. â€¦â€¦.Hier sollte noch Text hinzukommen, sobald ich Artikel von der Bibliothek erhalten habe.
In order to investigate the effect of H2S in physiological conditions, current clamp experiments were carried out. H2S reduced the amplitude of action potentials and changed the time course. In control bath solution the action potential overshoot peaked at +46.4 ± 2.33 mV, which is similar to the overshoot of +42 mV found in a previous study (Crest & Gola, 1993). Cell free single channel recordings in constant Ca2+ concentration suggest that the H2S effect on BK channels is independent of the external Ca2+ influx (Sitdikova et al., 2010). Given that no Ca2+ influx is necessary for the H2S effect on BK channels, a constant modulating of BK type channels by H2S can be assumed. This presumably leads to activation at lower membrane potentials, which is supported by the shift of the I-V current to the left. An activation of BK-type channels at lower potentials would overlap the inward current and consequently lead to a decreased net inward current during the action potential overshoot. This is in line with the finding that the Ca2+-activated K+ current overlaps the Ca2+ inward current during spike burst and leads to a reduction of the depolarizing tendency (Crest & Gola, 1993). A decrease of action potential amplitude by H2S was also obtained in a study carried out in rat atrial myocardium (Abramochkin et al., 2009). H2S changed the electrical activity by decreasing the action potential time course and amplitude. Furthermore 500 µM NaHS caused a depression of electrical activity after 4 min. of perfusion. This fits the results of our study, where a depression of firing activity was also observed in three out of four experiments after 6.4 ± 2.8 min. Activation of BK-type channels could be a possible explanation for this effect as well. Overlapping of a constantly increasing Ca2+-activated K+ current with the Ca2+ inward current was observed to cause a stop in firing activity of U-cells (Crest & Gola, 1993).
It is also very likely that the observed decrease of Ca2+ current reduces the action potential amplitude. Since the inward current is mainly carried by Ca2+ in U-cells and the action potentials are considered as Ca2+ spikes (Gola et al., 1990; H D Lux & Hofmeier, 1982; Crest & Gola, 1993), it is very likely that the decrease of the HVA Ca2+ current is involved in the reduction of the action potential amplitude after NaHS perfusion.
The action potential rise time and the action potential decay time was increased by H2S leading to a wider action potential, which also becomes apparent in the increased half-width time. Assuming an activation of BK-type channels by H2S a reduced duration of action potentials could be expected, which was already observed in rat atrial myocardium (Abramochkin et al., 2009). Further studies are required to find out which affect causes the increased half-width time of action potentials in Helix pomatia U-cells.
In further analysis a maximum rise slope of 14.35 ± 1.66 V/s was observed, which is similar to the rise slope of 13.5 V/s found by Crest & Gola (1993). H2S decreased the maximum rise slope to 8.62 ± 1.54 V/s. Given that the maximum rise slope of the action potential is proportional to the inward current (Hodgkin & Katz, 1949), the decreased Ca2+ current presumably leads to a lower rise slope. Furthermore an increase of BK-type channel activity could also result in a reduced net outward current which would lead to a decreased rise slope. It was observed that BK-type channels open a few milliseconds after the spike overshoot (Gola et al., 1990). But BK-type channels probably activate earlier in H2S conditions, and therefore could affect the rise slope.
The observed maximum decay slope of 6.93 ± 0.80 V/s was found to be similar to 8.8 V/s obtained by Crest & Gola (1993). H2S decreased the maximum decay slope to 4.02 ± 0.63 V/s. Further studies are needed to investigate which effect leads to the decreased action potential decay time and decay slope.
BK-type channels show a fast voltage dependence. BK-type K+ currents last a few tens of milliseconds after the action potential and it is assumed that these channels are not directly involved in shaping of interspike trajectory (Lancaster et al., 1991). Thus BK-type K+ channels are presumably not involved in the depolarizing effect of H2S on the membrane potential. Moreover activation of BK channels by H2S would lead to a hyperpolarization of the membrane potential. A decrease of the K+ outward current at the resting potential is one possible explanation that could lead to a depolarization of the membrane potential by H2S. But no decrease of the outward current was observed at resting potentials in the I-V curves by H2S, which could provide an explanation for the depolarizing effect of H2S on the membrane potential. Since Ca2+ inward currents are not activated at membrane potentials below -20 mV, it can be ruled out that an increase of this current accounts for the depolarizing effect. The reason for the depolarized resting potential remains to be determined and further current clamp and voltage clamp experiments are needed to investigate this effect.
The results strongly suggest an activating effect of H2S on BK-type channels. Given that H2S is a reducing agent the modulating effect on BK channels is linked to the reducing action on proteins. BK channel activity is increased by reducing agents in different cell types like human embryonic kidney 293 cells (DiChiara & Reinhart, 1997), CA1 pyramidal neurons from adult rat hippocampus (Gong et al., 2000), myocytes from rabbit pulmonary artery (Thuringer & Findlay, 1997) and smooth muscle cells (Zhao-Wen Wang et al., 1997). This is supported by the finding that Dithiothreitol (DTT) itself increases the open probability (Popen) of BK channels but abolishes the H2S effect on BK channels, whereas the oxidizing agent thimerosal reduces Popen of BK channels without inhibiting the H2S effect (Sitdikova et al., 2010). BK channel activity is modulated by DTT and thimerosal only when applied to the intracellular side of the patch (Zhao-Wen Wang et al., 1997), suggesting that the cysteine residue which is responsible for the redox modulation (Erxleben et al., 2002), is on the intracellular side of the ion channel. In the experiments of the present study NaHS was applied extracellularly, but since H2S is not charged and easily permeates cell membranes, presumably it acts from the cytosolic side on BK-type channels. BK channel activity is modulated by the redox state of critical sulfhydryl groups, located in the channel protein or an associated regulatory protein (DiChiara & Reinhart, 1997; Z W Wang et al., 1997).
In summary, the present study demonstrates that H2S increases the potassium outward current, whereas BK-type channels are very likely to contribute to this effect. Furthermore the HVA Ca2+ current is decreased and the activation and inactivation time is changed by H2S. These changes in inward as well as in outward currents, finally lead to a change in the firing activity of U-cells. It can be assumed that the reduced action potential amplitude, the changed time course of action potentials and the depolarized membrane potential have physiological effects. A link of electrical activity and H2S was also found in a study carried out on mice. H2S production was found to be enhanced by neural excitation and by the excitatory neurotransmitter L-glutamate. Furthermore long term potentiation (LTP) is altered in cystathionine Î²-synthase (CBS) knock-out mice and therefore H2S may regulate synaptic activity (Eto et al., 2002).
In order to investigate the effect of H2S on associative learning and the formation of memory, Rosenegger et al. (2004) carried out operant conditioning experiments on the snail Lymnaea stagnalis. If 100 µmol/l H2S was applied during the operant conditioning process neither learning nor formation of long-term memory (LTM) were observed. The experiments also showed that the memory consolidation process is not impeded by H2S. In rat hippocampal slices LTP was found to be facilitated by physiological concentrations of H2S, if it was applied together with a weak tetanic stimulation (Abe & H Kimura, 1996). In the presence of the N-methyl-D-aspartate (NMDA) receptor antagonist 2-amino-5-phosphonovalerate (APV), H2S did not induce LTP. This suggests that activation of NMDA receptors is required for induction of LTP. H2S might therefore act different on NMDA receptors than NO and CO, because these two gasotransmitters induce LTP even under the blockade of NMDA receptors (Zhuo et al., 1993), suggesting that NO and CO take action as retrograde messengers at synapses (O'Dell et al., 1991; Schuman & Madison, 1991; Charles F. Stevens & Yanyan Wang, 1993). These studies provide examples of the physiological relevance of H2S.
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