1University Department of Pharmacology, Oxford, United Kingdom; and 2Department of Cell Physiology and 3Department of Molecular Medicine and Clinical Science, Nagoya University Graduate School of Medicine, Nagoya, Japan
Submitted 25 March 2004 ; accepted in final form 13 August 2004
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ABSTRACT |
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G proteins; micturition; oscillation; carbachol; SKF-96365
Comparative physiological and pharmacological studies have revealed that in guinea pig and rabbit, detrusor smooth muscle contractions induced by parasympathetic nerve stimulation contains a large atropine-resistant component of excitatory neurotransmission (5, 6). This component is nonadrenergic and noncholinergic. On the other hand, in the normal human detrusor, there is no atropine-resistant contraction, and in the pig, there is only a small nonadrenergic and noncholinergic response to nerve stimuli, although these smooth muscles clearly possess purinergic receptors in the plasma membrane (8, 13, 15, 35). These results suggest that humans and pigs have similar excitation-contraction (E-C) coupling mechanisms in controlling micturition.
Lines of evidence have been provided showing that Ca2+-activated Cl channels play important roles in E-C coupling and myogenic spontaneous rhythmicity in various smooth muscles (18, 21, 22, 33). Recently, we found that ETA receptor agonists promptly cause a large inward current and that during their continuous application, oscillatory inward currents with relatively small amplitudes persist. Furthermore, Cl channels seem to be responsible for both the initial transient and subsequent oscillatory inward currents (16). In this article, we report that similar inward currents are mediated by muscarinic receptors, which play a major role in human micturition. We propose that distinct intracellular Ca2+ release channels, i.e., inositol 1,4,5-trisphosphate (IP3) receptors and ryanodine receptors, contribute to activating the two inward currents. This fact might provide a new therapeutic target to control micturition in a phase-dependent manner in functional diseases of lower urinary tracts. The emphasis of the present study is especially placed on the latter, sustained component, which is necessary to complete voiding urine.
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METHODS |
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Membrane current recording.
Whole cell membrane currents were recorded using a standard patch-clamp technique (11). A patch-clamp amplifier (EPC-7; List, Darmstadt, Germany) was operated through a Macintosh computer equipped with an analog-to-digital/digital-to-analog converter (ITC-16; Instrutech). The resistance of the patch pipette was 34 M when a Cs+-rich pipette solution was used. After rupture of the cell membrane, the series resistance was normally <10 M
. Smooth muscle cells used had a membrane capacitance of 61.6 ± 11.7 pF (n = 25). The capacitive surge was electrically compensated. A cut-off frequency of 10 kHz was applied to reduce the noise. Unless otherwise described, the cell membrane was clamped at 60 mV (holding potential). The experiments were carried out at room temperature (2025°C).
Solutions and chemicals. The normal extracellular solution had the following composition (in mM): 140 NaCl, 6 KCl, 2.4 CaCl2, 12 glucose, and 5 HEPES; pH was adjusted to 7.4 with Tris base. This solution was also used as normal solution for cell isolation. Isosmotic substitution was used for all other changes in the ionic composition of the extracellular medium, including solutions used for cell isolation. In the Ca2+-free, Mg2+-free solution used for cell isolation, the osmotic pressure was also adjusted by modifying the NaCl concentration. In low extracellular Cl (low [Cl]out) solution, Cl was reduced to a concentration of 115 mM by substitution with equimolar aspartate.
The composition of the normal pipette solution was (in mM) as follows: 144 CsCl, 2 MgCl2, 0.05 EGTA, 2 ATP, and 10 HEPES-Tris (pH 7.2). The ionized Ca2+ concentration was set to 100 nM by adding 25 µM CaCl2. This solution results in the blocking of all of the K+ channels in the membrane. In some experiments, 1 mM guanosine 5'-O-(2-thiodiphosphate) (GDP
S) or 5 mg/ml heparin were added to the pipette solution to suppress G protein action or antagonize IP3 receptors, respectively. In low [Cl] pipette (low [Cl]in) solution, Cl was reduced to 78 mM by substitution with equimolar aspartate.
With the normal extracellular and pipette solutions (a quasi-equivalent Cl condition), the reversal (equilibrium) potential (Erev) calculated for Cl is 0.5 mV (at 25°C). When the low [Cl]out solution with normal pipette solution or the low [Cl]in solution with normal extracellular solution was used, the Erev calculated for Cl was +6.5 or 16.9 mV, respectively.
The following chemicals, drugs, and enzymes were used in the present study: ATP (disodium salt), N-methyl-D-glucamine (NMDG), nifedipine, niflumic acid, GDPS (trilithium salt), EGTA (free acid), trypsin inhibitor (type 1-S), collagenase (type H), papain, carbamyl choline chloride (carbachol, CCh), and atropine, obtained from Sigma (St. Louis, MO); SKF-96365, obtained from Tocris (Ballwin, MO); and cyclopyazonic acid (CPA) and xestospongin C, obtained from Calbiochem (Nottingham, UK).
The volume of the recording chamber was 0.2 ml. The extracellular solution was changed quickly (within a second) using a tear-drop device.
Statistics. Numerical data are expressed as means ± SD. The averaged amplitude of the inward current oscillation was calculated from the peaks of four to six currents when the amplitude of the oscillations had become stable. Differences between means were evaluated using t-tests or ANOVA; when a significant difference was permitted by ANOVA in the same category of groups, differences between groups were evaluated using the Bonferroni-Dunn test. A P value <0.05 was normally taken as a statistically significant difference.
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RESULTS |
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Figure 1D shows repetitive applications of CCh. The first and second applications of 10 µM CCh induced essentially similar transient inward currents. Furthermore, in eight detrusor cells that showed oscillating inward currents, effects of prolonged application of 10 µM CCh were examined for up to 30 min. In all of the eight cells, inward current oscillation lasted until washout of CCh.
The effects of changing the CCh concentration and membrane potential are shown in Fig. 2. Figure 2A shows a typical tracing of the effects of 10 and 100 µM CCh. The frequency of the inward current oscillations [(no. of inward currents observed)/(duration of exposure to a particular CCh concentration)] significantly increased in a dose-dependent manner (Fig. 2Ba: 0.020 ± 0.002 Hz at 1 µM, 0.044 ± 0.008 Hz at 10 µM, and 0.086 ± 0.021 Hz at 100 µM; ANOVA, P = 0.0041), whereas the amplitude did not (Fig. 2Bb: 103 ± 26 pA at 1 µM, 283 ± 122 pA at 10 µM, and 244 ± 108 pA at 100 µM, n = 5). Figure 2C shows a typical current trace examining the voltage dependence of the inward current oscillations. During continuous exposure to 10 µM CCh, the holding potential was altered from 80 to 20 mV (n = 6). The frequency of the inward current oscillations increased with increasing negativity of the membrane potential (Fig. 2Da: 0.063 ± 0.029 Hz at 80 mV, 0.049 ± 0.012 Hz at 60 mV, 0.034 ± 0.006 Hz at 40 mV, and 0.017 ± 0.009 Hz at 20 mV). The oscillation frequency at 80 mV was more than three times greater than that at 20 mV. The amplitude of the inward current was maximal at 60 mV (Fig. 2Db: 314 ± 213 at 80 mV, 372 ± 233 pA at 60 mV, 276 ± 190 pA at 40 mV, and 128 ± 97 pA at 20 mV).
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The Ca2+ dependence of the inward current oscillation was further examined. As shown in Fig. 3C, the extracellular Ca2+ concentration was changed during continuous application of CCh (10 µM) (n = 6). The frequency of the inward current oscillations was significantly increased by increasing the extracellular Ca2+ concentration in a dose-dependent manner (Fig. 3Da: 0.0095 ± 0.0005 Hz at 0 mM, 0.016 ± 0.003 Hz at 1.2 mM, 0.044 ± 0.019 Hz at 2.4 mM, and 0.064 ± 0.024 Hz at 4.8 mM; ANOVA, P = 0.0087). However, the amplitude of the inward current was less sensitive to extracellular Ca2+ (Fig. 3Db: 295 ± 144 pA at 0 mM, 265 ± 132 pA at 1.2 mM, 308 ± 161 pA at 2.4 mM, and 207 ± 37 at 4.8 mM; ANOVA, P = 0.4495).
Effects of channel blockers. The effects of blockers for plasmalemmal ion channels and modulators for intracellular Ca2+ release channels were next examined. Oscillatory inward currents were induced by 10 µM CCh. Nifedipine (100 nM), which would cause complete suppression of voltage-sensitive (L-type) Ca2+ channel current in detrusor smooth muscle (17, 27), had little affect on the CCh-induced current oscillation (control: 0.035 ± 0.010 Hz, 560 ± 383 pA; 100 nM nifedipine: 0.033 ± 0.020 Hz, 540 ± 333 pA, n = 4) (Fig. 4 Aa). This result suggests that voltage-sensitive Ca2+ channels are not essentially required.
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SKF-96365, a known general channel blocker that would suppress Ca2+ influx through transient receptor potential (TRP) homolog channels (12, 28, 31, 38), significantly reduced the frequency and amplitude of the oscillating inward currents at 10 µM (to 0.68 ± 0.24 and 0.66 ± 0.05 of control, respectively, n = 4) and completely suppressed them at 30 µM (Fig. 4B). Similar inhibitory effects of this drug were observed in all cells examined (n = 5). Niflumic acid, a known blocker of Ca2+-activated Cl channels (10), significantly suppressed the oscillatory inward currents at a concentration of 100 µM, as shown in Fig. 4C (n = 8).
Figure 4D shows that ryanodine (30 µM) completely and irreversibly inhibited the CCh-induced oscillatory inward currents (n = 4). Caffeine is also known to deplete intracellular Ca2+ stores in smooth muscle (14). Figure 4E shows that application of 10 mM caffeine in the presence of CCh (10 µM) abolished oscillatory inward currents and that subsequent washout completely restored them (n = 6). In addition, after caffeine was washed out in the presence of CCh (10 µM), the frequency of the oscillation increased (3.44 ± 0.98 times, n = 6) and the amplitude decreased for 24 min (0.26 ± 0.14 times, n = 5). These results suggest that Ca2+ release from the intracellular stores plays an important role in generating the inward current oscillations seen during CCh application.
Assessment of IP3 signaling pathway. In detrusor smooth muscle, muscarinic agonists are known to release Ca2+ from the intracellular stores via G protein activation and subsequent IP3 formation (26, 36). Figure 5 shows the effects of the IP3 receptor antagonists heparin and xestospongin C (cell membrane-impermeable and -permeable IP3 receptor antagonists, respectively) (9, 32). In Fig. 5Aa, the patch pipette contained 5 mg/ml heparin. Approximately 15 min after rupture of the cell membrane, application of 10 µM CCh still caused oscillatory inward currents, and 10 mM caffeine completely abolished them. Note that this heparin treatment caused remarkable changes in the features of the first CCh-induced inward current. The latency (time until the first inward current observed after application of CCh) was significantly prolonged from 10.5 ± 4.7 (control, n = 9) to 28.4 ± 8.8 s (heparin, n = 5) (Fig. 5Ab). Furthermore, the amplitude of the first inward current (Fig. 5Ac) was decreased from 2.83 ± 1.46 (control, n = 9) to 1.26 ± 0.18 (heparin, n = 5) relative to the mean amplitude of the following oscillatory inward currents.
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In Fig. 5C, the pipette solution contained 1 mM GDPS, which would completely inhibit the dissociation of
- and
-complexes of GTP-binding proteins. Application of 10 µM CCh caused neither the initial transient inward current nor the subsequent inward current oscillation (n = 25). In the detrusor cell study shown in Fig 5C, three procedures that would increase the [Ca2+]i independently of G proteins were subsequently carried out: 1) step depolarization to 0 mV (Ca2+ influx through voltage-sensitive Ca2+ channels), 2) application of 100 µM ATP (activation of Ca2+-permeable nonselective cation channels) (17), and 3) application of 10 mM caffeine (Ca2+ release from intracellular Ca2+ stores). Inward currents induced by the three procedures showed that Ca2+-activated ionic conductances, responses to P2X receptors, and Ca2+ release from intracellular stores are preserved even in the presence of GDP
S. These results suggest that G proteins play an essential role in generating intracellular Ca2+ oscillations during continuous application of CCh.
In addition, we characterized intracellular signaling of the CCh-induced single transient inward current seen in the majority of detrusor cells. As shown in Fig. 6A, 10µM CCh evoked a transient inward current even in the absence of extracellular Ca2+ (amplitude: 317 ± 275 pA; duration: 9.35 ± 8.57, n = 4). Furthermore, after observing that 10 µM CCh failed to induce any inward current in the presence of heparin (5 mg/ml) in the pipette, we examined the effect of caffeine, which would cause a transient rise in [Ca2+]i. As shown in Fig. 6B, subsequent application of 10 mM caffeine evoked a transient inward current. Together, the results suggest that the single transient inward current is due to Ca2+ release from IP3 receptors.
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DISCUSSION |
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The present study suggests differences in the mechanisms involved in the production of the initial inward current evoked by CCh application and the subsequent oscillatory inward currents observed during CCh application. The initial inward current, but not the oscillatory inward currents, was observed even in the Ca2+-free solution (Figs. 3A and 6A). The amplitude and duration of the initial inward current were larger than those of oscillatory inward currents (Fig. 1C). Inclusion of the IP3 receptor antagonist heparin in the patch pipette resulted in failure of CCh to induce a larger initial inward current than the following oscillatory inward currents (Fig. 5). In addition, CCh could not induce any inward current in the presence of GDPS in the patch pipette. These results suggest that the initial inward current was mainly due to G protein-coupled IP3 formation, with the resultant Ca2+ release from the intracellular stores activating Cl channels. Similar membrane depolarizations coupled to a G protein-related mechanism have been reported in various types of smooth muscles (19, 34).
In contrast to the initial inward current, the oscillatory inward currents subsequently observed during continuous applications of muscarinic agonists show rather unique features, although the inward current itself flows through the same Ca2+-activated Cl channels. First, inclusion of heparin in the patch pipette and bath application of xestospongin C did not affect inward current oscillations (Fig. 5, A and B), suggesting a signaling pathway other than IP3 formation. However, when the G protein was inactivated by GDPS in the patch pipette, CCh could never induce oscillatory inward currents (Fig. 5C). Second, the CCh-induced inward current oscillations require Ca2+ influx from the extracellular space, although nifedipine-sensitive Ca2+ channels do not seem to be involved (Fig. 4Aa). Consistent with this feature, the oscillation frequency depends on the membrane potential (Fig. 2, C and D) and extracellular Ca2+ concentration (Fig. 3).
As shown in Fig. 2Db, the amplitude of oscillating inward current was decreased by hyperpolarizing the cell membrane to 80 mV, at which potential the driving force of Cl was the largest among the membrane potentials applied in the experiment. This may be explained by interaction between the frequency and amplitude of the oscillating inward current. At 80 mV, inward current oscillation is most frequent (Fig. 2Da). It is likely that frequent Ca2+ release from the sarcoplasmic reticulum (SR) would decrease the amount of Ca2+ to be released if the frequency were to exceed the ability for Ca2+ uptake into the SR. This hypothesis is also compatible with the fact that CCh applications from 1 to 100 µM consistently increased the frequency of oscillating inward current, while the amplitude decreased at 100 µM (Fig. 2, A and B).
Various oscillating membrane currents have been reported in other smooth muscles. We were able to compare the properties of membrane current oscillation seen in the present study with those previously described. Application of nifedipine affected neither amplitude nor frequency of the inward current oscillations induced by CCh in the present study, indicating that voltage-sensitive Ca2+ channels were not a major pathway in the Ca2+ influx maintaining the Ca2+ oscillations in pig detrusor cells. Similar muscarinic agonist-induced oscillating inward currents have previously been reported in several smooth muscles, for instance, pig tracheal and mouse anococcygeus smooth muscle cells (23, 34). Pharmacological examinations have revealed that the oscillating inward currents seen in pig tracheal and mouse anococcygeus muscles are due to Ca2+-activated Cl channels driven by rhythmic Ca2+ release from the intracellular Ca2+ stores. Ca2+ influx from the extracellular space is also required for these oscillations. However, unlike in pig detrusor cells, Ca2+ influx through voltage-sensitive Ca2+ channels does not make a major contribution to muscarinic agonist-induced inward current oscillation in these muscles. Furthermore, in the presence of IP3 receptor monoclonal antibodies or heparin in the patch pipette, muscarinic agonists did not induce any inward current, suggesting that IP3 plays an important role in those smooth muscles (24, 34). A different type of IP3-dependent oscillating inward currents has been reported in intestinal smooth muscle (20, 37). This oscillating inward current is ascribed to nonselective cation channels, and Ca2+ influx through voltage-sensitive Ca2+ channels is involved in generating this oscillation.
In pig detrusor cells, we found unique features of muscarinic agonist-induced current oscillations. CCh-induced oscillating inward currents are not affected by the IP3 receptor inhibitors heparin and xestospongin C but are terminated by ryanodine and caffeine. It is known that smooth muscles express ryanodine as well as IP3 receptors on the SR membranes and that these two receptors share common structural and functional features (2, 14). Therefore, it is considered that rather than the IP3 receptors previously reported in other smooth muscles, periodic Ca2+ release from ryanodine receptors produces the inward current oscillations seen in pig detrusor cells during CCh application. In relation to ryanodine receptors, it has been reported that subcellular Ca2+ sparks evoke spontaneous transient inward currents (STICs) in tracheal smooth muscle cells (39). The STICs seen in normal solution are sensitive to niflumic acid and ryanodine, but the amplitude (several tens of pA) is much smaller than that of the CCh-induced oscillatory inward currents in pig detrusor cells. It is speculated that more global intracellular Ca2+ events occur via muscarinic receptor activation in detrusor cells (see Supplemental Fig. 1, available online).1
SKF-96365 is often used to block the TRP homologs that are considered to form receptor-operated nonselective cation channels and store-operated Ca2+ channels in the plasma membrane (12, 28, 31, 38). (We have detected trp1 and trp6 in RT-PCR examinations of pig detrusor muscle; see Supplemental Fig. 2.) In the present study, applications of SKF-96365 completely abolished CCh-induced inward current oscillations, although the basal membrane currents suppressed by this drug were often below detectable levels. This result suggests that Ca2+ entry through this type of cation channel is the primary cause of the generation of the CCh-induced inward current oscillations in pig detrusor cells. The fact that CCh-induced basal inward current was too small to be observed in pig detrusor cells makes it tempting to speculate that SKF-sensitive Ca2+-permeable channels, presumably TRP channels, are closely coupled to ryanodine receptors in superficial SR and can efficiently activate Ca2+-induced Ca2+ release and/or that Ca2+-induced Ca2+ release is facilitated by some G protein-related mechanisms. Also, these channels may be highly Ca2+ selective, like ICRAC (Ca2+ release-activated Ca2+ current) (29). Furthermore, if the SKF-sensitive channels are store-operated type Ca2+ channels, there may be some factors linking the SKF-sensitive channels and the SR, where ryanodine receptors are present. In support of this hypothesis, the frequency of inward current oscillations just after the removal of caffeine was faster than that before application of caffeine (Fig. 4E), indicating that some unknown signal could be transmitted from the depleted Ca2+ store to this channel. Further investigation of this finding is necessary.
CCh-induced inward current oscillations were resistant to nifedipine. It should be noted that the present experiments were carried out under voltage-clamp conditions to clearly demonstrate the importance of SKF-sensitive Ca2+-influx pathways. In intact tissues, it is possible that Ca2+ influx through voltage-sensitive Ca2+ channels interferes with the mechanisms yielding inward current oscillation. Spontaneous inward currents are, however, indispensable in activating voltage-sensitive Ca2+ channels. The frequency of CCh-induced inward current oscillations is considered to be an index of the electrical excitability (not indicating the frequency of the action potentials in intact tissue directly).
In conclusion, the present experiments have demonstrated that application of parasympathomimetic agents produces an initial transient large inward current and subsequent relatively small oscillating inward currents through distinct mechanisms (Fig. 7). The initial inward current is mainly ascribed to IP3-induced Ca2+ release from the SR. On the other hand, the latter CCh-induced inward current oscillation is caused by IP3-independent mechanisms. Nifedipine-insensitive Ca2+ pathways, presumably nonselective cation channels activated by a G protein-related mechanism, seem to be a primary factor in pacing the oscillation. Also, ryanodine receptors are essential in periodically activating Cl channels to generate oscillatory inward currents.
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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. F. Brading, University Department of Pharmacology, Oxford OX1 3QT, UK (E-mail: alison.brading{at}pharm.ox.ac.uk)
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.
1 Supplemental figures for this article may be found at http://ajpcell.physiology.org/cgi/content/full/00161.2004/DC1.
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