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1 Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, NV, USA
2 Division of Neuroscience, John Curtin School of Medical Research, Australian National University, Canberra, ACT, Australia 2601
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Abstract |
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(Received 18 February 2004;
accepted after revision 17 June 2004;
first published online 24 June 2004)
Corresponding author G. D. S. Hirst: Division of Neuroscience, John Curtin School of Medical Research, ANU, Acton, Australia 2601. Email: david.hirst{at}anu.edu.au
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Introduction |
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Fundus muscles lack networks of ICCMY, and these tissues do not generate spontaneous electrical activity (Burns et al. 1996; Ward et al. 2000). In wild-type animals both the longitudinal and circular layers of the fundus contain abundant populations of ICCIM and generate spontaneous electrical activity in the form of a discharge of membrane noise: this is only the case if ICCIM are present (Burns et al. 1996; Ward et al. 2000; Beckett et al. 2002). Thus in the fundus unitary potentials do not summate to produce regenerative potentials but the reasons why antral and fundus muscles do not share the ability to produce regenerative potentials are unclear.
In the present study we examined the properties of isolated bundles of fundus circular muscle from wild-type mice and guinea pigs containing ICCIM and from W/WV animals which lack ICCIM. Neither preparation generated spontaneous regenerative potentials, but wild-type mice displayed an ongoing discharge of membrane noise. The discharge of membrane noise in wild-type mice and guinea pig fundus showed many temporal characteristics similar to the activity recorded in the antrum; however, several electrical characteristics and pharmacological sensitivities differed.
Our observations suggest that ICCIM produce the membrane noise in electrical recordings from gastric fundus muscles but that their frequency cannot be changed by changing their membrane potential. The results provide a possible explanation for the lack of electrical rhythmicity in the fundus.
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Methods |
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With either animal the stomach was exposed and transferred to a dissecting chamber filled with oxygenated (97% O2–3% CO2) physiological saline (composition; mM: NaCl, 120.7; NaHCO3, 15.5; NaH2PO4, 1.2; KCl, 5.9; MgCl2, 1.2; CaCl2, 2.5; and dextrose, 11.5). The stomach was cut along the lower curvature and the mucosa dissected away from the fundus. Subsequently the preparation was re-pinned serosal surface uppermost and the longitudinal muscle layer was dissected away. Single bundles of circular muscle (diameter 50–150 µm, length 400–800 µm) were dissected free and pinned in a recording chamber (see Suzuki & Hirst, 1999). Intracellular recordings were made using sharp microelectrodes (90–150 M
) filled with 3 M KCl. In some experiments the preparations were impaled with two independently mounted electrodes; one was used to record membrane potential changes and the other to inject current so changing the membrane potential of the preparations. Signals were amplified with an Axoprobe amplifier, low pass filtered (cut-off frequency 1 kHz) digitized and stored on a computer for later analysis. Preparations were constantly perfused with physiological saline solution warmed to 37°C. In many experiments, nifedipine (1.0 µM), which has been shown not to significantly affect the waveform of antral regenerative potentials (Suzuki & Hirst, 1999), was added to the physiological saline to suppress muscle movements.
Atropine sulphate, apamin, N
-nitro-L-arginine (L-NA), anthracene-9-carboxylic acid (9-AC), acetoxy-methyl ester of bis-(2-amino-5-phenoxy)ethane-N,N, N',N'-tetraacetic acid (BAPTA-AM), carbonyl cyanide m-chlorophenyl hydrazone (CCCP), diisothio-cyanatostilbene-2,2'-disulphonic acid (DIDS), and nifedipine (obtained from Sigma Chemical Co., St Louis, MO, USA) were used in these experiments.
To examine the distribution of ICC in bundles of circular muscle, immunohistochemistry was performed using an antibody against the Kit receptor (ACK2; Gibco-BRL, Gaithersburg, MD, USA), which has been shown previously to be specific for ICC in the gastrointestinal tract (Torihashi et al. 1995). ICC were labelled with ACK2 that was conjugated to the fluorescent dye Alexa Fluor 594 (AF 594) using the Alexa Fluor 594 Protein Labeling Kit (Molecular Probes, Eugene, OR, USA). Tissues were placed in cooled physiological saline (4°C) and refrigerated for 1 h to reduce non-specific binding. ACK2-AF 594 conjugates were diluted to 5 µg ml–1 in cold saline and applied to tissues for 40 min at 4°C. Following antibody loading and a brief wash in cold saline, gastric tissues were fixed with paraformaldehyde solution (PFS; 4% w/v; 10 min) and washed in phosphate buffered saline (PBS) to remove excess fixative before mounting on glass slides. Tissues were examined with a Zeiss LSM 510 Meta confocal microscope (Carl Zeiss Inc., Germany) with an excitation wavelength appropriate for Alexa Fluor 594. ICCIM distribution was determined by optically sectioning through the entire muscle bundle, followed by reconstruction of z-stacks. Confocal micrographs shown in this paper are digital composites of Z-series scans of 9–24 optical sections through a depth of 7.5 µm to 15.0 µm. Final images were constructed using Zeiss LSM 5 Image Examiner software.
All data are expressed as the mean ± standard error of the mean (S.E.M.). Student's t test was used to determine if data sets differed; P values of less than 0.05 were taken to indicate significant differences between sets of observations.
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Results |
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Confocal micrographs of isolated bundles of circular muscle, dissected from either C57BL/6 wild-type or W/WV mice and labelled with an antibody to the Kit receptor (ACK2), showed that ICCIM were distributed throughout the wild-type muscle bundles and were observed running parallel to the circular muscle fibres (n= 6; Fig. 1A). The number of ICCIM counted per cross-sectional area in each bundle ranged between 8 and 20 cells (average 13.7 ± 1.7, n= 6). ICCIM were not detected in muscle bundles from W/WV mice (n= 5; Fig. 1E). Kit immunohistochemistry also confirmed that fundus circular muscle bundles were devoid of ICCMY.
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(6.0 ± 1.7 M, n= 8) and membrane time constants in the range 28–71 ms (44.3 ± 5.0 ms, n= 8). An ongoing discharge of membrane noise (unitary potentials) was recorded in each of the wild-type circular muscle bundles. This activity never summated into regenerative potentials (n= 14; Fig. 1B) as previously observed in similar preparations of muscle bundles from the gastric antrum (see Suzuki et al. 2003). Occasionally, the membrane noise appeared to trigger action potentials (n= 3), and these events were abolished by nifedipine (1 µM), clearly distinguishing them from regenerative potentials. When intracellular recordings were made from bundles from W/WV fundus, resting potentials in the range –42 to –48 mV were recorded (average –45.0 ± 1.0 mV, n= 5). In all 5 W/WV preparations, the membrane potential recordings displayed low frequency transient hyperpolarizing potentials (Fig. 1F). These events remained in the presence of TTX (0.5 µM) but were readily abolished by apamin (0.1 µM; Fig. 1H). The discharge of membrane noise, as recorded in wild-type muscles was not recorded in W/WV tissues under control conditions (Fig. 1F), in the presence of nifedipine (Fig. 1G) or in the presence of nifedipine and apamin (Fig. 1H).
Spectral density curves were constructed from membrane noise recordings obtained from five wild-type and five W/WV preparations (Fig. 2). These data were recorded in the presence of nifedipine (1 µM) and apamin (0.1 µM). Typical spectra are shown in Fig. 2B and D. Power spectral density curves from wild-type muscle recordings had characteristics and shapes similar to those calculated from recordings from the circular layer of guinea-pig antrum (Edwards et al. 1999). Energy increased from low values at frequencies above 10 Hz to reach a plateau at frequencies between 3 and 1 Hz. At frequencies above 10 Hz, the power spectral density curves were dominated by electrode recording noise (Fig. 2B). Power spectral density curves, determined from isolated bundles of antral circular muscle containing ICCIM could be well described by assuming that the noise was made up of many unitary potentials (Edwards et al. 1999). When the same approach was applied to spectral density curves obtained from fundal preparations, similarly good fits were obtained (Fig. 2B). In this series of experiments constant A had values in the range 261–321 ms (294 ± 12 ms) and constant B had values in the range 33–42 ms (36.6 ± 1.5 ms; n= 5). In muscle bundles from W/WV mutants a plateau between 3 and 1 Hz was not observed and was better fitted with a linear function. The electrode recording noise dominated the power spectra at frequencies above 10 Hz (Fig. 2D).
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In some experiments bundles of wild-type fundus circular muscle were impaled with two recording electrodes. One electrode was used to inject current and the other recorded changes in membrane potential. In each of eight fundus preparations, periods of membrane depolarization failed to initiate regenerative potentials as activated by depolarization in bundles of antral muscle (Suzuki & Hirst, 1999; Hirst et al. 2002b; Kito et al. 2002; Teramoto & Hirst, 2003). Regenerative potentials were also not activated at the break of a period of membrane hyperpolarization (Fig. 3A). In the antrum, the discharge of membrane noise is abolished by making the membrane potential some 10–20 mV more negative for 10 s (Teramoto & Hirst, 2003). In each of eight wild-type fundus muscles, making the membrane potential by some 20 mV more negative failed to abolish the discharge of membrane noise (Fig. 4). The shape of the power spectral density curve was unchanged but the power was slightly increased (Fig. 4C and D). Together these observations show that the discharge of membrane noise by fundal ICCIM is little affected by changes in membrane potential.
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In the circular layer of the murine gastric antrum, it has previously been demonstrated that the discharge of membrane noise by ICCIM is abolished by the chloride channel blockers DIDS and 9-AC (Suzuki et al. 2003). In contrast the discharge of membrane noise by ICCIM in the murine fundus was unaffected by DIDS (100 µM; n= 5) or by 9-AC (500 µM; n= 4). An example of these experiments is shown in Fig. 5.
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In the antrum the discharge of membrane noise results from the discharge of unitary potentials by ICCIM. This also appeared to be the case with the discharge of membrane noise recorded from the mouse fundus. The effects of BAPTA-AM (20–30 µM) were examined in nine wild-type fundus bundles. In four preparations BAPTA-AM produced membrane hyperpolarization, ranging from 3.5 to 18.0 mV (average 8.4 ± 3.2 mV, n= 4). In three preparations BAPTA did not change the resting membrane potential and in the remaining two muscle bundles BAPTA caused slight membrane depolarization (of 3.0 and 4.5 mV). Regardless of the effect on resting membrane potential, in all preparations BAPTA produced a decrease in the discharge of membrane noise (n= 9; Fig. 6C and D).
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All of the previous observations on the mouse fundus have suggested that membrane noise arises from a discharge of unitary potentials by ICCIM but that the discharge is not affected by changes in membrane potential, nor does it involve the activation of chloride channels. This suggests that mouse antral and fundal ICCIM although sharing some properties have a number of differences. To check whether this simply reflected a species variation, a brief series of experiments was carried out on bundles of circular muscle obtained from guinea pig fundus. In brief the observations made on the guinea pig were similar to those made on the mouse. The resting membrane potentials of the bundles ranged from –40 to –53 mV (–44.8 ± 1.2 mV), their input resistance ranged from 1.2 to 15.0 M (4.9 ± 1.8 M) and their membrane time constants ranged from 55 to 153 ms (115 ± 12 ms). Depolarizing or hyperpolarizing bundles of guinea pig fundus failed to evoke regenerative potentials (Fig. 8A; n= 7). The discharge of membrane noise was also unaffected by the chloride channel antagonist 9-AC (500 µM–1 mM; n= 4). An experiment is illustrated in Fig. 8B, where the power spectral density curve determined in control is compared to that determined in the presence of 9-AC (1 mM). However, again the discharge of membrane noise was inhibited by BAPTA-AM (30 µM), which dramatically reduced the membrane noise, associated with a membrane hyperpolarization of 5–15 mV (9.4 ± 1.6 mV; n= 5; Fig. 8C).
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Discussion |
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In the stomach both the antrum and pylorus generate an ongoing discharge of slow waves. In these regions ICCMY generate pacemaker potentials which passively depolarize the circular muscle layer (Hirst & Ward, 2003; Cousins et al. 2003). The passive waves of pacemaker depolarization are then augmented by the voltage activation of ICCIM (Hirst & Ward, 2003). In both regions when ICCMY are dissected away, a low frequency discharge of rhythmical activity (regenerative potentials) is generated by ICCIM (Suzuki & Hirst, 1999; Van Helden et al. 2000). The discharge of regenerative potentials appears to rely on the ability of ICCIM to electrically entrain neighbouring ICCIM so that many are activated together (Van Helden & Imtiaz, 2003). In the fundus, although there is no myenteric network of pacemaker ICC (ICCMY; Burns et al. 1996), both the longitudinal and circular layers contain numerous ICCIM that produce unitary potentials as in the antrum (Burns et al. 1996; Beckett et al. 2002). It was not clear why this population of ICCIM could not sustain an irregular discharge of rhythmical activity analogous to that detected in isolated circular layers of the pylorus and antrum. The present experimental observations provide an explanation for this difference since fundal ICCIM did not appear to be electrically excitable (Fig. 3). ICCIM within other regions of the gastrointestinal tract may also be electrically unexcitable. For example, in the small intestine ICCMY generate pacemaker potentials (Kito & Suzuki, 2003). However in the small intestine of mutant mice which lack ICCMY but retain ICCIM, rhythmical activity is not detected (Ward et al. 1994, 1995). This might suggest that the ICC distributed amongst the intestinal smooth muscle cells also lack voltage sensitivity. Similarly in the dog colon, although recordings have not been made from identified pacemaking ICC, the slow waves recorded from smooth muscle cells immediately adjacent to the pacemaking region bear a remarkable similarity to pacemaker potentials recorded from identified pacemaker ICC in other regions of the gastrointestinal tract (Ward et al. 1991; Dickens et al. 1999; Kito & Suzuki, 2003). Furthermore when colonic slow waves are recorded at sites distant from the pacemaker region there is a decrement in the amplitude of the signal (Ward et al. 1991), this would suggest that colonic ICCIM also lack voltage sensitivity and are unable to augment the waves of pacemaker depolarization which passively propagate through the muscle layers. Finally it is of interest to note that the voltage sensitivity of antral ICCIM can be abolished by treating preparations with n-ethylamide but when this is done a resting discharge of membrane noise continues to occur (Hirst et al. 2002b).
The discharge of membrane noise in antral muscles results from the random generation of unitary potentials by ICCIM. These normally occur at a sufficiently high frequency so that individual unitary potentials cannot be resolved. However, when internal calcium ions are buffered by treating tissues with BAPTA-AM, the frequency of unitary potentials is reduced and individual events are readily resolved (Edwards et al. 1999). Similar observations were made on preparations of fundus muscle; buffering [Ca2+]i resulted in a greatly reduced frequency of unitary potential discharge (Fig. 6). Given that this was associated with hyperpolarization in several preparations, the simplest explanation is that in the fundus the continuous discharge of unitary potentials by ICCIM results in net inward current. The similar importance of mitochondrial function in the generation of unitary potentials in both antrum (Kito & Suzuki, 2003) and fundus was shown by the ability of mitochondrial Ca2+ uptake inhibitors to abolish the discharge of membrane noise (Fig. 7). Together these observations suggest that unitary potentials, and the discharge of membrane noise, reflect the internal handling of Ca2+ in both tissues. However it appears likely that the channels activated as a consequence of changes in [Ca2+]i, differ between antral and fundal ICCIM. Thus, whereas the discharge of membrane noise in antral ICCIM is abolished by agents that block chloride channels (Hirst et al. 2002b), that generated by fundal ICCIM is unchanged (Figs 5 and 8). However, as the power spectral density curves determined from both antral and fundal preparations have similar characteristics, it would appear likely that the time courses of individual unitary potentials in either tissue are very similar. Clearly the time courses of signals in both sets of ICCIM are governed by similar rate limiting steps which are unrelated to the kinetics of the channels finally activated.
It seems that very similar spontaneous activity in the proximal and distal stomach subserves different functions. The ability of unitary potentials in the antrum to summate means that these events can amplify slow wave potentials generated by ICCMY and potentially help to preserve the magnitude of these depolarization events as they conduct through the thickness of the muscle layers. The ability to summate also allows ICCIM in the antrum to function as a secondary source of rhythmic activity. The role of unitary potentials in the fundus, which does not have the mechanism to produce slow waves and cannot summate unitary potentials, may be to regulate the level of membrane excitability. ICCIM receive and transduce neural inputs in the stomach, and the ongoing discharge of unitary potentials in the fundus may precondition postjunctional cells to generate appropriate responses to excitatory and inhibitory neurotransmitters.
In summary these observations have shown that ICCIM in the proximal and distal stomach have quite different properties. Those that are sensitive to voltage may contribute to rhythmical electrical activity either directly or by augmenting pacemaker signals generated by ICCMY. Those that lack sensitivity to voltage presumably do not contribute to rhythmical electrical activity but continue to serve an essential function in the transmission of neural information from enteric motor nerves to the layers of smooth muscle making up the gut wall (Burns et al. 1996; Ward et al. 2000; Beckett et al. 2002, 2003; Suzuki et al. 2003).
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References |
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, hyperpolarized region, a in panel C; •, baseline region, b in panel D). Note that hyperpolarization did not change the shape of the power spectral density curve but the power function was increased by approximately 100%.
