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MS 0513 Received 23 December 1999; accepted after revision 1 March 2000.
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ABSTRACT |
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INTRODUCTION |
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Gastric smooth muscles are spontaneously active, and they rhythmically generate slow waves and action potentials (Tomita, 1981). The action potentials are inhibited by organic L-type Ca2+-channel antagonists such as nifedipine and diltiazem, whilst the slow waves are insensitive to Ca2+-channel antagonists (Ishikawa et al. 1985; Dickens et al. 1999). Interstitial cells of Cajal (ICC) are considered to trigger rhythmical activity, since animals which lack ICC have digestive disorders and lack rhythmic contractile activity in the gatrointestinal tract (Sanders, 1996; Huizinga et al. 1997).
Gastrointestinal smooth muscles receive cholinergic and non-adrenergic non-cholinergic (NANC) projections, as well as on some occasions an adrenergic projection (Furness & Costa, 1987). Transmural nerve stimulation (TNS) evokes cholinergic excitatory junction potentials (EJPs) and non-adrenergic, non-cholinergic (NANC) inhibitory junction potentials (IJPs) in isolated preparations of rat and guinea-pig stomach muscle (Komori & Suzuki, 1986; Xue et al. 1996). The cholinergic depolarization is thought to result from the activation of cation selective channels following the activation of a muscarinic receptor that is coupled to a G-protein. At some point the pathway involves the second messenger inositol trisphosphate (InsP3) (Bolton & Large, 1986). IJPs appear to involve the co-release of nitric oxide (NO) and a second unidentified substance which activates apamin-sensitive K+ channels (Ohno et al. 1996).
The present experiments were carried out to find out how the properties of gastric smooth muscle and the functioning of its different innervations were changed in mutant mice which lacked InsP3 type 1 receptors.
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METHODS |
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Mice lacking type 1 InsP3 receptors (mutant mice) were bred using the method reported previously (Matsumoto et al. 1996). All experiments were carried out using 18- to 22-day-old mutant and age-matched wild-type littermates. All animals were handled and treated according to the rules of the JST Animal Use and Care Committee. Mice were anaesthetized with ethyl ether, and exsanguinated by cutting the femoral artery. The stomach was excised and, after opening, the mucosal layer was removed. Pieces of muscle wall, cut in a circular orientation (about 1 mm width, 5 mm long) were dissected from the antrum region. As such the preparations contained both the circular and longitudinal muscle layers.
The presence or absence of InsP3 receptors in antral muscles was checked by the methods reported previously (Li et al. 1996). Briefly, segments of the antrum were pulverized in liquid nitrogen, and then homogenized in 5 ml of 10 mM ice-cold Tris-HCl (pH 8·0 at 0°C) containing 0·32 M sucrose, 1 mM EDTA, 0·1 mM phenylmethylsulfonyl fluoride (PMSF), 10 mM pepstatin A, 10 mM leupeptin and 1 mM 2-mercaptoethanol. The homogenates were centrifuged at 2000g for 5 min at 4°C. The supernatants were further centrifuged at 90000g for 20 min at 2°C. The pellets were resuspended in 50 mM of Tris-HCl (pH 8·0 at 0°C) containing 1 mM EDTA and 1 mM 2-mercaptoethanol. The membrane fraction dissolved in the sample buffer (final concentrations: 2 % SDS, 10 % 2-mercaptoethanol, 6·25 mM Tris-HCl, 0·02 % Bromophenol Blue and 10 % glycerol; pH 6·8) was subjected to 5 % SDS-PAGE, followed by electroblotting onto nitrocellulose membranes (Hybond TM-ECL, Amersham, UK). The blots were blocked with skimmed milk and immunoreacted with the mouse antibody KM 1112 for type 1, KM 1083 for type 2 and KM 1082 for type 3 (Sugiyama et al. 1994), and then with horseradish peroxidase (HRP)-conjugated anti-mouse IgG (Amersham).
Immunostaining for c-kit was performed by the methods reported previously (Komuro & Zhou, 1996; Seki et al. 1998). Briefly, segments of antrum muscles were moderately inflated with injections of OCT compounds and immediately frozen with liquid nitrogen in the embedding medium. Sections (10 µm thick) were cut with a Micron HM 505E cryostat, and mounted on glass slides. The specimens were fixed with acetone for 10 min at room temperature, rinsed in phosphate-buffered saline (PBS) several times and incubated with 4 % Block Ace solution (Dainippon Seiyaku, Osaka, Japan) for 20 min at room temperature to prevent non-specific antibody binding. Then, the specimens were incubated overnight at 4°C with the rat monocronal antibody against c-kit(ACK-2, Gibco BRL, Gaitherburg, MD, USA) at a dilution ratio of 1:200. After rinsing in PBS several times, the specimens were incubated overnight at 4°C with peroxidase-conjugated secondary antibody (rabbit anti-rat IgG; DAKO, Glostrup, Denmark) at a dilution ratio of 1:80. Horseradish peroxidase reaction was developed in 50 ml 0·1 M Tris-HCl buffer (pH = 7·4) solution containing 6 mg 4-chloro-naphthol (Sigma, USA) and 8 µl 30 % H2O2. Control tissues were processed in a similar manner, but the primary incubation solution did not contain ACK-2.
For the electrophysiological experiments, the preparations were pinned on a rubber plate using tiny pins in the recording chamber with the mucosal layer uppermost. The tissue was superfused with warmed (36°C) oxygenated Krebs solution (composition (mM): Na+ 137·4, K+ 5·9, Ca2+ 2·5, Mg2+ 1·2, HCO3- 15·5, H2PO4- 1·2, glucose 11·5, Cl- 135) at a constant flow rate (about 3 ml min-1). Solutions were aerated with 95 % O2-5 % CO2, which maintained the pH of the solution at 7·2-7·3. Intracellular recordings were made using conventional microelectrode techniques. Intramural nerves were stimulated using brief electrical pulses transmurally using methods described previously (Komori & Suzuki, 1986). The selectivity of nerve stimulation was routinely confirmed by checking that the responses could be abolished by adding tetrodotoxin (0·5 µM) to the physiological saline. Drugs used were acetylcholine chloride (ACh), apamin, guanethidine sulfate, nifedipine, noradrenaline hydrochloride (NA), propranolol hydrochloride, tetrodotoxin (Sigma Chemical Co, St Louis, MO, USA), atropine sulfate (Merck, Germany), N
-nitro-L-arginine (nitroarginine, Peptide Institute, Osaka, Japan) and phentolamine mesylate (CIBA Geigy, Basel, Switzerland).
All measured values were expressed as the means ± standard deviation (S.D.). The statistical difference between the measured values was tested using Student's t test, and probabilities less than 5 % were considered significant.
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RESULTS |
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Western blot analysis performed to verify the expression of InsP3 receptor proteins using type-specific mouse antibodies, KM 1112 for type 1, KM 1083 for type 2 and KM 1082 for type 3, indicated that the immunoreactive band for KM 1112 was detected at 250 kDa with cell fragments obtained from wild-type mice, but this band was absent in mutant mice. Proteins for KM 1083 and KM 1082 were found expressed, in both wild-type and mutant mice (Fig. 1A). These observations show that whilst InsP3 type 1 receptors are present in the antral muscles of wild-type mice they are absent in those taken from mutant mice. Type 2 and type 3 InsP3 receptor proteins were expressed in both wild-type and mutant mice.
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A, Western blot analysis showing the expression of proteins for type 1 (KM 1112), type 2 (KM 1083) and type 3 (KM 1082) InsP3 receptors in the antrum muscles from wild-type (+/+) and mutant mice (-/-) (arrowhead indicates 250 kDa level). B and C, longitudinal sections of the stomach antrum obtained from 18-day-old wild-type and mutant mice, respectively, showing cells stained by immunohistochemical reactions for c-kit. CM, circular muscle layer; LM, longitudinal muscle layer. Scale bar, 100 µm. | ||
Immunostaining for c-kit, which is a reliable marker for ICC (Komuro, 1996), indicated that in the antrum from wild-type mice the c-kitpositive cells were distributed in the myenteric plexus and within both the circular and longitudinal muscle layers (Fig. 1B). The cells characteristically had elongated cell bodies with a few long cytoplasmic processes (Komuro, 1996). Immunoreactive cells were also found in the antrum from the mutant mice without detectable differences in the structure and distribution (Fig. 1C). These results indicate that the development of ICC is not impaired in the absence of InsP3 type 1 receptors.
The circular smooth muscle isolated from the antrum of wild-type mice generated rhythmic oscillations of the membrane potential, termed slow waves (Tomita, 1981) (Fig. 2A). The amplitude of slow waves varied between 4·1 and 21·2 mV (mean, 12·9 ± 0·5 mV, n = 24) and their frequency varied between 3·0 and 9·8 waves min-1 (mean, 5·5 ± 1·6 waves min-1, n = 24). The membrane potential at its most negative value (the resting membrane potential) ranged between -50 and -70 mV (mean, -57·4 ± 0·8 mV, n = 14). Often bursts of spike potentials with amplitudes of 5-20 mV were generated during the peak of the slow wave. These membrane potential changes persisted when tetrodotoxin (0·3 µM) was added to the physiological saline (n = 3, data not shown), indicating that they were myogenic in origin. Nifedipine (1 µM) abolished the spike potentials and reduced the amplitude of slow waves, without changing the resting membrane potential (Fig. 2B).
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Spontaneous activities recorded from the antral smooth muscle of wild-type and mutant mice, before (A and C, respectively) and after (B and D, respectively) application of nifedipine (1 µM). A and B were recorded from a single cell in the antral region of a 20-day-old wild-type mouse, C and D from a single cell of a 19-day-old mutant mouse. Amplitude of slow wave in wild-type mice: control, 12·3 ± 0·5 mV, n = 16; in nifedipine, 10·8 ± 0·4 mV, n = 19 (P < 0·05). Membrane potential in wild-type mice: control, -56·8 ± 2·2 mV, n = 12; in nifedipine, -57·1 ± 2·8 mV, n = 7 (P > 0·05). Membrane potential in mutant mice: control, -53·2 ± 1·8 mV, n = 8; in nifedipine, -53·0 ± 2·2 mV, n = 5 (P > 0·05). | ||
In mutant mice, the resting membrane potential ranged between -48 and -58 mV (mean, -51·7 ± 4·5 mV, n = 11), with the values being significantly different from those of wild-type mice (P < 0·05). Antral smooth muscles from mutant mice failed to generate slow waves. In about half the preparations, the membrane potential was stable (n = 5); in the others (n = 6), groups of spike potentials were superimposed on irregularly occurring small depolarization (Fig. 2C). All spontaneous activity, recorded from antral muscle of the mutant mice, was abolished by nifedipine (Fig. 2D), with no significant alteration of the membrane potential.
Stimulation of antral muscles isolated from wild-type mice with a brief electrical pulses, in the interval between slow waves, evoked an inhibitory junction potential (IJP) (Fig. 3A). Nitroarginine (10 µM) reduced the amplitude of IJP by about 30 % (Fig. 3B). The IJPs were unchanged when either propranolol (1 µM), phentolamine (1 µM) or guanethidine (5 µM) was added to the physiological saline (data not shown). Apamin (0·1 µM) converted the IJP to an excitatory junction potential (EJP) (Fig. 3C). The membrane depolarizations evoked in the presence of apamin were abolished by atropine (1 µM, Fig. 3D). These results indicate that gastric smooth muscle of wild-type mice is innervated by cholinergic excitatory and non-adrenergic non-cholinergic (NANC) inhibitory nerves. One of the inhibitory transmitters may be nitric oxide (NO). Both NO and the unidentified NANC inhibitory transmitter activate an apamin sensitive increase in potassium conductance. When the effects of the inhibitory transmitters are blocked then the effect of stimulating the cholinergic excitatory projection is apparent, EJPs are detected and these are abolished by atropine.
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A-D, recordings from an 18-day-old wild-type mouse; E-H, recordings from a 20-day-old mutant mouse. In wild-type mice, transmural nerve stimulation (0·05 ms duration, 30 V intensity, 3 stimuli at 20 Hz frequency) was applied. Junction potentials evoked in control solution (A) and in the presence of 10 µM nitroarginine (B), 0·1 µM apamin (C), and 1 µM atropine (D). After the addition of each drug the cell remained in the physiological saline (membrane potential, -58 mV). Mean amplitude of IJPs (n = 8); control, 5·7 ± 1·8 mV; in nitroarginine, 4·2 ± 1·0 mV, P < 0·05; in atropine, 6·1 ± 1·3 mV, P > 0·05. Mean amplitude of EJPs: in apamin, 6·5 ± 2·5 mV; in atropine with apamin, 0 mV. In mutant mice, transmural stimulation (0·05 ms duration, 30 V intensity, 2 stimuli at 20 Hz frequency) was applied before (E) and after (F) application of 0·1 µM apamin, 10 µM nitroarginine (G) or 1 µM atropine (H). Responses E-H were recorded from the same cell; membrane potential, -50 mV. Amplitude of IJPs (n = 5); control, 4·3 ± 1·7 mV, in apamin, 0 mV; in nitroarginine, 4·1 ± 1·7 mV (P > 0·05); in atropine, 4·5 ± 1·2 mV (P > 0·05). | ||
In mutant mice, IJPs were also evoked by nerve stimulation. The IJPs were abolished in the presence of apamin (0·1 µM). Unlike the recordings from wild-type mice, abolishing the IJP did not reveal an EJP (Fig. 3E and F). Furthermore neither nitroarginine (10 µM) nor atropine (1 µM) altered the IJPs (Fig. 3G and H, respectively), indicating that the contribution of nitrergic and cholinergic projections was insignificant. IJPs were also unaffected by guanethidine (5 µM).
The membrane potential changes elicited by acetylcholine (ACh), noradrenaline (NA) and sodium nitroprusside (SNP) were measured in antrum smooth muscles. In both wild-type and mutant mice, ACh (0·1-10 µM) depolarized the membrane in a concentration-dependent manner; the depolarization in each concentration was significantly smaller in mutant mice than in wild-type mice (Fig. 4A, C and E). In mutant mice, the depolarization was invariably associated with the discharge of spike potentials (Fig. 4C). The ACh-induced depolarization was abolished by 1 µM atropine (data not shown). NA in concentrations of 1 µM or higher hyperpolarized the membrane in wild-type (Fig. 4B) and mutant mice (Fig. 4D), to a similar extent (Fig. 4F). The responses to NA were inhibited by phentolamine (1 µM) but not by propranolol (1 µM) (data not shown). In wild-type mice, SNP (1 µM), an NO donor, hyperpolarized the membrane by 6·4 ± 1·4 mV (n = 7) and prevented the generation of slow waves. However, the SNP-induced hyperpolarization was significantly smaller in mutant mice (2·7 ± 0·7 mV, n = 6, P < 0·05).
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Membrane potential changes recorded in antral muscle of 19-day-old wild-type (A and B) and mutant (C and D) mice, in response to acetylcholine (ACh) or noradrenaline (NA). ACh (1 µM) was applied in A and C. NA (1 µM) was applied in B and D. The resting membrane potential: A and B, -58 mV; C and D, -50 mV. The graphs show the mean responses to ACh (E) and NA (F) when applied to antral smooth muscles of wild-type ( | ||
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DISCUSSION |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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The present experiments show that antral smooth muscle of mice lacking InsP3 type 1 receptors differ from those of the wild-type in three ways. The preparations lacked slow waves, and appeared to lack a cholinergic transmission and the response to NANC inhibitory nerve stimulation was changed in that a nitrergic component was absent. These changes were not associated with a detectable change in sensitivity to applied NA but were associated with a reduced responsiveness to applied ACh and SNP.
The cellular mechanism underlying the spontaneous activity of gastrointestinal smooth muscle cells remains unclear. In mice, inhibiting the development of ICC by injecting antibodies for the Kit receptor protein or breeding mutant mice which lack ICC disrupts the normal pattern of spontaneous activity (Maeda et al. 1992; Ward et al. 1994; Torihashi et al. 1995). Cultured ICC show spontaneous activity (Tokutomi et al. 1995; Thomsen et al. 1998). These observations suggest that the pacemaker cells responsible for the spontaneous activity may be the ICC (Sanders, 1996; Huizinga et al. 1997). In the guinea-pig stomach antrum, ICC appear to fulfil the role of pacemaker cells (Dickens et al. 1999). However, the antrum smooth muscles also possess the ability of generating spontaneous activity (Suzuki & Hirst, 1999). The present experiments indicated that slow waves are absent in gastric muscle of the mutant mice. As the development of ICC is not impaired in the mutant mice, InsP3 type 1 receptors may play a key role in the generation of slow waves, either within ICC or in smooth muscle cells. In the guinea-pig stomach, the generation of much of the slow wave is inhibited by depleting Ca2+ from the internal store with caffeine, inhibiting Ca2+-ATPase at the sarcoplasmic reticulum (SR) membrane with cyclopiazonic acid or chelating intracellular Ca2+ with BAPTA (Dickens et al. 1999; Suzuki & Hirst, 1999). These observations suggest that the release of Ca2+ from internal stores is involved in the generation of slow waves. Similarly the activity of smooth muscle in lymphatic vessels (Van Helden, 1993) or the urethra (Hashitani et al. 1996) is initiated by depolarization of the membrane through the opening of Ca2+-activated Cl- channels after the release of Ca2+ from intracellular stores. Although Cl- channels do not seem to be involved in the generation of slow waves in the guinea-pig stomach (Suzuki et al. 1999), the release of Ca2+ from internal stores may be a common factor in the initiation of activity in several smooth muscle cells. The release of Ca2+ from internal stores frequently involves the activation of InsP3 receptors on the SR (Berridge, 1993). Thus we suggest that the generation of slow waves is initiated by a release of Ca2+ from internal stores following the activation of InsP3 receptors. A similar suggestion has been made on circular smooth muscle of the antrum in which depolarization of the membrane elicits regenerative potentials after a long latency (about 1 s) only when functioning of SR has not been disrupted (Suzuki & Hirst, 1999).
Gastric smooth muscle receives excitatory and inhibitory innervations, and stimulation of these nerves evokes cholinergic EJPs, nitrergic IJPs and NANC IJPs in smooth muscles (Komori & Suzuki, 1986; Ohno et al. 1994; Xue et al. 1996). The present experiments showed that the lack of InsP3 type 1 receptors is accompanied by impaired cholinergic and nitrergic transmission in the mouse stomach. The sensitivity of smooth muscles to both the stimulating effect of ACh and the inhibitory effect of NO was reduced in mutant mice, and these alterations could partly explain the changes which appeared in the junction potential. However it remains unclear whether the impaired junctional transmission in the mutant mice reflects the impaired development of cholinergic and nitrergic nerves. The finding that the NANC component of the inhibitory response was unaltered suggests that this is not the case.
It is concluded that in gastric smooth muscle of mice, a lack of type 1 InsP3 receptors is associated with an inability to generate slow waves and an impairment of cholinergic and nitrergic transmissions, with no significant change in the adrenergic pathway. There are three subtypes of InsP3 receptors which are distributed heterogeneously in many cells (Berridge, 1993; Furuichi et al. 1994; Mikoshiba et al. 1996). Each of these subtypes of InsP3 receptors differs in its functions and properties for the release of Ca2+ from internal stores (Miyakawa et al. 1996). It remains unclear whether the alteration of membrane properties appearing in gastric smooth muscle of the mutant mice has a direct causal relationship with the absence of type 1 InsP3 receptors or a quantitative imbalance of InsP3 receptor subtypes.
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REFERENCES |
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The authors are grateful to Miss A. Hoshino and M. Saito for identifying the genotypes of the mutant mice and care of the animals. The authors are also grateful to Professor G. D. S. Hirst, The University of Melbourne, for critical reading of the manuscript.
Corresponding author
H. Suzuki: Department of Physiology, Nagoya City University Medical School, Mizuho-ku, Nagoya 467-8601, Japan.
Email: hisuzuki{at}med.nagoya-cu.ac.jp
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H. Hashitani, A. P. Garcia-Londono, G. D. S. Hirst, and F. R. Edwards Atypical slow waves generated in gastric corpus provide dominant pacemaker activity in guinea pig stomach J. Physiol., December 1, 2005; 569(2): 459 - 465. [Abstract] [Full Text] [PDF]
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 N. Toda and A. G. Herman Gastrointestinal Function Regulation by Nitrergic Efferent Nerves Pharmacol. Rev., September 1, 2005; 57(3): 315 - 338. [Abstract] [Full Text] [PDF]
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 E. Bradley, M. A. Hollywood, N. G. McHale, K. D. Thornbury, and G. P. Sergeant Pacemaker activity in urethral interstitial cells is not dependent on capacitative calcium entry Am J Physiol Cell Physiol, September 1, 2005; 289(3): C625 - C632. [Abstract] [Full Text] [PDF]
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F. R Edwards and G. D. S Hirst An electrical description of the generation of slow waves in the antrum of the guinea-pig J. Physiol., April 1, 2005; 564(1): 213 - 232. [Abstract] [Full Text] [PDF]
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G. Boddy and E. E. Daniel Role of L-Ca2+ channels in intestinal pacing in wild-type and W/WV mice Am J Physiol Gastrointest Liver Physiol, March 1, 2005; 288(3): G439 - G446. [Abstract] [Full Text] [PDF]
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Y. Kito, S. M. Ward, and K. M. Sanders Pacemaker potentials generated by interstitial cells of Cajal in the murine intestine Am J Physiol Cell Physiol, March 1, 2005; 288(3): C710 - C720. [Abstract] [Full Text] [PDF]
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 H.-N. Liu, S. Ohya, S. Furuzono, J. Wang, Y. Imaizumi, and S. Nakayama Co-contribution of IP3R and Ca{superscript 2}+ Influx Pathways to Pacemaker Ca{superscript 2}+ Activity in Stomach ICC J Biol Rhythms, February 1, 2005; 20(1): 15 - 26. [Abstract] [PDF]
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S. M Ward, R. E. Dixon, A. de Faoite, and K. M Sanders Voltage-dependent calcium entry underlies propagation of slow waves in canine gastric antrum J. Physiol., December 15, 2004; 561(3): 793 - 810. [Abstract] [Full Text] [PDF]
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G. D. S. Hirst, R. A. R. Bywater, N. Teramoto, and F. R. Edwards An analysis of inhibitory junction potentials in the guinea-pig proximal colon J. Physiol., August 1, 2004; 558(3): 841 - 855. [Abstract] [Full Text] [PDF]
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T. Ishikawa, S. Nakayama, T. Nakagawa, K. Horiguchi, H. Misawa, M. Kadowaki, A. Nakao, S. Inoue, T. Komuro, and M. Takaki Characterization of in vitro gutlike organ formed from mouse embryonic stem cells Am J Physiol Cell Physiol, June 1, 2004; 286(6): C1344 - C1352. [Abstract] [Full Text] [PDF]
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M. Craven, G. P. Sergeant, M. A. Hollywood, N. G. McHale, and K. D. Thornbury Modulation of spontaneous Ca2+-activated Cl- currents in the rabbit corpus cavernosum by the nitric oxide-cGMP pathway J. Physiol., April 15, 2004; 556(2): 495 - 506. [Abstract] [Full Text] [PDF]
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G. Boddy, A. Bong, W. Cho, and E. E. Daniel ICC pacing mechanisms in intact mouse intestine differ from those in cultured or dissected intestine Am J Physiol Gastrointest Liver Physiol, April 1, 2004; 286(4): G653 - G662. [Abstract] [Full Text] [PDF]
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S. P. Parsons and T. B. Bolton Localised calcium release events in cells from the muscle of guinea-pig gastric fundus J. Physiol., February 1, 2004; 554(3): 687 - 705. [Abstract] [Full Text] [PDF]
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T. Ordog, D. Redelman, L. J. Miller, V. J. Horvath, Q. Zhong, G. Almeida-Porada, E. D. Zanjani, B. Horowitz, and K. M. Sanders Purification of interstitial cells of Cajal by fluorescence-activated cell sorting Am J Physiol Cell Physiol, February 1, 2004; 286(2): C448 - C456. [Abstract] [Full Text] [PDF]
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 S. Torihashi, T. Fujimoto, C. Trost, and S. Nakayama Calcium Oscillation Linked to Pacemaking of Interstitial Cells of Cajal. REQUIREMENT OF CALCIUM INFLUX AND LOCALIZATION OF TRP4 IN CAVEOLAE J. Biol. Chem., May 17, 2002; 277(21): 19191 - 19197. [Abstract] [Full Text] [PDF]
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 J. G. McCarron, J. W. Craig, K. N. Bradley, and T. C. Muir Agonist-induced phasic and tonic responses in smooth muscle are mediated by InsP3 J. Cell Sci., May 15, 2002; 115(10): 2207 - 2218. [Abstract] [Full Text] [PDF]
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K. D. Keef, U. Anderson, K. O'Driscoll, S. M. Ward, and K. M. Sanders Electrical activity induced by nitric oxide in canine colonic circular muscle Am J Physiol Gastrointest Liver Physiol, January 1, 2002; 282(1): G123 - G129. [Abstract] [Full Text] [PDF]
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J. D. Huizinga Physiology and Pathophysiology of the Interstitial Cell of Cajal: From Bench to Bedside: II. Gastric motility: lessons from mutant mice on slow waves and innervation Am J Physiol Gastrointest Liver Physiol, November 1, 2001; 281(5): G1129 - G1134. [Abstract] [Full Text] [PDF]
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 C. Herr, N. Smyth, S. Ullrich, F. Yun, P. Sasse, J. Hescheler, B. Fleischmann, K. Lasek, K. Brixius, R. H. G. Schwinger, et al. Loss of Annexin A7 Leads to Alterations in Frequency-Induced Shortening of Isolated Murine Cardiomyocytes Mol. Cell. Biol., July 1, 2001; 21(13): 4119 - 4128. [Abstract] [Full Text] [PDF]
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G. P. Sergeant, M. A. Hollywood, K. D. McCloskey, N. G. McHale, and K. D. Thornbury Role of IP3 in modulation of spontaneous activity in pacemaker cells of rabbit urethra Am J Physiol Cell Physiol, May 1, 2001; 280(5): C1349 - C1356. [Abstract] [Full Text] [PDF]
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J. Malysz, G. Donnelly, and J. D. Huizinga Regulation of slow wave frequency by IP3-sensitive calcium release in the murine small intestine Am J Physiol Gastrointest Liver Physiol, March 1, 2001; 280(3): G439 - G448. [Abstract] [Full Text] [PDF]
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H. Fukuta, Y. Kito, and H. Suzuki Spontaneous electrical activity and associated changes in calcium concentration in guinea-pig gastric smooth muscle J. Physiol., April 1, 2002; 540(1): 249 - 260. [Abstract] [Full Text] [PDF]
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S. D. Koh, J. Y. Jun, T. W. Kim, and K. M. Sanders A Ca2+-inhibited non-selective cation conductance contributes to pacemaker currents in mouse interstitial cell of Cajal J. Physiol., May 1, 2002; 540(3): 803 - 814. [Abstract] [Full Text] [PDF]
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G. D. S. Hirst, N. J. Bramich, N. Teramoto, H. Suzuki, and F. R. Edwards Regenerative component of slow waves in the guinea-pig gastric antrum involves a delayed increase in [Ca2+]i and Cl- channels J. Physiol., May 1, 2002; 540(3): 907 - 919. [Abstract] [Full Text] [PDF]
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) or mutant mice (
). *Significant difference between wild-type and mutant mice (P < 0·05).