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Volume 123 (2004)
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Volume 123, Issue 3
Displaying 1-10 of 10 articles from this issue
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Reviews: Regulatory Mechanism of Motility of the Gastrointestinal Tract
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Kei-ichiro NAKAMURA, Kiyomasa NISHII, Yosaburo SHIBATA2004 Volume 123 Issue 3 Pages 134-140
Published: 2004
Released on J-STAGE: February 29, 2004
JOURNAL FREE ACCESSIn the wall of the digestive tract, there are pacemaker and conduction systems which can be compared with those in the heart. The introduction of c-Kit as a specific marker of the cells, ICCs, have dramatically clarified morphological and functional understanding of the cells. Mutant animals that lack c-Kit lose or decrease intestinal motility. Four classes of ICCs have been identified and these are distributed along the digestive tract in an organ- and tissue-specific manner: 1) IC-MY locate along the myenteric plexus; 2) IC-DMP, along the deep muscular plexus of small intestine; 3) IC-SMP, along the interface between the submucosa and circular muscle layer of large intestine; and 4) IC-IM, within the muscular layer of the stomach and large intestine. Basically, IC-MY and IC-SMP have pacemaker functions, whereas IC-DMP and IC-IM link signals between the enteric nervous system and smooth muscle cells (SMC). All classes of the cells are connected by gap junctions. Immunocytochemical observations using specific antibodies against various gap junction proteins, connexins (Cx), revealed that Cx43 was localized in the gap junctions between SMC and ICCs, whereas Cx45 was specifically expressed in IC-DMP as it is in the cardiac conduction systems. Mutant animals that we produced enabled us to show cells expressing Cx45 mRNA by replacing the Cx45 locus with a LacZ reporter gene and revealed that most of SMC express Cx45, where so far gap junctions were not demonstrated by electron microscopy or immunocytochemistry, probably due to their small size.
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Eri NAKAMURA, Yoshihiko KITO, Hiroyasu FUKUTA, Yoshimasa YANAI, Hikaru ...2004 Volume 123 Issue 3 Pages 141-148
Published: 2004
Released on J-STAGE: February 29, 2004
JOURNAL FREE ACCESSIn gastric smooth muscles, interstitial cells of Cajal (ICC) might be the pacemaker cells of spontaneous activities since ICC are rich in mitochondria and are connected with smooth muscle cells via gap junctions. Several types of ICC are distributed widely in the stomach wall. A group of ICC distributed in the myenteric layer (ICC-MY) were the pacemaker cells of gastrointestinal smooth muscles. Pacemaker potentials were generated in ICC-MY, and the potentials were conducted to circular smooth muscles to trigger slow waves and also conducted to longitudinal muscles to form follower potentials. In circular muscle preparations, interstitial cells distributed within muscle bundles (ICC-IM) produced unitary potentials, which were conducted to circular muscles to form slow potentials by summation. In mutant mice lacking inositol trisphosphate (IP3) receptor, slow waves were absent in gastric smooth muscles. The generation of spontaneous activity was impaired by the inhibition of Ca2+-release from internal stores through IP3 receptors, inhibition of mitochondrial Ca2+-handling with proton pump inhibitors, and inhibition of ATP-sensitive K+-channels at the mitochondrial inner membrane. These results suggested that mitochondrial Ca2+-handling causes the generation of spontaneous activity in pacemaker cells. Possible involvement of protein kinase C (PKC) in the Ca2+ signaling system was also suggested.
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Shinsuke NAKAYAMA, Susumu OHYA, Yuji IMAIZUMI2004 Volume 123 Issue 3 Pages 149-154
Published: 2004
Released on J-STAGE: February 29, 2004
JOURNAL FREE ACCESSGastointestinal tract motility is driven by pacemaker depolarization referred to slow waves. In order to investigate mechanisms underlying the spontaneous rhythmicity, we have developed a cell cluster preparation. Cell clusters were enzymatically isolated from the muscle layers of mouse small intestine and cultured for several days. They include smooth muscle, enteric neurons and c-Kit-immunopositive cells (interstitial cells of Cajal: ICC), and preserve spontaneous mechanical and electrical activities. A characteristic feature of the pacemaker potential is resistance to dihydropyridine (DHP) Ca2+ antagonist. In the presence of nifedipine, a DHP Ca2+ antagonist, spontaneous intracellular Ca2+ ([Ca2+]i) oscillation was recorded from c-Kit-immunopositive cells in the cell cluster preparation. The [Ca2+]i oscillation seen in ICC was terminated by applications of drugs affecting ryanodine receptors as well as those for InsP3 receptors and TRP family channels. It is considered that these intracellular Ca2+ release channels and the Ca2+ influx pathway from the extracellular space cooperate to produce pacemaker activity in the gastrointestinal tract.
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Toshiko YAMAZAWA, Masamitsu IINO2004 Volume 123 Issue 3 Pages 155-162
Published: 2004
Released on J-STAGE: February 29, 2004
JOURNAL FREE ACCESSSpontaneous contraction of intestinal smooth muscles is required for bowel movement and its failure results in disorders including irritable bowel syndrome. Rhythmic spontaneous depolarizations in intestinal smooth muscle cells, often referred to as slow waves, are essential for the movement of the gastrointestinal tract. Interstitial cells of Cajal (ICC) lie adjacent to smooth muscle layers and are implicated to be the pacemaker cells generating slow waves, because mutant mice lacking this cell type show gut rhythm disorders. However, the pace-making mechanism remains unclear. Here we review intracellular Ca2+ signals of both ICC and smooth muscle cells during rhythmic activity in the gastrointestinal tract.
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Naofumi TOKUTOMI, Yoshiko TOKUTOMI, Katsuhide NISHI2004 Volume 123 Issue 3 Pages 163-169
Published: 2004
Released on J-STAGE: February 29, 2004
JOURNAL FREE ACCESSDrug-induced contraction of gastrointestinal tracts seems to depend upon the extent of their rhythmic contraction that is driven by the activity of gastrointestinal pacemaker cells. In BALB/c mice chronically administrated with a neutralizing anti-c-Kit monoclonal antibody (ACK2), rhythmic contraction of the gastrointestinal tract was impaired and contractile responses to drugs, including acetylcholine, prostaglandin F2α, and bradykinin, were anomalously augmented. Histochemical analysis of the c-kit-positive cells in the gastrointestinal tract revealed the decreased number of c-kit-positive cells in the ACK2-treated animals, which lead to the impaired rhythmic contraction. Since the intestinal c-kit-positive cells in primary culture developed Ca2+-dependent rhythmic Cl− current, the rhythmic current is supposed to be an origin of gastrointestinal pacemakers. The extent of anomaly in drug-induced contraction correlated with the extent of impairment in rhythmic contraction. The drug-induced anomalous contraction in the preparation from ACK2-treated animals, which is accompanied by the impaired rhythmic contraction, was mimicked when the gastrointestinal segments from control animals were superfused with a low temperature organ bath solution at 25°C. These results suggest that rhythmic discharge of excitation of smooth muscle cells, which is triggered by rhythmic excitatory input from c-kit cells, regulates the extent of drug-induced contraction.
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Akikazu FUJITA, Yutaka OKISHIO, Tadayoshi TAKEUCHI, Fumiaki HATA2004 Volume 123 Issue 3 Pages 170-178
Published: 2004
Released on J-STAGE: February 29, 2004
JOURNAL FREE ACCESSThe role of interstitial cells of Cajal (ICC) in contractile activity of the gastrointestinal tract has been intensely studied. Among ICC present within various regions of the gastrointestinal tissue, ICC within the myenteric plexus (ICC-MY) and within the submuscular plexus (ICC-SMP) are regarded as the pacemaker. Action potentials initiated in ICC were suggested to propagate to adjacent smooth muscle cells and to induce the spontaneous activity. It was suggested that ACh-mediated contraction and nitric oxide-mediated relaxation were induced after these neuronal signals were transmitted to ICC and then to smooth muscle via the gap junction. This suggestion was based on the findings mainly in the esophagus, stomach, and small intestine by using ICC-deficient mice (W/WV and Sl/Sld). In our studies, ICC-MY were shown to be closely associated with neuron-mediated contractile and relaxant responses and to be associated with neural reflexes for peristalsis, since ascending and descending reflexes were not seen in W/WV mice. In the distal colon of W/WV mice, in which ICC-MY and -IM were lost, these neural responses remained unchanged. It seems likely that ICC-MY and ICC-IM do not have any role in inducing these responses in the distal colon. It is concluded that the extent of association of ICC with the motility and the manner of the association vary from region to region in the gastrointestinal tract.
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Award Lecture
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Takeshi FUJII2004 Volume 123 Issue 3 Pages 179-188
Published: 2004
Released on J-STAGE: February 29, 2004
JOURNAL FREE ACCESSAcetylcholine (ACh) is classically thought of as a neurotransmitter in mammalian species. However, lymphocytes express most of the cholinergic components found in the nervous system, including ACh, choline acetyltransferase (ChAT), high-affinity choline transporter, and acetylcholinesterase as well as both muscarinic and nicotinic ACh receptors (mAChRs and nAChRs, respectively). Activation of T cells via the T cell receptor/CD3 complex, contact of T cells with antigen presenting cells, or activation of the adenylyl cyclase pathway in T cells modulates cholinergic activity, as evidenced by up-regulation of ChAT and M5 mAChR mRNA expression. Stimulation of mAChRs on T and B cells with ACh or another mAChR agonists elicits intracellular Ca2+ signaling, up-regulation of c-fos expression, increased nitric oxide synthesis and interleukin-2-induced signal transduction via M3 and M5 mAChR-mediated pathways. Acute stimulation of nAChRs with ACh or nicotine causes rapid and transient Ca2+ signaling in T and B cells, probably via α7 nAChRs subunit-mediated pathways. Chronic nicotine stimulation, by contrast, down-regulates nAChR expression and suppresses T cell activity. Abnormalities in lymphocytic cholinergic system have been seen in animal models of immune deficiency and immune acceleration. Collectively, these data provided a compelling picture in which immune function is, at least partly, under the control of an independent, non-neuronal cholinergic system in lymphocytes.
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Yasuhito SHIRAI2004 Volume 123 Issue 3 Pages 189-196
Published: 2004
Released on J-STAGE: February 29, 2004
JOURNAL FREE ACCESSProtein kinase C (PKC) changes its subcellular localization depending on extracellular signals including hormones and neurotransmitters. Such translocation is referred to as “targeting” in this review. The live imaging technique using GFP has allowed the dynamic movement of PKC to be visualized in living cells and revealed a remarkable diversity in PKC targeting. These studies indicate an importance of targeting in regulating the physiological and isotype-specific function of PKC. Like PKC, diacylglycerol kinase (DGK), which phosphorylates diacylglycerol resulting in attenuation of PKC, subtype-specifically translocates to particular subcellular compartments including the plasma membrane and Golgi complex. In addition, it has been shown that the localization and activation of the two functionally-related kinases are well organized by direct interaction and phosphorylation. This review summarizes diversity in targeting of PKC and DGK and the molecular mechanisms regulating their targeting.
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Satomi ADACHI-AKAHANE2004 Volume 123 Issue 3 Pages 197-209
Published: 2004
Released on J-STAGE: February 29, 2004
JOURNAL FREE ACCESSThe voltage-dependent L-type Ca2+ channel plays a key role in the spacial and temporal regulation of Ca2+. In cardiac excitation-contraction coupling, Ca2+-induced Ca2+ release (CICR) from ryanodine receptors (RyRs), triggered by Ca2+ entry through the nearby L-type Ca2+ channel, induces the Ca2+-dependent inactivation (CDI) of the Ca2+ channel. We demonstrated that the CICR-dependent CDI of L-type Ca2+ channels, under control of the privileged cross-signaling between L-type Ca2+ channels and RyRs, plays important roles for monitoring and tuning the SR Ca2+ content via changes of AP waveform and the amount of Ca2+-influx during AP in ventricular myocytes. L-type Ca2+ channels are modulated by the binding of Ca2+ channel antagonists and agonists to the pore-forming α1C subunit. We identified Phe1112 and Ser1115 in the pore-forming IIIS5-S6 linker region of the α1C subunit as critical determinants of the binding of dihydropyridines (DHP). Interestingly, double mutant Ca2+ channel (F1112A/S1115A) failed to discriminate between a DHP Ca2+ channel agonist and antagonist stereoisomers. We proposed that Phe1112 and Ser1115 in the pore-forming IIIS5-S6 linker region is required for the stabilization of the Ca2+ channel in the open state by Ca2+ channel agonists and further proposed a novel model for the DHP-binding pocket of the α1C subunit. These integrative studies on the gating regulation of cardiac L-type Ca2+ channels will provide the molecular basis for the pharmacology of Ca2+ channel modulators.
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Technical Note
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Shin-ichiro KARAKI, Atsukazu KUWAHARA2004 Volume 123 Issue 3 Pages 211-218
Published: 2004
Released on J-STAGE: February 29, 2004
JOURNAL FREE ACCESSThe short-circuit current (Ussing chamber) technique is one of the most powerful methods to measure transepithelial ion transport across a variety of epithelial membranes including intestinal mucosa. This method is very useful for many researchers in physiology and pharmacology. This review article shows the theory and practice of the short-circuit current technique.
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