title: Pharmacological differences of endothelin receptors-mediated modulation in cultured interstitial cells of Cajal from the murine small and large intestine.
abstract: Interstitial cells of Cajal (ICCs) are pacemaker cells that activate the periodic spontaneous depolarization (pacemaker potentials) responsible for the production of slow waves in gastrointestinal smooth muscle. Under current clamping, ICCs had a mean resting membrane potential of -58 ± 3 mV and externally applied ET produced membrane depolarization in a dosedependent manner. These effects were reduced by intracellular GDP beta S. A comparison of the concentration-dependent membrane depolarizations on pacemaker potentials to ET-1, ET-2 and ET-3 showed a rank order of potency ET-1≥ET-2≥ET-3 in cultured murine small intestinal ICCs. The pretreatment with Ca(2+)-free solution and thapsigargin, a Ca(2+)-ATPase inhibitor in endoplasmic reticulum, abolished the generation of pacemaker potentials and suppressed the ET-1 induced membrane depolarizations. Chelerythrine and calphostin C, protein kinase C inhibitors or naproxen, an inhibitor of cyclooxygenase, did not block the ET-1 induced effects on pacemaker potentials. Pretreatment with BQ-123 (ET(A )receptor antagonist) or BQ-788 (ET(B )receptor antagonist) blocked the ET-1 induced effects on pacemaker potentials in cultured murine small intestinal ICCs. However, pretreatment with BQ-788 selectively did not block the ET-1 induced effects on pacemaker potentials in cultured murine large intestinal ICCs. Also, only externally applied selective ET(B )receptor agonist, IRL 1620 did not show any influence on pacemaker potentials in cultured murine large intestine ICCs. RT-PCR results indicated the presence of the ET(A )and ET(B )receptor in ICCs. These results suggested that ET-1 modulates pacemaker potentials through ET(A )and ET(B )receptor activation in murine small intestinal ICCs and ET(A )receptor activation in murine large intestinal ICCs by external Ca(2+) influx and internal Ca(2+) release via protein kinase C or cyclooxygenase-independent mechanism. Therefore, the ICCs are targets for ET and their interaction can affect intestinal motility.
authors: Division of Longevity and Biofunctional Medicine, Pusan National University School of Korean Medicine, Yangsan, Korea. vision@pusan.ac.kr
authors: Byung Joo
authors: BJ
authors: Kim
authors: In Youb
authors: IY
authors: Chang
authors: Insuk
authors: I
authors: So
mesh_terms: D000818:Animals; D053119:Benzophenanthridines / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000037:antagonists & inhibitors / Q000378:metabolism; D002462:Cell Membrane / Q000502:physiology; D002478:Cells, Cultured; D019332:Endothelin-1 / Q000494:pharmacology; D019333:Endothelin-2 / Q000494:pharmacology; D019334:Endothelin-3 / Q000494:pharmacology; D056885:Interstitial Cells of Cajal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D007420:Intestine, Large / Q000166:cytology*; D007421:Intestine, Small / Q000166:cytology*; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D009288:Naproxen / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D010456:Peptides, Cyclic / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011451:Prostaglandin-Endoperoxide Synthases / Q000737:chemistry / Q000378:metabolism; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D044022:Receptor, Endothelin A / Q000378:metabolism; D044023:Receptor, Endothelin B / Q000378:metabolism; D017466:Receptors, Endothelin / Q000819:agonists / Q000378:metabolism*; D019284:Thapsigargin / Q000494:pharmacology
chemical_list: D053119:Benzophenanthridines; D019332:Endothelin-1; D019333:Endothelin-2; D019334:Endothelin-3; D009842:Oligopeptides; D010456:Peptides, Cyclic; D010880:Piperidines; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; C086539:BQ 788; D009288:Naproxen; D019284:Thapsigargin; C016299:chelerythrine; D011451:Prostaglandin-Endoperoxide Synthases; D011493:Protein Kinase C; D000252:Calcium-Transporting ATPases; C072247:cyclo(Trp-Asp-Pro-Val-Leu); D002118:Calcium