title: 5-HT2B receptor signaling in the rat stomach fundus: dependence on calcium influx, calcium release and protein kinase C.
abstract: The rat stomach fundus is enriched with the 5-hydroxytryptamine (5-HT)2B receptor, a recently cloned subtype of the 5-HT2 receptor family. Unlike other members of the 5-HT2 receptor family, the 5-HT2B receptor in the rat stomach fundus was not coupled to phosphatidylinositol (PI) hydrolysis. The purpose of this study was to characterize further the signal transduction mechanism of the 5-HT2B receptor in rat stomach fundus. Nitrendipine (1 microM) inhibited the maximal contraction to 5-HT (10 microM) by approx. 60%. 5-HT contractions were inhibited by approximately the same magnitude in the absence of extracellular calcium as in the presence of nitrendipine, indicating that calcium influx through voltage-dependent calcium channels accounted fully for the dependence of the 5-HT contraction on extracellular calcium. Depletion of both extracellular calcium and intracellular calcium stores abolished 5-HT contraction. Ryanodine (30 microM), an inhibitor of calcium release from internal stores, inhibited significantly the nitrendipine-insensitive 5-HT contraction, suggesting that this component of the contraction was due to calcium release from a ryanodine-sensitive site. Bisindolylmaleimide (5 microM), a specific inhibitor of protein kinase C (PKC), inhibited 5-HT contraction in either the absence or presence of nitrendipine, suggesting that activation of PKC is also important. Taken together, these data indicate that the 5-HT2B contractile receptor in the rat stomach fundus is coupled to calcium influx through voltage-dependent calcium channels, intracellular calcium release, and activation of PKC. These actions may reflect a novel coupling mechanism unrelated to increases in PI hydrolysis.
authors.affiliation: Department of Cardiovascular Pharmacology, Eli Lilly and Co., Indianapolis, IN 46285, USA.
authors.forename: D A
authors.initials: DA
authors.lastname: Cox
authors.forename: M L
authors.initials: ML
authors.lastname: Cohen
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D004594:Electrophysiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D005748:Gastric Fundus / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D005753:Gastric Mucosa / Q000378:metabolism; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D008297:Male; D008301:Maleimides / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D009568:Nitrendipine / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000187:drug effects*; D012433:Ryanodine / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013270:Stomach / Q000187:drug effects / Q000502:physiology*
chemical_list: D002121:Calcium Channel Blockers; D004791:Enzyme Inhibitors; D007211:Indoles; D008301:Maleimides; D011985:Receptors, Serotonin; D012433:Ryanodine; D009568:Nitrendipine; D011493:Protein Kinase C; C088060:bisindolylmaleimide; D002118:Calcium