5-Hydroxytryptamine2B receptor signaling in rat stomach fundus: role of voltage-dependent calcium channels, intracellular calcium release and protein kinase C.
The rat stomach fundus is enriched with the 5-hydroxytryptamine (5-HT)2B receptor, the newest subtype of the 5-HT2 receptor family to be cloned. Although the 5-HT2A and 5-HT2C receptor subtypes couple to phosphatidylinositol hydrolysis, such a coupling has not been established for the 5-HT2B receptor in tissues. Thus, 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 (1 microM) by approximately 50%. Removal of extracellular calcium did not inhibit 5-HT contraction to a greater extent than that produced by nitrendipine, indicating that calcium influx through voltage-dependent calcium channels was predominantly responsible 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), a compound which inhibits calcium release from intracellular stores, significantly inhibited the maximal contraction to carbamylcholine (3 microM). In contrast, ryanodine (30 microM) did not inhibit the maximal contraction to 5-HT (1 microM) in the absence of nitrendipine. However, ryanodine (30 microM) did significantly inhibit the nitrendipine-insensitive 5-HT contraction, suggesting that this component of the contraction was due in part to calcium release from a ryanodine-sensitive store. 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 involved.(ABSTRACT TRUNCATED AT 250 WORDS)
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Lilly Research Laboratories, Eli Lilly and Co., Indianapolis, Indiana.
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D000818:Animals; D002110:Caffeine / Q000494:pharmacology; D002118:Calcium / Q000502:physiology*; D015220:Calcium Channels / Q000502:physiology*; D002217:Carbachol / Q000494:pharmacology; D005769:Gastrointestinal Motility / Q000187:drug effects; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D008297:Male; D008301:Maleimides / Q000494:pharmacology; D008564:Membrane Potentials; D009119:Muscle Contraction / Q000187:drug effects; D009568:Nitrendipine / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000502:physiology*; D012433:Ryanodine / Q000494:pharmacology; D012701:Serotonin / Q000494:pharmacology; D015398:Signal Transduction; D013270:Stomach / Q000502:physiology*
D015220:Calcium Channels; D007211:Indoles; D008301:Maleimides; D011985:Receptors, Serotonin; D012433:Ryanodine; D012701:Serotonin; D002110:Caffeine; D002217:Carbachol; D009568:Nitrendipine; D011493:Protein Kinase C; C088060:bisindolylmaleimide; D002118:Calcium