title: Insulin induces internalization of the plasma membrane 5-hydroxytryptamine2A (5-HT2A) receptor in the isolated human endothelium-denuded saphenous vein via the phosphatidylinositol 3-kinase pathway.
abstract: The aim of this study was to investigate the relaxant effect of insulin on the 5-hydroxytryptamine (5-HT)-induced constriction of the human endothelium-denuded saphenous vein (SV) and its signal transduction pathway. During the 5-HT-induced sustained constriction of vessels, insulin induced vasorelaxation in a concentration-dependent manner. This insulin-induced vasorelaxation was partially attenuated by L-NAME, a nitric oxide synthase (NOS) inhibitor, and was abolished by wortmannin, a phosphatidylinositol 3-kinase (PI3-K) inhibitor. Insulin increased the Ser(473) phosphorylation of Akt. Endothelial NOS and inducible NOS protein expressions were observed in SV smooth muscle when insulin induced relaxation of SV vessels preconstricted with 5-HT. Although insulin did not affect the total protein level of 5-HT(2A) receptors, it decreased the particulate protein level and reciprocally increased the soluble protein level of 5-HT(2A) receptors in a concentration-dependent manner. These results demonstrate that insulin can induce the internalization of 5-HT(2A) receptors from the plasma membrane to the cytoplasm. The insulin-induced internalization of 5-HT(2A) receptors was abolished by wortmannin but was not affected by L-NAME. These results suggest that the relaxant effect of insulin on 5-HT-induced vasoconstriction is mediated in part by the internalization of plasma membrane 5-HT(2A) receptors and the production of nitric oxide via the PI3-K/Akt pathway.
authors.affiliation: First Department of Pharmacology, School of Pharmaceutical Sciences, Kyushu University of Health and Welfare, Japan.
authors.forename: Tasuku
authors.initials: T
authors.lastname: Kanai
authors.forename: Masachika
authors.initials: M
authors.lastname: Kuwabara
authors.forename: Naoko
authors.initials: N
authors.lastname: Tanaka-Totoribe
authors.forename: Eisaku
authors.initials: E
authors.lastname: Nakamura
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Matsuo
authors.forename: Shuji
authors.initials: S
authors.lastname: Gamoh
authors.forename: Akito
authors.initials: A
authors.lastname: Suzuki
authors.forename: Yujiro
authors.initials: Y
authors.lastname: Asada
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Hisa
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Yamamoto
mesh_terms: D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000494:pharmacology; D007328:Insulin / Q000008:administration & dosage / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism*; D012501:Saphenous Vein / Q000187:drug effects / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects*; D014664:Vasodilation / Q000187:drug effects*
chemical_list: D007004:Hypoglycemic Agents; D007328:Insulin; D044402:Receptor, Serotonin, 5-HT2A; D009569:Nitric Oxide; D012701:Serotonin; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt