title: Agonist-induced internalization of histamine H2 receptor and activation of extracellular signal-regulated kinases are dynamin-dependent.
abstract: Histamine H2 receptor (H2R) is a member of G protein-coupled receptor family. Agonist stimulation of H2R results in several cellular events including activation of adenylate cyclase and phospholipase C, desensitization of the receptor, activation of extracellular signal-regulated kinases ERK1/2, and receptor endocytosis. In this study, we identified a GTPase dynamin as a binding partner of H2R. Dynamin could associate with H2R both in vitro and in vivo. Functional analyses using dominant-negative form of dynamin (K44E-dynamin) revealed that cAMP production and the following H2R desensitization are independent of dynamin. However, the agonist-induced H2R internalization was inhibited by co-expression of K44E-dynamin. Furthermore, activation of extracellular-signal regulated kinases ERK1/2 in response to dimaprit, an H2R agonist, was attenuated by K44E-dynamin. Although H2R with truncation of 51 amino acids at its carboxy-terminus did not internalize after agonist stimulation, it still activated ERK1/2, but the degree of this activation was less than that of the wild-type receptor. Finally, K44E dynamin did not affect ERK1/2 activation induced by internalization-deficient H2R. These results suggest that the agonist-induced H2R internalization and ERK1/2 activation are partially dynamin-dependent. Furthermore, ERK1/2 activation via H2R is likely dependent of the endocytotic process rather than dynamin itself.
authors.affiliation: Departments of Pharmacology, Tohoku University School of Medicine, Seiryo-machi, Aoba-ku, Sendai, Japan.
authors.forename: A-Jing
authors.initials: AJ
authors.lastname: Xu
authors.forename: Atsuo
authors.initials: A
authors.lastname: Kuramasu
authors.forename: Kay
authors.initials: K
authors.lastname: Maeda
authors.forename: Kazuki
authors.initials: K
authors.lastname: Kinoshita
authors.forename: Shiori
authors.initials: S
authors.lastname: Takayanagi
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Fukushima
authors.forename: Takehiko
authors.initials: T
authors.lastname: Watanabe
authors.forename: Teruyuki
authors.initials: T
authors.lastname: Yanagisawa
authors.forename: Jun
authors.initials: J
authors.lastname: Sukegawa
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Yanai
mesh_terms: D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D000242:Cyclic AMP / Q000096:biosynthesis; D017259:Dimaprit / Q000494:pharmacology; D034281:Dynamins / Q000378:metabolism*; D004705:Endocytosis / Q000187:drug effects / Q000502:physiology*; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000187:drug effects / Q000378:metabolism*; D017442:Histamine Agonists / Q000494:pharmacology*; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000187:drug effects / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000187:drug effects / Q000378:metabolism; D017434:Protein Structure, Tertiary / Q000502:physiology; D021381:Protein Transport / Q000187:drug effects / Q000502:physiology; D011970:Receptors, Histamine H2 / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D017442:Histamine Agonists; D011970:Receptors, Histamine H2; D000242:Cyclic AMP; D048049:Extracellular Signal-Regulated MAP Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D034281:Dynamins; D017259:Dimaprit