title: Involvement of protein kinase Cdelta/extracellular signal-regulated kinase/poly(ADP-ribose) polymerase-1 (PARP-1) signaling pathway in histamine-induced up-regulation of histamine H1 receptor gene expression in HeLa cells.
abstract: The histamine H(1) receptor (H1R) gene is up-regulated in patients with allergic rhinitis. However, the mechanism and reason underlying this up-regulation are still unknown. Recently, we reported that the H1R expression level is strongly correlated with the severity of allergic symptoms. Therefore, understanding the mechanism of this up-regulation will help to develop new anti-allergic drugs targeted for H1R gene expression. Here we studied the molecular mechanism of H1R up-regulation in HeLa cells that express H1R endogenously in response to histamine and phorbol 12-myristate 13-acetate (PMA). In HeLa cells, histamine stimulation caused up-regulation of H1R gene expression. Rottlerin, a PKCδ-selective inhibitor, inhibited up-regulation of H1R gene expression, but Go6976, an inhibitor of Ca(2+)-dependent PKCs, did not. Histamine or PMA stimulation resulted in PKCδ phosphorylation at Tyr(311) and Thr(505). Activation of PKCδ by H(2)O(2) resulted in H1R mRNA up-regulation. Overexpression of PKCδ enhanced up-regulation of H1R gene expression, and knockdown of the PKCδ gene suppressed this up-regulation. Histamine or PMA caused translocation PKCδ from the cytosol to the Golgi. U0126, an MEK inhibitor, and DPQ, a poly(ADP-ribose) polymerase-1 inhibitor, suppressed PMA-induced up-regulation of H1R gene expression. These results were confirmed by a luciferase assay using the H1R promoter. Phosphorylation of ERK and Raf-1 in response to PMA was also observed. However, real-time PCR analysis showed no inhibition of H1R mRNA up-regulation by a Raf-1 inhibitor. These results suggest the involvement of the PKCδ/ERK/poly(ADP-ribose) polymerase-1 signaling pathway in histamine- or PMA-induced up-regulation of H1R gene expression in HeLa cells.
authors: Departments of Molecular Pharmacology, Tokushima 770-8505, Japan.
authors: Hiroyuki
authors: H
authors: Mizuguchi
authors: Departments of Molecular Pharmacology, Tokushima 770-8505, Japan.
authors: Takuma
authors: T
authors: Terao
authors: Departments of Molecular Pharmacology, Tokushima 770-8505, Japan.
authors: Mika
authors: M
authors: Kitai
authors: Departments of Molecular Pharmacology, Tokushima 770-8505, Japan.
authors: Mitsuhiro
authors: M
authors: Ikeda
authors: Medical Pharmacology, Tokushima 770-8505, Japan.
authors: Yoshiyuki
authors: Y
authors: Yoshimura
authors: Departments of Molecular Pharmacology, Tokushima 770-8505, Japan.
authors: Asish Kumar
authors: AK
authors: Das
authors: Otolaryngology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima 770-8505, Japan.
authors: Yoshiaki
authors: Y
authors: Kitamura
authors: Otolaryngology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima 770-8505, Japan.
authors: Noriaki
authors: N
authors: Takeda
authors: Departments of Molecular Pharmacology, Tokushima 770-8505, Japan. Electronic address: hfukui@ph.tokushima-u.ac.jp.
authors: Hiroyuki
authors: H
authors: Fukui
mesh_terms: D002070:Butadienes / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002227:Carbazoles / Q000494:pharmacology; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006632:Histamine / Q000378:metabolism*; D006801:Humans; D009570:Nitriles / Q000494:pharmacology; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D051745:Protein Kinase C-delta / Q000378:metabolism*; D021381:Protein Transport; D012333:RNA, Messenger / Q000378:metabolism; D011969:Receptors, Histamine H1 / Q000096:biosynthesis*; D015398:Signal Transduction
chemical_list: D002070:Butadienes; D002227:Carbazoles; D004791:Enzyme Inhibitors; D009570:Nitriles; D012333:RNA, Messenger; D011969:Receptors, Histamine H1; C113580:U 0126; C081021:Go 6976; D006632:Histamine; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; D051745:Protein Kinase C-delta; D048049:Extracellular Signal-Regulated MAP Kinases; D002118:Calcium