title: Stimulation of fibroblast proliferation by neokyotorphin requires Ca influx and activation of PKA, CaMK II and MAPK/ERK.
abstract: Neokyotorphin [TSKYR, hemoglobin alpha-chain fragment (137-141)] has previously been shown to enhance fibroblast proliferation, its effect depending on cell density and serum level. Here we show the dependence of the effect of neokyotorphin on cell type and its correlation with the effect of protein kinase A (PKA) activator 8-Br-cAMP, but not the PKC activator 4beta-phorbol 12-myristate, 13-acetate (PMA). In L929 fibroblasts, the proliferative effect of neokyotorphin was suppressed by the Ca2+ L-type channel inhibitors verapamil or nifedipine, the intracellular Ca2+ chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid acetoxymethyl ester, kinase inhibitors H-89 (PKA), KN-62 (Ca2+/calmodulin-dependent kinase II) and PD98059 (mitogen-activated protein kinase). The proliferative effect of 8-Br-cAMP was also suppressed by KN-62 and PD98059. PKC suppression (downregulation with PMA or inhibition with bisindolylmaleimide XI) did not affect neokyotorphin action. The results obtained point to a cAMP-like action for neokyotorphin.
authors.affiliation: Regulatory Peptides Group, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia. sazonova@mail.ibch.ru
authors.forename: Olga V
authors.initials: OV
authors.lastname: Sazonova
authors.forename: Elena Yu
authors.initials: EY
authors.lastname: Blishchenko
authors.forename: Anna G
authors.initials: AG
authors.lastname: Tolmazova
authors.forename: Dmitry P
authors.initials: DP
authors.lastname: Khachin
authors.forename: Konstantin V
authors.initials: KV
authors.lastname: Leontiev
authors.forename: Andrey A
authors.initials: AA
authors.lastname: Karelin
authors.forename: Vadim T
authors.initials: VT
authors.lastname: Ivanov
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects*; D002614:Chelating Agents / Q000494:pharmacology; D002522:Chlorocebus aethiops; D004723:Endorphins / Q000737:chemistry* / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D005419:Flavonoids / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology; D020935:MAP Kinase Signaling System; D051379:Mice; D009543:Nifedipine / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D014700:Verapamil / Q000494:pharmacology
chemical_list: D000927:Anticonvulsants; D002614:Chelating Agents; D004723:Endorphins; D005419:Flavonoids; D007546:Isoquinolines; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; C063302:KN 62; C036450:neo-kyotorphin; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D014700:Verapamil; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D009543:Nifedipine; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D002118:Calcium