title: Effects of protein kinase inhibitor, 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine, on beta-2 adrenergic receptor activation and desensitization in intact human lymphocytes.
abstract: To investigate the role of protein kinases in agonist-mediated beta-2 adrenergic receptor regulation, the effects of the protein kinase A and C inhibitor, H-7 [1-(5-isoquinolinylsulfonyl)-2-methylpiperazine], on isoproterenol-induced beta adrenoceptor activation and desensitization have been studied in intact human lymphocytes. In the presence of the phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine, H-7 potentiated 10(-8) to 10(-4) M isoproterenol or prostaglandin E1-induced cyclic AMP (cAMP) accumulation in a dose-dependent manner. We failed to observe any effect of H-7 on forskolin-induced cAMP accumulation. These effects of H-7 are probably not due to its inhibition of phosphodiesterase. In addition, whereas up to 10(-3) M H-7 had no beta adrenergic receptor blocking effect, preincubation of intact cells with 10(-3.5) M H-7 partially prevented 50 nM isoproterenol-induced beta-2 adrenergic receptor desensitization in terms of decreases in beta adrenoceptor density (maximum binding), isoproterenol-mediated cAMP responsiveness and high affinity receptor binding for agonist. Interestingly, 10(-3.5) M H-7 alone treated cells also showed an up-regulation of cell surface beta receptor density (maximum binding) and increased cAMP responsiveness to isoproterenol stimulation. The mechanisms are unclear. If these effects occur as a result of inhibition by H-7 of protein kinase A and/or C, it may suggest an important role of protein kinase A and/or C in agonist-induced beta-2 adrenergic receptor regulation.
authors: Department of Medicine, School of Medicine, University of California, Los Angeles.
authors: K K
authors: KK
authors: Hui
authors: J L
authors: JL
authors: Yu
mesh_terms: D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000328:Adult; D000242:Cyclic AMP / Q000378:metabolism; D004357:Drug Synergism; D006801:Humans; D020120:Iodocyanopindolol; D007545:Isoproterenol / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology*; D008214:Lymphocytes / Q000187:drug effects; D010869:Pindolol / Q000031:analogs & derivatives / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors; D011943:Receptors, Adrenergic, beta / Q000187:drug effects*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
chemical_list: D007546:Isoquinolines; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011943:Receptors, Adrenergic, beta; D020120:Iodocyanopindolol; D019307:1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; D010869:Pindolol; D000242:Cyclic AMP; D007545:Isoproterenol; D013755:Tetradecanoylphorbol Acetate; D015056:1-Methyl-3-isobutylxanthine