title: A xanthine-derivative K(+)-channel opener protects against serotonin-induced cardiomyocyte hypertrophy via the modulation of protein kinases.
abstract: This study investigated whether KMUP-1, a xanthine-derivative K(+) channel opener, could prevent serotonin-induced hypertrophy in H9c2 cardiomyocytes via L-type Ca(2+) channels (LTCCs). Rat heart-derived H9c2 cells were incubated with serotonin (10 μM) for 4 days. The cell size increased by 155.5%, and this was reversed by KMUP-1 (≥1 μM), and attenuated by the LTCC blocker verapamil (1 μM) and the 5-HT2A antagonist ketanserin (0.1 μM), but unaffected by the 5-HT2B antagonist SB206553. A perforated whole-cell patch-clamp technique was used to investigate Ca(2+) currents through LTCCs in serotonin-induced H9c2 hypertrophy, in which cell capacitance and current density were increased. The LTCC current (ICa,L) increased ~2.9-fold in serotonin-elicited H9c2 hypertrophy, which was attenuated by verapamil and ketanserin, but not affected by SB206553 (0.1 μM). Serotonin-increased ICa,L was reduced by KMUP-1, PKA and PKC inhibitors (H-89, 1 μM and chelerythrine, 1 μM) while the current was enhanced by the PKC activator PMA, (1 μM) but not the PKA activator 8-Br-cAMP (100 μM), and was abolished by KMUP-1. In contrast, serotonin-increased ICa,L was blunted by the PKG activator 8-Br-cGMP (100 μM), but unaffected by the PKG inhibitor KT5823 (1 μM). Notably, KMUP-1 blocked serotonin-increased ICa,L but this was partially reversed by KT5823. In conclusion, serotonin-increased ICa,L could be due to activated 5-HT2A receptor-mediated PKA and PKC cascades, and/or indirect interaction with PKG. KMUP-1 prevents serotonin-induced H9c2 cardiomyocyte hypertrophy, which can be attributed to its PKA and PKC inhibition, and/or PKG stimulation.
authors.affiliation: 1. Department of Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Hsuan-Fu
authors.initials: HF
authors.lastname: Kuo
authors.affiliation: 2. Department of Pharmacology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Yan-Jie
authors.initials: YJ
authors.lastname: Lai
authors.affiliation: 3. Division of Cardiology, Department of Internal Medicine, Pingtung Christian Hospital, Pingtung, Taiwan.
authors.forename: Jung-Chou
authors.initials: JC
authors.lastname: Wu
authors.affiliation: 4. Division of Cardiology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Kun-Tai
authors.initials: KT
authors.lastname: Lee
authors.affiliation: 1. Department of Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan ; 4. Division of Cardiology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Chih-Sheng
authors.initials: CS
authors.lastname: Chu
authors.affiliation: 2. Department of Pharmacology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Ing-Jun
authors.initials: IJ
authors.lastname: Chen
authors.affiliation: 5. Department of Pediatrics, Division of Pediatric Pulmonology and Cardiology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Jiunn-Ren
authors.initials: JR
authors.lastname: Wu
authors.affiliation: 2. Department of Pharmacology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Bin-Nan
authors.initials: BN
authors.lastname: Wu
mesh_terms: D000818:Animals; D002460:Cell Line; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D004789:Enzyme Activation; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000473:pathology; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000187:drug effects*; D051381:Rats; D012701:Serotonin / Q000494:pharmacology*; D019820:Xanthine / Q000494:pharmacology*
chemical_list: D015221:Potassium Channels; D019820:Xanthine; D012701:Serotonin; D017868:Cyclic AMP-Dependent Protein Kinases
keywords: H9c2 cardiomyocyte-like cell line; L-type Ca2+ channels; Serotonin; cardiac hypertrophy; perforated whole-cell patch-clamp technique; protein kinases