Int J Biol Sci 2014; 10(1):64-72. doi:10.7150/ijbs.7894
A Xanthine-Derivative K+-Channel Opener Protects against Serotonin-Induced Cardiomyocyte Hypertrophy via the Modulation of Protein Kinases
1. Department of Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
This study investigated whether KMUP-1, a xanthine-derivative K+ channel opener, could prevent serotonin-induced hypertrophy in H9c2 cardiomyocytes via L-type Ca2+ 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 Ca2+ 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.
Keywords: Serotonin, H9c2 cardiomyocyte-like cell line, perforated whole-cell patch-clamp technique, L-type Ca2+ channels, protein kinases, cardiac hypertrophy
This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) License. See http://ivyspring.com/terms for full terms and conditions.
How to cite this article:
Kuo HF, Lai YJ, Wu JC, Lee KT, Chu CS, Chen IJ, Wu JR, Wu BN. A Xanthine-Derivative K+-Channel Opener Protects against Serotonin-Induced Cardiomyocyte Hypertrophy via the Modulation of Protein Kinases. Int J Biol Sci 2014; 10(1):64-72. doi:10.7150/ijbs.7894. Available from http://www.ijbs.com/v10p0064.htm