Caroline SunggipKakeru ShimodaSayaka OdaTomohiro TanakaKazuhiro NishiyamaSupachoke MangmoolAkiyuki NishimuraTakuro Numaga-TomitaMotohiro NishidaNational Institutes of Natural Sciences - Exploratory Research Center on Life and Living SystemsThe Graduate University for Advanced StudiesUniversiti Malaysia SabahMahidol UniversityKyushu University2019-08-282019-08-282018-05-22Frontiers in Pharmacology. Vol.9, No.MAY (2018)166398122-s2.0-85047409869https://repository.li.mahidol.ac.th/handle/20.500.14594/46663© 2018 Sunggip, Shimoda, Oda, Tanaka, Nishiyama, Mangmool, Nishimura, Numaga-Tomita and Nishida. Cardiac hypertrophy, induced by neurohumoral factors, including angiotensin II and endothelin-1, is a major predisposing factor for heart failure. These ligands can induce hypertrophic growth of neonatal rat cardiomyocytes (NRCMs) mainly through Ca2+-dependent calcineurin/nuclear factor of activated T cell (NFAT) signaling pathways activated by diacylglycerol-activated transient receptor potential canonical 3 and 6 (TRPC3/6) heteromultimer channels. Although extracellular nucleotide, adenosine 5'-triphosphate (ATP), is also known as most potent Ca2+-mobilizing ligand that acts on purinergic receptors, ATP never induces cardiomyocyte hypertrophy. Here we show that ATP-induced production of nitric oxide (NO) negatively regulates hypertrophic signaling mediated by TRPC3/6 channels in NRCMs. Pharmacological inhibition of NO synthase (NOS) potentiated ATP-induced increases in NFAT activity, protein synthesis, and transcriptional activity of brain natriuretic peptide. ATP significantly increased NO production and protein kinase G (PKG) activity compared to angiotensin II and endothelin-1. We found that ATP-induced Ca2+ signaling requires inositol 1,4,5-trisphosphate (IP3) receptor activation. Interestingly, inhibition of TRPC5, but not TRPC6 attenuated ATP-induced activation of Ca2+/NFAT-dependent signaling. As inhibition of TRPC5 attenuates ATP-stimulated NOS activation, these results suggest that NO-cGMP-PKG axis activated by IP3-mediated TRPC5 channels underlies negative regulation of TRPC3/6-dependent hypertrophic signaling induced by ATP stimulation.Mahidol UniversityMedicinePharmacology, Toxicology and PharmaceuticsArticleSCOPUS10.3389/fphar.2018.00523