title: The regulation of transient receptor potential canonical 4 (TRPC4) channel by phosphodiesterase 5 inhibitor via the cyclic guanosine 3'5'-monophosphate.
abstract: The transient receptor potential (TRP) protein superfamily consists of a diverse group of cation channels that bear structural similarities to the fruit fly Drosophila TRP. The TRP superfamily is distinct from other groups of ion channels in displaying a large diversity in ion selectivity, modes of activation, and physiological functions. Classical TRP (transient receptor potential canonical (TRPC)) channels are activated by stimulation of Gq-PLC-coupled receptors and modulated by phosphorylation. The cyclic guanosine monophosphate (cGMP)-PKG pathway is involved in the regulation of TRPC3 and TRPC6 channels. Phosphodiesterase (PDE) 5 inhibitor induced muscle relaxation in corporal smooth muscle cells and was used to treat erectile dysfunction by inhibiting cGMP degradation. Here, we report the functional relationship between TRPC4 and cGMP. In human embryonic kidney (HEK) 293 cells overexpressing TRPC4, cGMP selectively activated TRPC4 channels and increased cytosolic calcium level through TRPC4 channel. We investigated phosphorylation sites in TRPC4 channels and identified S688 as an important phosphorylation site for the cGMP-PKG pathway. Cyclic GMP also activated TRPC4-like current with doubly rectifying current-voltage relationship in prostate smooth muscle cell lines. Taken together, these results show that TRPC4 is phosphorylated by the cGMP-PKG pathway and might be an important target for modulating prostate function by PDE5 inhibitors.
authors.affiliation: Department of Physiology, Seoul National University College of Medicine, 28 Yongon-dong Chongno-Gu, Seoul, 110-799, South Korea.
authors.forename: Jinhong
authors.initials: J
authors.lastname: Wie
authors.affiliation: Department of Physiology, Seoul National University College of Medicine, 28 Yongon-dong Chongno-Gu, Seoul, 110-799, South Korea.
authors.forename: SeungJoo
authors.initials: S
authors.lastname: Jeong
authors.affiliation: Department of Physiology, Seoul National University College of Medicine, 28 Yongon-dong Chongno-Gu, Seoul, 110-799, South Korea.
authors.forename: Misun
authors.initials: M
authors.lastname: Kwak
authors.affiliation: Department of Physiology, Seoul National University College of Medicine, 28 Yongon-dong Chongno-Gu, Seoul, 110-799, South Korea.
authors.forename: Jongyun
authors.initials: J
authors.lastname: Myeong
authors.affiliation: Department of Urology, Samsung Medical Center, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Seoul, South Korea.
authors.forename: MeeRee
authors.initials: M
authors.lastname: Chae
authors.affiliation: Department of Urology, Chonbuk National University Medical School, Jeonju, South Korea.|Institute for Medical Sciences, Chonbuk National University, Jeonju, South Korea.|Institute and Clinical Trial Center of Medical Device, Chonbuk National University Hospital, Jeonju, South Korea.
authors.forename: Jong Kwan
authors.initials: JK
authors.lastname: Park
authors.affiliation: Department of Urology, Samsung Medical Center, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Seoul, South Korea.
authors.forename: Sung Won
authors.initials: SW
authors.lastname: Lee
authors.affiliation: Department of Physiology, Seoul National University College of Medicine, 28 Yongon-dong Chongno-Gu, Seoul, 110-799, South Korea. insuk@snu.ac.kr.
authors.forename: Insuk
authors.initials: I
authors.lastname: So
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D050052:TRPC Cation Channels / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D058986:Phosphodiesterase 5 Inhibitors; D050052:TRPC Cation Channels; C489571:TRPC4 ion channel; D006152:Cyclic GMP; D002118:Calcium
keywords: BPH; LUTS; PDE inhibitors; PKG; Prostate; TRPC4; cGMP