title: Intracellular spermine blocks TRPC4 channel via electrostatic interaction with C-terminal negative amino acids.
abstract: Transient receptor potential canonical (TRPC) 4 channels are calcium-permeable, nonselective cation channels and are widely expressed in mammalian tissue, especially in the GI tract and brain. TRPC4 channels are known to be involved in neurogenic contraction of ileal smooth muscle cells via generating cationic current after muscarinic stimulation (muscarinic cationic current (mIcat)). Polyamines exist in numerous tissues and are believed to be involved in cell proliferation, differentiation, scar formation, wound healing, and carcinogenesis. Besides, physiological polyamines are essential to maintain inward rectification of cardiac potassium channels (Kir2.1). At membrane potentials more positive than equilibrium potential, intracellular polyamines plug the cytosolic surface of the Kir2.1 so that potassium ions cannot pass through the pore. Recently, it was reported that polyamines inhibit not only cardiac potassium channels but also nonselective cation channels that mediate the generation of mIcat. Here, we report that TRPC4, a definite mIcat mediator, is inhibited by intracellular spermine with great extent. The inhibition was specific to TRPC4 and TRPC5 channels but was not effective to TRPC1/4, TRPC1/5, and TRPC3 channels. For this inhibition to occur, we found that glutamates at 728th and 729th position of TRPC4 channels are essential whereby we conclude that spermine blocks the TRPC4 channel with electrostatic interaction between negative amino acids at the C-terminus of the channel.
authors.affiliation: College of Medicine, Catholic University of Korea, Seoul, 137-701, Republic of Korea.|Department of Physiology, College of Medicine, Seoul National University, Seoul, 110-799, Republic of Korea.
authors.forename: Jinsung
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Surgery, College of Medicine, Seoul National University, Seoul, 110-799, Republic of Korea.
authors.forename: Sang Hui
authors.initials: SH
authors.lastname: Moon
authors.affiliation: Department of Physiology, College of Medicine, Seoul National University, Seoul, 110-799, Republic of Korea.
authors.forename: Young-Cheul
authors.initials: YC
authors.lastname: Shin
authors.affiliation: Department of Physiology, College of Medicine, Seoul National University, Seoul, 110-799, Republic of Korea.
authors.forename: Ju-Hong
authors.initials: JH
authors.lastname: Jeon
authors.affiliation: Department of Surgery, College of Medicine, Seoul National University, Seoul, 110-799, Republic of Korea.
authors.forename: Kyu Joo
authors.initials: KJ
authors.lastname: Park
authors.affiliation: Department of Physiology, College of Veterinary Medicine, Chungnam National University, Daejeon, 305-764, Republic of Korea. leekyupil@gmail.com.
authors.forename: Kyu Pil
authors.initials: KP
authors.lastname: Lee
authors.affiliation: Department of Physiology, College of Medicine, Seoul National University, Seoul, 110-799, Republic of Korea. insuk@snu.ac.kr.
authors.forename: Insuk
authors.initials: I
authors.lastname: So
mesh_terms: D000200:Action Potentials; D000818:Animals; D001665:Binding Sites; D018698:Glutamic Acid / Q000737:chemistry / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D024661:Potassium Channels, Inwardly Rectifying / Q000378:metabolism; D011485:Protein Binding; D013096:Spermine / Q000378:metabolism*; D055672:Static Electricity; D050052:TRPC Cation Channels / Q000737:chemistry / Q000378:metabolism*
chemical_list: C489461:Kir2.1 channel; D024661:Potassium Channels, Inwardly Rectifying; D050052:TRPC Cation Channels; C489571:TRPC4 ion channel; D013096:Spermine; D018698:Glutamic Acid
keywords: GI physiology; NSCC; Polyamine; Spermine; TRPC4