title: Dexamethasone activates transient receptor potential canonical 4 (TRPC4) channels via Rasd1 small GTPase pathway.
abstract: Canonical transient receptor potential 4 (TRPC4) channels are calcium-permeable, nonselective cation channels that are widely distributed in mammalian cells. It is generally speculated that TRPC4 channels are activated by Gq/11-PLC pathway or directly activated by Gi/o proteins. Although many mechanistic studies regarding TRPC4 have dealt with heterotrimeric G proteins, here, we first report the functional relationship between TRPC4 and small GTPase, Rasd1. Rasd1 selectively activated TRPC4 channels, and it was the only Ras protein among Ras protein family that can activate TRPC4 channels. For this to occur, it was found that certain population of functional Gαi1 and Gαi3 proteins are essential. Meanwhile, dexamethasone, a synthetic glucocorticoid and anti-inflammatory drug was known to increase messenger RNA (mRNA) level of Rasd1 in pancreatic β-cells. We have found that dexamethasone triggers TRPC4-like cationic current in INS-1 cells via increasing protein expression level of Rasd1. This relationship among dexamethasone, Rasd1, and TRPC4 could suggest a new therapeutic agent for hospitalized diabetes mellitus (DM) patients with prolonged dexamethasone prescription.
authors.affiliation: Department of Physiology, Seoul National University College of Medicine, Seoul, 110-799, Republic of Korea.
authors.forename: Jinhong
authors.initials: J
authors.lastname: Wie
authors.affiliation: Department of Physiology, Seoul National University College of Medicine, Seoul, 110-799, Republic of Korea.|Catholic University of Korea, College of Medicine, Seoul, 137-701, Republic of Korea.
authors.forename: Jinsung
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Physiology, Seoul National University College of Medicine, Seoul, 110-799, Republic of Korea.
authors.forename: Kotdaji
authors.initials: K
authors.lastname: Ha
authors.affiliation: Department of Physiology, Seoul National University College of Medicine, Seoul, 110-799, Republic of Korea.
authors.forename: Yin Hua
authors.initials: YH
authors.lastname: Zhang
authors.affiliation: Department of Physiology, Seoul National University College of Medicine, Seoul, 110-799, Republic of Korea.
authors.forename: Ju-Hong
authors.initials: JH
authors.lastname: Jeon
authors.affiliation: Department of Physiology, Seoul National University College of Medicine, Seoul, 110-799, Republic of Korea. insuk@snu.ac.kr.
authors.forename: Insuk
authors.initials: I
authors.lastname: So
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D003907:Dexamethasone / Q000494:pharmacology*; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D050052:TRPC Cation Channels / Q000378:metabolism*; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D000893:Anti-Inflammatory Agents; D050052:TRPC Cation Channels; C489571:TRPC4 ion channel; D003907:Dexamethasone; C498511:Rasd1 protein, mouse; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D018631:ras Proteins
keywords: Dexamethasone; GPCR; Insulin; Rasd1; Small G protein; TRPC4