title: Resveratrol enhances 5-hydroxytryptamine type 3A receptor-mediated ion currents: the role of arginine 222 residue in pre-transmembrane domain I.
abstract: Resveratrol, which is found in grapes, red wine, and berries, has many beneficial health effects, such as anti-cancer, neuro-protective, anti-inflammatory, and life-prolonging effects. However, the cellular mechanisms by which resveratrol acts are relatively unknown, especially in terms of possible regulation of receptors involved in synaptic transmission. 5-Hydroxytryptamine type 3A (5-HT(3A)) receptor is one of several ligand-gated ion channels involved in fast synaptic transmission. In the present study, we investigated the effect of resveratrol on mouse 5-HT(3A) receptor channel activity. 5-HT(3A) receptor was expressed in Xenopus oocytes, and the current was measured using a two-electrode voltage clamp technique. Treatment of resveratrol itself had no effect on the oocytes injected with H(2)O as well as on the oocytes injected with 5-HT(3A) receptor cRNA. In the oocytes injected with 5-HT(3A) receptor cRNA, co- or pre-treatment of resveratrol with 5-HT potentiated 5-HT-induced inward peak current (I(5-HT)) with concentration-, reversible, and voltage-independent manners. The EC(50) of resveratrol was 28.0±2.4 µM. The presence of resveratrol caused a leftward shift of 5-HT concentration-response curve. Protein kinase C (PKC) activator or inhibitor had no effect on resveratrol action on I(5-HT). Site-directed mutations of pre-transmembrane domain 1 (pre-TM1) such as R222A, R222D, R222E, R222K, and R222T abolished or attenuated resveratrol-induced enhancement of I(5-HT), indicating that resveratrol might interact with pre-TM1 of 5-HT(3A) receptor. These results indicate that resveratrol might regulate 5-HT(3A) receptor channel activity via interaction with the N-terminal domain and these results further show that resveratrol-mediated regulation of 5-HT(3A) receptor channel activity might be one of cellular mechanisms of resveratrol action.
authors.affiliation: Department of Physiology, College of Veterinary Medicine and Bio/Molecular Informatics Center, Konkuk University, Seoul, Korea.
authors.forename: Byung-Hwan
authors.initials: BH
authors.lastname: Lee
authors.forename: Sung-Hee
authors.initials: SH
authors.lastname: Hwang
authors.forename: Sun-Hye
authors.initials: SH
authors.lastname: Choi
authors.forename: Tae-Joon
authors.initials: TJ
authors.lastname: Shin
authors.forename: Jiyeon
authors.initials: J
authors.lastname: Kang
authors.forename: Sang-Mok
authors.initials: SM
authors.lastname: Lee
authors.forename: Seung-Yeol
authors.initials: SY
authors.lastname: Nah
mesh_terms: D000818:Animals; D001120:Arginine / Q000378:metabolism*; D005638:Fruit; D015640:Ion Channel Gating / Q000187:drug effects*; D017136:Ion Transport / Q000187:drug effects; D051379:Mice; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D018377:Neurotransmitter Agents / Q000494:pharmacology; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010936:Plant Extracts / Q000494:pharmacology*; D017434:Protein Structure, Tertiary / Q000187:drug effects; D018075:RNA, Complementary / Q000378:metabolism; D044406:Receptors, Serotonin, 5-HT3 / Q000235:genetics / Q000378:metabolism*; D000077185:Resveratrol; D012701:Serotonin / Q000378:metabolism*; D013267:Stilbenes / Q000494:pharmacology*; D013570:Synaptic Membranes / Q000187:drug effects / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects*; D027843:Vitis / Q000737:chemistry; D014920:Wine; D014981:Xenopus
chemical_list: D018377:Neurotransmitter Agents; D010936:Plant Extracts; D018075:RNA, Complementary; D044406:Receptors, Serotonin, 5-HT3; D013267:Stilbenes; D012701:Serotonin; D001120:Arginine; D000077185:Resveratrol