A Role for the Val291 Residue within the Transmembrane Domain 2 in Diltiazem- and TMB-8 [3,4,5-Trimethoxybenzoic Acid 8-(Diethylamino)octyl Ester]-Mediated 5-Hydroxytryptamine Type 3A Receptor Regulations

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概要

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• Previous reports have shown that diltiazem and TMB, calcium channel antagonists, inhibit 5-hydroxytryptamine type 3A (5-HT3A) receptor-mediated currents (I5-HT) in cell lines and in heterologously expressed Xenopus oocytes. In the present study, we sought to elucidate the molecular mechanisms underlying diltiazem- and TMB-induced 5-HT3A receptor regulations. We used the two-microelectrode voltage clamp technique to investigate the effect of diltiazem and TMB on 5-HT-mediated ion currents in Xenopus oocytes expressing wild-type or 5-HT3A receptors harboring mutations in the gating pore region of transmembrane domain 2 (TM2). In oocytes expressing wild-type 5-HT3A receptors, diltiazem and TMB dose-dependently inhibited peak I5-HT with an IC50 of 71.4±4.9 and 4.5±0.3 μM, respectively. Among various mutants of TM2, mutation V291A greatly attenuated and abolished the TMB- and diltiazem-induced inhibition of peak I5-HT, respectively. Mutation V291A also induced constitutively active ion currents in the absence of 5-HT. Diltiazem and TMB inhibited constitutively active ion currents in a dose-dependent manner. The IC50 values of constitutively active ion currents in V291A receptors were 165.3±11.1 and 6.6±0.5 μM for diltiazem and 3,4,5-trimethoxybenzoic acid 8-(diethylamino)octyl ester (TMB-8), respectively. Results of site-directed mutagenesis experiments suggest that the Val291 residue could be a candidate for common interaction site for diltiazem- and TMB-8-mediated 5-HT3A receptor regulations.

• 日本薬学会の論文

著者

• Lee Jun-ho

  Department Of Physiology College Of Oriental Medicine Kyung-hee University

• LEE Byung-Hwan

  Department of Physiology, College of Veterinary Medicine, Konkuk University

• PYO Mi

  Department of Physiology, College of Veterinary Medicine, Konkuk University

• CHOI Sun-Hye

  Department of Physiology, College of Veterinary Medicine, Konkuk University

• SHIN Tae-Joon

  Department of Physiology, College of Veterinary Medicine, Konkuk University

• NAH Seung-Yeol

  Department of Physiology, College of Veterinary Medicine, Konkuk University

• KIM Hyoung-Choon

  Neurotoxicology Program, College of Pharmacy, Kangwon National University

• RHIM Hyewhon

  Biomedical Research Center

• Choi Sun

  Ginsentology Research Laboratory And Department Of Physiology College Of Veterinary Medicine Konkuk

• Nah Seung-yeol

  Department Of Physiology College Of Veterinary Medicine Chonnam National University

• Lee Byung-hwan

  Ginsentology Research Laboratory And Department Of Physiology College Of Veterinary Medicine Konkuk

• Hwang Sung-Hee

  Department of Physiology, College of Veterinary Medicine, Konkuk University

• Kim Bo-Ra

  Department of Physiology, College of Veterinary Medicine, Konkuk University

• Kim Hyoung-choon

  Neuropsychopharmacology And Toxicology Program Coll. Of Pharmacy Kangwon National Univ.

• Pyo Mi

  Department Of Physiology College Of Veterinary Medicine Konkuk University

• Hwang Sung-Hee

  Department of Physiology, College of Veterinary Medicine and Bio/Molecular Informatics Center, Konkuk University

• Lee Jun-Ho

  Department of Physiology, College of Oriental Medicine Kyung-Hee University

• Lee Byung-Hwan

  Department of Physiology, College of Veterinary Medicine and Bio/Molecular Informatics Center, Konkuk University

• Hwang Sung-Hee

  Department of Applied Physics, Hanyang University, Ansan, Gyeonggi-do 426-791, Korea

• Rhim Hyewhon

  Biomedical Research Center, KIST

• Shin Tae-Joon

  Department of Physiology, College of Veterinary Medicine and Bio/Molecular Informatics Center, Konkuk University

• Choi Sun-Hye

  Department of Physiology, College of Veterinary Medicine and Bio/Molecular Informatics Center, Konkuk University

• Kim Hyoung-Choon

  Neurotoxicology Program, College of Pharmacy, Korea Institute of Drug Abuse, Kangwon National University

• Kim Bo-Ra

  Department of Physiology, College of Veterinary Medicine and Bio/Molecular Informatics Center, Konkuk University

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