Amino acid residues involved in agonist binding and its linking to channel gating, proximal to transmembrane domain of 5-HT3A receptor for halothane modulation / 대한마취과학회지

BACKGROUND: The 5-hydroxytryptamine type 3 (5-HT3) receptor is a member of the Cys-loop superfamily of ligand-gated ion channels (LGICs) and modulated by pharmacologic relevant concentrations of volatile anesthetics or n-alcohols like most receptors of LGICs. The goal of this study was to reveal whether the site-directed single mutations of E-106, F-107 and R-222 in 5-HT3 receptor may affect the anesthetic modulation of halothane known as positive modulator. METHODS: The wild-type and mutant receptors, E106D, F107Y, R222F, R222V, were expressed in Xenopus Laevis oocytes and receptor function was assessed using two electrode voltage clamp techniques. RESULTS: E106D, F107Y, R222F, R222V mutant 5-HT3A receptors were functionally expressed. F107Y mutant 5-HT3A receptors displayed decreased sensitivity to 5-HT compared to the wild type 5-HT3A receptor (P < 0.05). Halothane showed positive modulation in both wild and F107Y mutant 5-HT3A receptors but F107Y mutant 5-HT3 receptor showed greater enhancing modulation comparing to wild-type receptor. Meanwhile, R222F and R222V mutant 5-HT3 receptor lost positive modulation with 1 and 2 MAC of halothane. Most interestingly, positive modulation by halothane was converted into negative modulation in E106D mutant 5-HT3A receptor. CONCLUSIONS: The present study implicate the amino acid residues known for agonist binding and linking agonist binding to channel gating might also have important role for anesthetic modulation in 5-HT3A receptor.

Association of 5-HT3A receptor Pro16Ser polymorphism with the incidence of PONV and the response to ondansetron in Korean patients

BACKGROUND: Postopertative nausea and vomiting (PONV) are frequent and distressing side effects of surgery. Even though many drugs has been developed, PONV still remains unsolved problem. Ondansetron is a commonly used 5-HT3 receptor antagonist. It acts through specific binding to the 5-HT3A, 5-HT3B receptor complex. We hypothesized that patients with genetic variation in 5-HT3A receptor might have variable incidence of PONV and respond differently to ondansetron. METHODS: We included 204 patients undergoing gynecologic laparoscopic surgery. PONV were documented during 24 hours after operation. Ondansetron was injected to every patient who had PONV at PACU and PONV reassessed after 15 minutes. DNA was extracted from blood and 5-HT3A Pro16Ser missense mutation was analyzed by using real-time PCR. RESULTS: The incidence of PONV were 50% for wild type, 53% for heterozygote and 0% for homozygote. There were no significant differences between wild type and heterozygote in VAS of nausea and VAS change after ondansetron. CONCLUSIONS: 5-HT3A receptor Pro16Ser polymorphism is not associated with the incidence of PONV and the response to ondansetron in Korean patients.