Molecular actions of propofol on human 5-HT3A receptors: enhancement as well as inhibition by closely related phenol derivatives.

摘要: BACKGROUND: 5-Hydroxytryptamine type 3 (5-HT3) receptors are excitatory ligand-gated ion channels which involved in postoperative nausea and vomiting. They depressed by the anesthetic propofol, which, contrast, enhances activity of inhibitory such as gamma-aminobutyric acid A glycine receptors. To investigate molecular mechanisms responsible for these contrasting actions, we examined kinetics action propofol its lesser hydrophobic derivatives 2-isopropylphenol phenol on human 5-HT3A METHODS: Human embryonic kidney 293 cells containing stably transfected cDNA receptor subunit were patch clamped (excised outside-out patches). Drugs applied with a fast solution exchange system (within 2 ms) their concentrations determined high performance liquid chromatography. RESULTS: When equilibrium (60 s before during 5-HT pulse), inhibited (IC50 = 18 +/- 1.0 microM). In equilibrium, less was surprisingly similarly potent inhibitor 17 3.2 microM), whereas considerably 1.6 0.2 mM). Varying duration drug application currents elicited, then applying still presence revealed that slow processes contributed to (equilibrium) effects (tau(IN-1) 35 ms tau(IN-2) 4.8 s), 64 6.6 < 10 ms, 20.4 s). transiently together (open channel application), accelerated 5-HT-induced desensitization significantly, whereas, increased slowed desensitization. Slowed also observed 5-hydroxyindole (1 mM), derivative, but not benzene. The phenol, 2-isopropylphenol, more pronounced when concentration decreased from 30 microM, sensitive 5-HT. CONCLUSIONS: At least two separate actions could be identified enhancing seen related smaller no longer detected. 5-HT-dependent 5-HT-independent interactions distinguished all three drugs. Propofol than expected properties. Underlying appear involve phenolic hydroxyl group, interactions, steric restrictions.