Effects of ondansetron on the activity of glutamate transporter type 3 and the modulation mechanism

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의과대학 의학과
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서울대학교 대학원
학위논문 (박사)-- 서울대학교 대학원 : 의학과, 2014. 2. 도상환.
Background: The dysfunction of excitatory amino acid transporters (EAATs) is associated with neurologic disorders by increasing extracellular glutamate concentrations. Ondansetron, which is a serotonin antagonist used for anti-emesis, is known to provoke neurologic adverse events such as seizures. We investigated the effects of ondansetron on the EAAT type 3 (EAAT3, the major neuronal EAAT) and the role of protein kinase C (PKC) and phosphatidylinositol 3-kinase (PI3K).

Methods: EAAT3 was expressed in Xenopus oocytes following the injection of rat mRNA for EAAT3. Using the two-electrode voltage clamping method, the inward currents induced by L-glutamate were measured for 1 min. The trace of currents was integrated and described in microCoulombs (μC). Oocytes in study groups were exposed to ondansetron for 3 min. In addition, oocytes were exposed to PKC activator/inhibitors or PI3K inhibitors to elucidate the modulating mechanisms of ondansetron on EAAT3.

Results: Serial concentrations of ondansetron except 1 μM significantly decreased the activity of EAAT3 in a dose-dependent manner (IC50 = 8.57 μM, p < 0.05). In the kinetic study, 10 μM of ondansetron reduced Vmax but not Km compared to control group. Phorbol-12-myristate-13-acetate (PKC activator) abolished ondansetron-induced decrease in EAAT3 activity. Staurosporine and chelerythrine, PKC inhibitors, significantly reduced the EAAT3 activity, but there were no interactions between ondansetron and PKC inhibitors. The two PI3K inhibitors (wortmannin and LY294002) decreased EAAT3 responses, although there were no differences among ondansetron, PI3K inhibitors, and ondansetron plus PI3K inhibitors groups.

Conclusions: Our results suggest that ondansetron decreases the activity of EAAT3 and this effect seems to be mediated by PKC and PI3K.
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College of Medicine/School of Medicine (의과대학/대학원)Dept. of Medicine (의학과)Theses (Ph.D. / Sc.D._의학과)
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