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Biomed Res Int
2018 May 20;2018:6817932. doi: 10.1155/2018/6817932.
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Aminophylline and Ephedrine, but Not Flumazenil, Inhibit the Activity of the Excitatory Amino Acid Transporter 3 Expressed in Xenopus Oocytes and Reverse the Increased Activity by Propofol.
Moon S
,
Baik HJ
.
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We investigated the effects of flumazenil, aminophylline, and ephedrine on the excitatory amino acid transporter type 3 (EAAT3) activity and the interaction with propofol. EAAT3 was expressed in the Xenopus oocytes. L-Glutamate-induced membrane currents were measured using the two-electrode voltage clamp at various drug concentrations. Oocytes were preincubated with protein kinase C- (PKC-) activator, or inhibitor, and phosphatidylinositol 3-kinase (PI3K) inhibitor. To study the interaction with propofol, oocytes were exposed to propofol, propofol + aminophylline, or ephedrine. Aminophylline and ephedrine significantly decreased EAAT3 activity. Aminophylline (95 μM) and ephedrine (1.19 μM) significantly decreased Vmax, but not Km of EAAT3, for glutamate. The phorbol 12-myristate-13-acetate-induced increase in EAAT3 activity was abolished by aminophylline or ephedrine. The decreased EAAT3 activities by PKC inhibitors (staurosporine, chelerythrine) and PI3K inhibitor (wortmannin) were not significantly different from those by aminophylline or ephedrine, as well as those by PKC inhibitors or PI3K inhibitor + aminophylline or ephedrine. The enhanced EAAT3 activities induced by propofol were significantly abolished by aminophylline or ephedrine. Aminophylline and ephedrine inhibit EAAT3 activity via PKC and PI3K pathways and abolish the increased EAAT3 activity by propofol. Our results indicate a novel site of action for aminophylline and ephedrine.
Figure 1. Schematic representation of the protocol used in the experiment for interactions between the effects of aminophylline or ephedrine and propofol on EAAT3 activity.
Figure 2. Dose-response curves of the effects of flumazenil (a), aminophylline (b), and ephedrine (c) on EAAT3 responses to l-glutamate (30 μM). Data are means ± SEM, n = 26–38 (a), 27–36 (b), and 41–60 (c) for each data point. ∗P < 0.05 compared with the control.
Figure 3. Concentration-response curves of excitatory amino acid transporter type 3 (EAAT3) to l-glutamate in the presence or absence of 95.1 μM aminophylline (a) and 1.19 μM ephedrine (b). Data are means ± SEM, n = 8–28 for each data point. ∗P < 0.05 compared with the corresponding controls.
Figure 4. Effects of protein kinase C (PKC) activation on excitatory amino acid transporter type 3 (EAAT3) activity in the presence or absence of 95.1 μM aminophylline (a) and 1.19 μM ephedrine (b). PMA, phorbol 12-myristate 13-acetate. Data are means ± SEM, n = 22–46 for each data point. ∗P < 0.05 compared with control; †P < 0.05 compared with PMA alone; ‡P < 0.05 compared with aminophylline or ephedrine alone.
Figure 5. Effects of protein kinase C (PKC) inhibition on excitatory amino acid transporter type 3 (EAAT3) activity in the presence or absence of 95.1 μM aminophylline. Whereas oocytes exposed to PKC inhibitor, aminophylline, or both showed a significant decrease in EAAT3 activity by 30 μM glutamate compared with the control, the EAAT3 activities were not significantly different among oocytes treated with PKC inhibitor, aminophylline, or PKC inhibitor plus aminophylline. Data are means ± SEM, n = 31–41 for each data point. ∗P < 0.05 compared with the control.
Figure 6. Effects of protein kinase C (PKC) inhibition on excitatory amino acid transporter type 3 (EAAT3) activity in the presence or absence of 1.19 μM ephedrine. Whereas oocytes exposed to PKC inhibitor, ephedrine, or both showed a significant decrease in EAAT3 activity by 30 μM glutamate compared with the control, the EAAT3 activities were not significantly different among oocytes treated with PKC inhibitor, ephedrine, or PKC inhibitor plus ephedrine. Data are means ± SEM, n = 31–46 for each data point. ∗P < 0.05 compared with the control.
Figure 7. Effects of PI3K inhibition on excitatory amino acid transporter type 3 (EAAT3) activity in the presence or absence of 95.1 μM aminophylline (a) and 1.19 μM ephedrine (B). Whereas preincubation of oocytes with the PI3K inhibitor, wortmannin (1 μM for 1 h), significantly reduced basal EAAT3 activity by 30 μM glutamate, the activity did not differ among wortmannin, aminophylline, or both (a) and among wortmannin, ephedrine, or both (b). PI3K, phosphatidylinositol 3-kinase. Data are means ± SEM, n = 31–46 for each data point. ∗P < 0.05 compared with the control.
Figure 8. Reversible effects of aminophylline or ephedrine on enhanced activity of excitatory amino acid transporter type 3 (EAAT3) by propofol (30 and 100 μM). Data are means ± SEM, n = 26–41 for each data point. ∗P < 0.05 compared with control; †P < 0.05 compared with 30 μM propofol; ‡P < 0.05 compared with 100 μM propofol.
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