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Clonidine has been shown to be a potent neuroprotectant by acting at α(2) receptors on glutamatergic neurons to inhibit the release of glutamate. The aim of this study is to investigate the effects of clonidine on the activity of EAAT3 that can regulate extracellular glutamate. EAAT3 was expressed in the Xenopus oocytes. Using a two-electrode voltage clamp, membrane currents were recorded after application of 30 µM L-glutamate both in the presence and absence of various concentrations of clonidine. To determine the effects of clonidine on the K(m) and Vmax of EAAT3 and the reversibility of clonidine effects, membrane currents were recorded after the application of various concentrations of L-glutamate both in the presence and absence of 1.50 × 10(-7) M clonidine. Clonidine reduced the EAAT3 responses to L-glutamate in a concentration-dependent manner. This inhibition was statistically significant at higher concentrations than at the clinically relevant range. Clonidine at 1.50 × 10(-7) M reduced the Vmax, but did not affect the K(m) of EAAT3 for L-glutamate. These results suggest that the direct inhibition of EAAT3 activity is not related to the sedation effect of clonidine and that the clonidine-induced reduction of EAAT3 activity provides additional data for the possible involvement of glutamatergic hyperactivity in the proconvulsant effect of clonidine.
Fig. 1. Dose-response of clonidine inhibition of EAAT3 responses to 30 µM L-glutamate. The IC50 value for this inhibition was 2.72 à 10-8 M. The upper graphs show typical current traces induced by the application of 30 µM L-glutamate. Data show the means ± SEM (n = 25-50 in each data point). *P < 0.05 compared to control.
Fig. 2. Effects of clonidine on EAAT3 activity. The EAAT3 responses to various L-glutamate concentrations were measured before (control group) and immediately after clonidine treatment (clonidine group) and after a 4-min Tyrode's perfusion (Tyrode's washout). The Vmax and Km values of EAAT3 response to L-glutamate are listed in the table above the figure. Data show the means ± SEM (n = 9-17 in each data point). *P < 0.05 compared to the corresponding values in the control group.
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