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	Figure 2. Glutamate-induced currents as a function of glutamate concentration in EAAT3/EAAT4-expressing Xenopus oocytes wihout or with Klotho coexpression.A, C: Means ± SEM of glutamate-induced current (Iglu) as a function of glutamate concentration in Xenopus oocytes injected with cRNA encoding EAAT3 (A, n = 9) or EAAT4 (C, n = 6) without (open circles) or with (closed circles) additional coexpression of Klotho.*,**(p<0.05, p<0.01) indicate statistically significant difference from Xenopus oocytes injected with cRNA encoding EAAT3 (A) or EAAT4 (C) alone (two-tailed unpaired t-test). B, D: Means ± SEM of glutamate induced current (Iglu) normalized to Iglu at 5 mM glutamate as a function of glutamate concentration in Xenopus oocytes injected with cRNA encoding EAAT3 (B, n = 9) or EAAT4 (D, n = 6) without (open circles) and with (closed circles) additional coexpression of Klotho. The values were fitted to a hyperbola function.
	Figure 3. Effect of Klotho coexpression on protein abundance of both EAAT3 and EAAT4 in the Xenopus oocyte cell membrane.A, C: Confocal images of EAAT3 (A) and EAAT4 (C) protein abundance in the plasma membrane of Xenopus oocytes injected with water (1st panel), injected with cRNA encoding EAAT3 (A) or EAAT4 (C) without (2nd panel) or with additional coexpression of Klotho (3rd panel). B, D: Means ± SEM of EAAT3 (B, n = 75–80) and EAAT4 (D, n = 82–87) protein abundance as determined by chemiluminescence in the plasma membrane of Xenopus oocytes injected with cRNA encoding EAAT3 (B) or EAAT4 (D) without (white bars) or with (black bars) coexpression of Klotho. For comparison, water injected oocytes (grey bars).**,***(p<0.01, p<0.001) indicate statistically significant difference from Xenopus oocytes injected with cRNA encoding EAAT3/EAAT4 alone (ANOVA).
	Figure 4. Effect of recombinant human β-Klotho protein on electrogenic glutamate transport in EAAT3 -expressing Xenopus oocytes.A: Means ± SEM (n = 7–16) of glutamate (2 mM)-induced current (Iglu) in Xenopus oocytes injected with water (grey bar) or injected with cRNA encoding EAAT3 and pretreated prior to measurements for 24 hours without (white bar) or with 10, 30 and 50 ng/ml recombinant human β-Klotho protein (1st, 2nd and 3rd black bar respectively).*,**(p<0.05, p<0.01) indicate statistically significant difference from untreated Xenopus oocytes (ANOVA). B: Means ± SEM (n = 12–17) of glutamate (2 mM)-induced current (Iglu) in Xenopus oocytes injected with water (grey bar) or injected with cRNA encoding EAAT3 pretreated prior to measurements with 30 ng/ml recombinant human β-Klotho protein for 0 hr (white bar) or 1, 6, 12 or 24hr (black bars respectively).**(p<0.01) indicates statistically significant difference from untreated Xenopus oocytes (ANOVA).
	Figure 5. Reversal of the effect of Klotho on electrogenic glutamate transport in EAAT3 or EAAT4 expressing Xenopus oocytes by β-glucuronidase inhibitor DSAL.A: Means ± SEM (n = 9–21) of glutamate (2 mM)-induced current (Iglu) in Xenopus oocytes injected with water (grey bar) or injected with cRNA encoding EAAT3 alone (white bar) or both EAAT3 and Klotho (black bars). Where indicated, the oocytes were treated with β-glucuronidase inhibitor DSAL (10 µM).**(p<0.01) indicates statistically significant difference from oocytes injected with cRNA encoding EAAT3 alone (ANOVA). ### (p<0.001) indicates statistically significant difference from oocytes injected with cRNA encoding both EAAT3 and Klotho (ANOVA).B: Means ± SEM (n = 11–23) of glutamate (2 mM)-induced current (Iglu) in Xenopus oocytes injected with water (grey bar) or injected with cRNA encoding EAAT3 alone (white bar) or pretreated for 24 hours with 30ng/ ml recombinant human β-Klotho protein without (first black bar) or with the presence of β-glucuronidase inhibitor DSAL (10µM ) (second black bar).***(p<0.001) indicates statistically significant difference from non-treated oocytes injected with cRNA encoding EAAT3 alone (ANOVA). ##(p<0.01). indicates statistically significant difference from oocytes injected with cRNA encoding EAAT3 and treated for 24 hours with 30ng/ ml recombinant human β-Klotho protein (ANOVA).C: Means ± SEM (n = 5–23) of glutamate (2 mM)-induced current (Iglu) in Xenopus oocytes injected with water (grey bar) or injected with cRNA encoding EAAT4 alone (white bar) or both EAAT4 and Klotho (black bars). Where indicated, the oocytes were treated with β-glucuronidase inhibitor DSAL (10 µM).***(p<0.001) indicates statistically significant difference from oocytes injected with cRNA encoding EAAT4 alone (ANOVA). ###(p<0.001) indicates statistically significant difference from oocytes injected with cRNA encoding both EAAT4 and Klotho (ANOVA).D: Means ± SEM (n = 9–21) of glutamate (2 mM)-induced current (Iglu) in Xenopus oocytes injected with water (grey bar) or injected with cRNA encoding EAAT4 alone (white bar) and pretreated for 24 hours with 30 ng/ ml recombinant human β-Klotho protein without (first black bar) or with the presence of β-glucuronidase inhibitor DSAL (10µM, second black bar).***(p<0.001) indicates statistically significant difference from non-treated oocytes injected with cRNA encoding EAAT4 alone (ANOVA). ##(p<0.01). indicates statistically significant difference from oocytes injected with cRNA encoding EAAT4 and treated for 24 hours with 30 ng/ml recombinant human Klotho protein (ANOVA).
	Figure 1. Effect of Klotho coexpression on electrogenic glutamate transport in EAAT3 or EAAT4 expressing Xenopus oocytes. A: Representative original tracings of glutamate (2 mM)-induced current (Iglu) at −60 mV in Xenopus oocytes injected with water (i), or with cRNA encoding Klotho alone (ii), EAAT3 alone (iii) or both, EAAT3 and Klotho (iv). B: Means ± SEM (n = 7–36) of glutamate (2 mM)-induced current (Iglu) in Xenopus oocytes injected without (left bars) or with (right bars) cRNA encoding EAAT3 and injected without (white bars) or with (black bars) cRNA encoding Klotho.***(p<0.001) indicates statistically significant difference from Xenopus oocytes injected with cRNA encoding EAAT3 alone (ANOVA). C: Representative original tracings of glutamate (2 mM)-induced current (Iglu) measured at a holding potential of −60 mV in Xenopus oocytes injected with water (i), or with cRNA encoding Klotho alone (ii), EAAT4 alone (iii) or both EAAT4 and Klotho (iv). D: Means ± SEM (n = 5–8) of glutamate (2 mM)-induced current (Iglu) in Xenopus oocytes injected without (left bars) or with (right bars) cRNA encoding EAAT4, and injected without (white bars) or with (black bars) cRNA encoding Klotho.**(p<0.01) indicate statistically significant difference from Xenopus oocytes injected with cRNA encoding EAAT3 or EAAT4 alone (ANOVA).

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