The Anticonvulsant Valproate Increases the Turnover Rate of γ-Aminobutyric Acid Transporters

Valproate is an important anticonvulsant currently in clinical use for the treatment of seizures. We used electrophysiological and tracer uptake methods to examine the effect of valproate on a γ-aminobutyric acid (GABA) transporter (mouse GAT3) expressed in Xenopus laevis oocytes. In the absence of GABA, valproate (up to 50 mm) had no noticeable effect on the steady-state electrogenic properties of mGAT3. In the presence of GABA, however, valproate enhanced the GABA-evoked steady-state inward current in a dose-dependent manner with a half-maximal concentration of 4.6 ± 0.5 mm. Maximal enhancement of the GABA-evoked current was 275 ± 10%. Qualitatively similar observations were obtained for human GAT1 and mouse GAT4. The valproate enhancement did not alter the Na+or Cl− dependence of the steady-state GABA-evoked currents. Uptake experiments under voltage clamp suggested that the valproate enhancement of the GABA-evoked current was matched by an enhancement in GABA uptake. Thus, despite the increase in GABA-evoked current, ion/GABA co-transport remained tightly coupled. Uptake experiments indicated that valproate is not transported by mouse GAT3 in the absence or presence of GABA. Valproate also enhanced the rate of the partial steps involved in transporter presteady-state charge movements. We propose that valproate increases the turnover rate of GABA transporters by an allosteric mechanism. The data suggest that at its therapeutic concentration, valproate may enhance the activity of neuronal and glial GABA transporters by up to 10%. Valproate is an important anticonvulsant currently in clinical use for the treatment of seizures. We used electrophysiological and tracer uptake methods to examine the effect of valproate on a γ-aminobutyric acid (GABA) transporter (mouse GAT3) expressed in Xenopus laevis oocytes. In the absence of GABA, valproate (up to 50 mm) had no noticeable effect on the steady-state electrogenic properties of mGAT3. In the presence of GABA, however, valproate enhanced the GABA-evoked steady-state inward current in a dose-dependent manner with a half-maximal concentration of 4.6 ± 0.5 mm. Maximal enhancement of the GABA-evoked current was 275 ± 10%. Qualitatively similar observations were obtained for human GAT1 and mouse GAT4. The valproate enhancement did not alter the Na+or Cl− dependence of the steady-state GABA-evoked currents. Uptake experiments under voltage clamp suggested that the valproate enhancement of the GABA-evoked current was matched by an enhancement in GABA uptake. Thus, despite the increase in GABA-evoked current, ion/GABA co-transport remained tightly coupled. Uptake experiments indicated that valproate is not transported by mouse GAT3 in the absence or presence of GABA. Valproate also enhanced the rate of the partial steps involved in transporter presteady-state charge movements. We propose that valproate increases the turnover rate of GABA transporters by an allosteric mechanism. The data suggest that at its therapeutic concentration, valproate may enhance the activity of neuronal and glial GABA transporters by up to 10%. γ-aminobutyric acid GABA transporter mouse GAT human GAT current-voltage charge-voltage maximum transporter-mediated charge γ-Aminobutyric acid (GABA)1 is the most abundant inhibitory neurotransmitter in the central nervous system. Transport of GABA into cells is accomplished by Na+-dependent and Cl−-facilitated GABA transporters (GATs) found in the plasma membrane of neurons and glia (1Kavanaugh M.P. Arriza J.L. North R.A. Amara S.G. J. Biol. Chem. 1992; 267: 22007-22009Abstract Full Text PDF PubMed Google Scholar, 2Keynan S. Suh Y.-J. Kanner B.I. Rudnick G. Biochemistry. 1992; 31: 1974-1979Crossref PubMed Scopus (121) Google Scholar, 3Mager S. Naeve J. Quick M. Labarca C. Davidson N. Lester H.A. Neuron. 1993; 10: 177-188Abstract Full Text PDF PubMed Scopus (276) Google Scholar, 4Clark J.A. Amara S.G. Mol. Pharmacol. 1994; 46: 550-557PubMed Google Scholar, 5Borden L.A. Neurochem. Int. 1996; 29: 335-356Crossref PubMed Scopus (518) Google Scholar, 6Nelson N. J. Neurochem. 1998; 71: 1785-1803Crossref PubMed Scopus (321) Google Scholar, 7Matskevitch I. Wagner C.A. Stegen C. Bröer S. Noll B. Risler T. Kwon H.M. Handler J.S. Waldegger S. Busch A.E. Lang F. J. Biol. Chem. 1999; 274: 16709-16716Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar, 8Lu C.-C. Hilgemann D.W. J. Gen. Physiol. 1999; 114: 429-444Crossref PubMed Scopus (101) Google Scholar, 9Loo D.D.F. Eskandari S. Boorer K.J. Sarkar H.K. Wright E.M. J. Biol. Chem. 2000; 275: 37414-37422Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar, 10Sacher A. Nelson N. Ogi J.T. Wright E.M. Loo D.D.F. Eskandari S. J. Membr. Biol. PubMed Scopus Google Thus, the GABA transporters and of GABA in for the of inhibitory in the nervous system. of the inhibitory of GABA, of or of the GABA transporters is to therapeutic in and 1999; PubMed Scopus Google Scholar, Amara S.G. 1999; Google Scholar, 2000; PubMed Scopus Google of the GABA transporters to increase GABA in the A. J. Pharmacol. 1992; PubMed Scopus Google Scholar, Neurochem. 1996; PubMed Scopus Google Scholar, 2000; PubMed Scopus Google anticonvulsant activity in and that the most abundant GABA transporter in the in clinical use 2000; PubMed Scopus Google Scholar, J. Pharmacol. Google Scholar, C. J. Pharmacol. PubMed Scopus Google Scholar, PubMed Scopus Google Scholar, J. Pharmacol. 1992; PubMed Scopus Google Scholar, C. A. J. B. B. PubMed Scopus Google Scholar, T. PubMed Scopus Google used to at in in the 1999; PubMed Scopus Google Scholar, Pharmacol. PubMed Scopus Google however, is the effect of on the GABA transporters J. J. Pharmacol. 1999; PubMed Scopus Google in clinical use and is of partial and the of valproate is not its a anticonvulsant is to a of at 1999; PubMed Scopus Google Scholar, Int. 2000; PubMed Scopus Google of that valproate by GABA in the 1999; PubMed Scopus Google Scholar, J. J. Neurochem. PubMed Scopus Google Scholar, A. J. Neurochem. PubMed Scopus Google Scholar, PubMed Scopus Google Scholar, PubMed Scopus Google Scholar, PubMed Scopus Google Scholar, 1992; PubMed Scopus Google Scholar, C.A. J. Pharmacol. PubMed Scopus Google The effect may to enhanced GABA of acid and GABA of GABA and 1999; PubMed Scopus Google Scholar, T. J. J. Neurochem. PubMed Scopus Google Scholar, I. A. PubMed Scopus Google Scholar, 1992; PubMed Scopus Google GABA neurons and not the effect of valproate on GABA uptake by neurons glial cells not however, the GABA in for 1999; PubMed Scopus Google and Int. 2000; PubMed Scopus Google In of is of to the effect of valproate on the GABA transporters expressed in an may by electrophysiological and tracer uptake methods to examine the effect of valproate on the GABA transporters expressed in Xenopus laevis oocytes. suggest that valproate the turnover rate of an allosteric mechanism. The of valproate with for the of propose that valproate to an increase in the turnover rate of GABA transporters and that the effect an important in the data not to the partial in the that is by however, that valproate increases the turnover rate for the of the transporter increases the of of the Valproate with the transporter to allosteric a the GABA valproate is not a transported of and valproate not with GABA. valproate GABA the plasma membrane in the enhancement of GABA the plasma the ion/GABA the that the tightly coupled. Valproate with the GABA transporters is acid and acid were effect not valproate did not enhance the rate of for the a transporter with similar to of the GABA of transporter presteady-state that valproate increases the of the transporter for The presteady-state charge suggest that valproate with the transporter in the absence of GABA and valproate with the transporter in the absence of no charge by valproate in the absence of enhancement is and by the of the and the enhancement is observations suggest that valproate with is not at the GABA Valproate an inward current is transported the plasma membrane or in the presence of GABA. of valproate enhance the GABA-evoked current and GABA at the GABA to to of GABA uptake. Valproate had no effect on the charge in to voltage is a of the of transporters to S. M. M.P. Wright E.M. S. A. 2000; PubMed Scopus Google transported to a in A. Nelson N. Ogi J.T. Wright E.M. Loo D.D.F. Eskandari S. J. Membr. Biol. PubMed Scopus Google S. Loo D.D.F. G. Wright E.M. N. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google the suggest that of valproate with the GABA transporters in an that of a transported of the membrane of is not to at the or of the effect of valproate to an increase in the of transporters by to the plasma observations The of transporters in the plasma membrane was not by The effect was and in the for the was that and by of in The effect was to the GABA transporters the rate for the was not was no in the in the presence of is in and B. We that membrane expressed in to the plasma membrane in of the expressed Loo D.D.F. M. Eskandari S. Wright E.M. J. Gen. Physiol. 1999; PubMed Scopus Google In the of the GABA-evoked current was enhanced by is that the enhancement was of of in the plasma that a of transporters were into the membrane is is the of is the turnover rate at 10Sacher A. Nelson N. Ogi J.T. Wright E.M. Loo D.D.F. Eskandari S. J. Membr. Biol. PubMed Scopus Google is the charge the membrane to is the that were of to to with the plasma to a increase in the of the with a of an increase in to at Loo D.D.F. Wright E.M. J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google effect of valproate was an increase in the rate of the presteady-state and of voltage the the of and Cl− by of the the voltage to the the the of the to the and Cl− into the membrane and S. Naeve J. Quick M. Labarca C. Davidson N. Lester H.A. Neuron. 1993; 10: 177-188Abstract Full Text PDF PubMed Scopus (276) Google Scholar, D.D.F. A. S. Wright E.M. S. A. 1993; PubMed Scopus Google Scholar, S. N. Davidson N. Kanner B.I. Lester H.A. J. 1996; PubMed Google Scholar, C.-C. Hilgemann D.W. J. Gen. Physiol. 1999; 114: PubMed Scopus Google Scholar, M. R.A. Lester H.A. J. Gen. Physiol. 2000; PubMed Scopus Google presteady-state charge obtained in the absence of GABA, the data suggest that valproate also increases the with of the also to a in the for GABA. the half-maximal concentration for steady-state GABA-evoked inward current and the GABA concentration for were by The in the absence of valproate to in the presence of valproate into a valproate was also to the GABA of the GABA uptake M. Neurochem. 1992; PubMed Scopus Google were not and Cl− valproate did not alter the charge in to voltage and that valproate of the membrane not to presteady-state charge movements. Valproate did not alter the of the charge that the of the the membrane in the absence or presence of Valproate to a in the half-maximal concentration for mm) of the charge had no effect on the half-maximal for Cl− enhancement mm) of the charge movements. the suggest that valproate increases the of the transporter for Thus, by the of the for charge at and Cl− effect may to the enhancement of transporter turnover rate by In valproate not alter the of the transporter the presteady-state a of of the the data suggest that the effect of valproate is and may also partial steps for the presteady-state The data not to the steps by in to obtained by J. J. Pharmacol. 1999; PubMed Scopus Google the of mouse GABA uptake by was also that valproate did not alter the steady-state or presteady-state of mouse The propose a of GABA uptake and currents. We were to under of GABA uptake and steady-state in the absence and presence of in the GAT valproate concentration used may for the and of J. J. Pharmacol. 1999; PubMed Scopus Google the therapeutic concentration of valproate in the plasma to 1999; PubMed Scopus Google of valproate to the valproate concentration in the is a of that in plasma and to 1999; PubMed Scopus Google The half-maximal concentration for valproate enhancement of the GAT turnover rate is and enhancement is that at therapeutic of the activity of the GABA transporters may enhanced by up to 10%. Valproate to to a of GABA in the Int. 2000; PubMed Scopus Google data not to on the by the GABA at in is that valproate enhancement of the GABA transporters may to the of GABA in the GABA and GABA valproate increases the GABA J. Pharmacol. PubMed Scopus Google Scholar, M. Pharmacol. PubMed Scopus Google may GABA the of the GABA transporters C.-C. Hilgemann D.W. J. Gen. Physiol. 1999; 114: 429-444Crossref PubMed Scopus (101) Google valproate enhancement of the GABA transporter turnover rate may to its in GABA to GABA in the to the that the of valproate an anticonvulsant its at in the its an anticonvulsant in valproate of the most used of its of its of anticonvulsant activity of seizures. The of activity most data for an of valproate in the central nervous the enhancement of the turnover rate of the GABA We that at therapeutic valproate may enhance the activity of neuronal and glial GABA transporters by up to 10%. γ-Aminobutyric acid (GABA)1 is the most abundant inhibitory neurotransmitter in the central nervous system. Transport of GABA into cells is accomplished by Na+-dependent and Cl−-facilitated GABA transporters (GATs) found in the plasma membrane of neurons and glia (1Kavanaugh M.P. Arriza J.L. North R.A. Amara S.G. J. Biol. Chem. 1992; 267: 22007-22009Abstract Full Text PDF PubMed Google Scholar, 2Keynan S. Suh Y.-J. Kanner B.I. Rudnick G. Biochemistry. 1992; 31: 1974-1979Crossref PubMed Scopus (121) Google Scholar, 3Mager S. Naeve J. Quick M. Labarca C. Davidson N. Lester H.A. Neuron. 1993; 10: 177-188Abstract Full Text PDF PubMed Scopus (276) Google Scholar, 4Clark J.A. Amara S.G. Mol. Pharmacol. 1994; 46: 550-557PubMed Google Scholar, 5Borden L.A. Neurochem. Int. 1996; 29: 335-356Crossref PubMed Scopus (518) Google Scholar, 6Nelson N. J. Neurochem. 1998; 71: 1785-1803Crossref PubMed Scopus (321) Google Scholar, 7Matskevitch I. Wagner C.A. Stegen C. Bröer S. Noll B. Risler T. Kwon H.M. Handler J.S. Waldegger S. Busch A.E. Lang F. J. Biol. Chem. 1999; 274: 16709-16716Abstract Full Text Full Text PDF PubMed Scopus (59) Google Scholar, 8Lu C.-C. Hilgemann D.W. J. Gen. Physiol. 1999; 114: 429-444Crossref PubMed Scopus (101) Google Scholar, 9Loo D.D.F. Eskandari S. Boorer K.J. Sarkar H.K. Wright E.M. J. Biol. Chem. 2000; 275: 37414-37422Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar, 10Sacher A. Nelson N. Ogi J.T. Wright E.M. Loo D.D.F. Eskandari S. J. Membr. Biol. PubMed Scopus Google Thus, the GABA transporters and of GABA in for the of inhibitory in the nervous system. of the inhibitory of GABA, of or of the GABA transporters is to therapeutic in and 1999; PubMed Scopus Google Scholar, Amara S.G. 1999; Google Scholar, 2000; PubMed Scopus Google of the GABA transporters to increase GABA in the A. J. Pharmacol. 1992; PubMed Scopus Google Scholar, Neurochem. 1996; PubMed Scopus Google Scholar, 2000; PubMed Scopus Google anticonvulsant activity in and that the most abundant GABA transporter in the in clinical use 2000; PubMed Scopus Google Scholar, J. Pharmacol. Google Scholar, C. J. Pharmacol. PubMed Scopus Google Scholar, PubMed Scopus Google Scholar, J. Pharmacol. 1992; PubMed Scopus Google Scholar, C. A. J. B. B. PubMed Scopus Google Scholar, T. PubMed Scopus Google used to at in in the 1999; PubMed Scopus Google Scholar, Pharmacol. PubMed Scopus Google however, is the effect of on the GABA transporters J. J. Pharmacol. 1999; PubMed Scopus Google Valproate in clinical use and is of partial and the of valproate is not its a anticonvulsant is to a of at 1999; PubMed Scopus Google Scholar, Int. 2000; PubMed Scopus Google of that valproate by GABA in the 1999; PubMed Scopus Google Scholar, J. J. Neurochem. PubMed Scopus Google Scholar, A. J. Neurochem. PubMed Scopus Google Scholar, PubMed Scopus Google Scholar, PubMed Scopus Google Scholar, PubMed Scopus Google Scholar, 1992; PubMed Scopus Google Scholar, C.A. J. Pharmacol. PubMed Scopus Google The effect may to enhanced GABA of acid and GABA of GABA and 1999; PubMed Scopus Google Scholar, T. J. J. Neurochem. PubMed Scopus Google Scholar, I. A. PubMed Scopus Google Scholar, 1992; PubMed Scopus Google GABA neurons and not the effect of valproate on GABA uptake by neurons glial cells not however, the GABA in for 1999; PubMed Scopus Google and Int. 2000; PubMed Scopus Google In of is of to the effect of valproate on the GABA transporters expressed in an may by electrophysiological and tracer uptake methods to examine the effect of valproate on the GABA transporters expressed in Xenopus laevis oocytes. suggest that valproate the turnover rate of an allosteric mechanism. The of valproate with for the of propose that valproate to an increase in the turnover rate of GABA transporters and that the effect an important in the data not to the partial in the that is by however, that valproate increases the turnover rate for the of the transporter increases the of of the Valproate with the transporter to allosteric a the GABA valproate is not a transported of and valproate not with GABA. valproate GABA the plasma membrane in the enhancement of GABA the plasma the ion/GABA the that the tightly coupled. Valproate with the GABA transporters is acid and acid were effect not valproate did not enhance the rate of for the a transporter with similar to of the GABA of transporter presteady-state that valproate increases the of the transporter for The presteady-state charge suggest that valproate with the transporter in the absence of GABA and valproate with the transporter in the absence of no charge by valproate in the absence of enhancement is and by the of the and the enhancement is observations suggest that valproate with is not at the GABA Valproate an inward current is transported the plasma membrane or in the presence of GABA. of valproate enhance the GABA-evoked current and GABA at the GABA to to of GABA uptake. Valproate had no effect on the charge in to voltage is a of the of transporters to S. M. M.P. Wright E.M. S. A. 2000; PubMed Scopus Google transported to a in A. Nelson N. Ogi J.T. Wright E.M. Loo D.D.F. Eskandari S. J. Membr. Biol. PubMed Scopus Google S. Loo D.D.F. G. Wright E.M. N. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google the suggest that of valproate with the GABA transporters in an that of a transported of the membrane of is not to at the or of the effect of valproate to an increase in the of transporters by to the plasma observations The of transporters in the plasma membrane was not by The effect was and in the for the was that and by of in The effect was to the GABA transporters the rate for the was not was no in the in the presence of is in and B. We that membrane expressed in to the plasma membrane in of the expressed Loo D.D.F. M. Eskandari S. Wright E.M. J. Gen. Physiol. 1999; PubMed Scopus Google In the of the GABA-evoked current was enhanced by is that the enhancement was of of in the plasma that a of transporters were into the membrane is is the of is the turnover rate at 10Sacher A. Nelson N. Ogi J.T. Wright E.M. Loo D.D.F. Eskandari S. J. Membr. Biol. PubMed Scopus Google is the charge the membrane to is the that were of to to with the plasma to a increase in the of the with a of an increase in to at Loo D.D.F. Wright E.M. J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google effect of valproate was an increase in the rate of the presteady-state and of voltage the the of and Cl− by of the the voltage to the the the of the to the and Cl− into the membrane and S. Naeve J. Quick M. Labarca C. Davidson N. Lester H.A. Neuron. 1993; 10: 177-188Abstract Full Text PDF PubMed Scopus (276) Google Scholar, D.D.F. A. S. Wright E.M. S. A. 1993; PubMed Scopus Google Scholar, S. N. Davidson N. Kanner B.I. Lester H.A. J. 1996; PubMed Google Scholar, C.-C. Hilgemann D.W. J. Gen. Physiol. 1999; 114: PubMed Scopus Google Scholar, M. R.A. Lester H.A. J. Gen. Physiol. 2000; PubMed Scopus Google presteady-state charge obtained in the absence of GABA, the data suggest that valproate also increases the with of the also to a in the for GABA. the half-maximal concentration for steady-state GABA-evoked inward current and the GABA concentration for were by The in the absence of valproate to in the presence of valproate into a valproate was also to the GABA of the GABA uptake M. Neurochem. 1992; PubMed Scopus Google were not and Cl− valproate did not alter the charge in to voltage and that valproate of the membrane not to presteady-state charge movements. Valproate did not alter the of the charge that the of the the membrane in the absence or presence of Valproate to a in the half-maximal concentration for mm) of the charge had no effect on the half-maximal for Cl− enhancement mm) of the charge movements. the suggest that valproate increases the of the transporter for Thus, by the of the for charge at and Cl− effect may to the enhancement of transporter turnover rate by In valproate not alter the of the transporter the presteady-state a of of the the data suggest that the effect of valproate is and may also partial steps for the presteady-state The data not to the steps by in to obtained by J. J. Pharmacol. 1999; PubMed Scopus Google the of mouse GABA uptake by was also that valproate did not alter the steady-state or presteady-state of mouse The propose a of GABA uptake and currents. We were to under of GABA uptake and steady-state in the absence and presence of in the GAT valproate concentration used may for the and of J. J. Pharmacol. 1999; PubMed Scopus Google the therapeutic concentration of valproate in the plasma to 1999; PubMed Scopus Google of valproate to the valproate concentration in the is a of that in plasma and to 1999; PubMed Scopus Google The half-maximal concentration for valproate enhancement of the GAT turnover rate is and enhancement is that at therapeutic of the activity of the GABA transporters may enhanced by up to 10%. Valproate to to a of GABA in the Int. 2000; PubMed Scopus Google data not to on the by the GABA at in is that valproate enhancement of the GABA transporters may to the of GABA in the GABA and GABA valproate increases the GABA J. Pharmacol. PubMed Scopus Google Scholar, M. Pharmacol. PubMed Scopus Google may GABA the of the GABA transporters C.-C. Hilgemann D.W. J. Gen. Physiol. 1999; 114: 429-444Crossref PubMed Scopus (101) Google valproate enhancement of the GABA transporter turnover rate may to its in GABA to GABA in the to the that the of valproate an anticonvulsant its at in the We propose that valproate to an increase in the turnover rate of GABA transporters and that the effect an important in the data not to the partial in the that is by however, that valproate increases the turnover rate for the of the transporter increases the of of the Valproate with the transporter to allosteric a the GABA valproate is not a transported of and valproate not with GABA. valproate GABA the plasma membrane in the enhancement of GABA the plasma the ion/GABA the that the tightly coupled. Valproate with the GABA transporters is acid and acid were effect not valproate did not enhance the rate of for the a transporter with similar to of the GABA of transporter presteady-state that valproate increases the of the transporter for The presteady-state charge suggest that valproate with the transporter in the absence of GABA and valproate with the transporter in the absence of no charge by valproate in the absence of enhancement is and by the of the and the enhancement is observations suggest that valproate with is not at the GABA Valproate an inward current is transported the plasma membrane or in the presence of GABA. of valproate enhance the GABA-evoked current and GABA at the GABA to to of GABA uptake. Valproate had no effect on the charge in to voltage is a of the of transporters to S. M. M.P. Wright E.M. S. A. 2000; PubMed Scopus Google transported to a in A. Nelson N. Ogi J.T. Wright E.M. Loo D.D.F. Eskandari S. J. Membr. Biol. PubMed Scopus Google S. Loo D.D.F. G. Wright E.M. N. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google the suggest that of valproate with the GABA transporters in an that of a transported of the membrane of is not to at the or of the The effect of valproate to an increase in the of transporters by to the plasma observations The of transporters in the plasma membrane was not by The effect was and in the for the was that and by of in The effect was to the GABA transporters the rate for the was not was no in the in the presence of is in and B. We that membrane expressed in to the plasma membrane in of the expressed Loo D.D.F. M. Eskandari S. Wright E.M. J. Gen. Physiol. 1999; PubMed Scopus Google In the of the GABA-evoked current was enhanced by is that the enhancement was of of in the plasma that a of transporters were into the membrane is is the of is the turnover rate at 10Sacher A. Nelson N. Ogi J.T. Wright E.M. Loo D.D.F. Eskandari S. J. Membr. Biol. PubMed Scopus Google is the charge the membrane to is the that were of to to with the plasma to a increase in the of the with a of an increase in to at Loo D.D.F. Wright E.M. J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google effect of valproate was an increase in the rate of the presteady-state and of voltage the the of and Cl− by of the the voltage to the the the of the to the and Cl− into the membrane and S. Naeve J. Quick M. Labarca C. Davidson N. Lester H.A. Neuron. 1993; 10: 177-188Abstract Full Text PDF PubMed Scopus (276) Google Scholar, D.D.F. A. S. Wright E.M. S. A. 1993; PubMed Scopus Google Scholar, S. N. Davidson N. Kanner B.I. Lester H.A. J. 1996; PubMed Google Scholar, C.-C. Hilgemann D.W. J. Gen. Physiol. 1999; 114: PubMed Scopus Google Scholar, M. R.A. Lester H.A. J. Gen. Physiol. 2000; PubMed Scopus Google presteady-state charge obtained in the absence of GABA, the data suggest that valproate also increases the with of the Valproate also to a in the for GABA. the half-maximal concentration for steady-state GABA-evoked inward current and the GABA concentration for were by The in the absence of valproate to in the presence of valproate into a valproate was also to the GABA of the GABA uptake M. Neurochem. 1992; PubMed Scopus Google were not and Cl− valproate did not alter the charge in to voltage and that valproate of the membrane not to presteady-state charge movements. Valproate did not alter the of the charge that the of the the membrane in the absence or presence of Valproate to a in the half-maximal concentration for mm) of the charge had no effect on the half-maximal for Cl− enhancement mm) of the charge movements. the suggest that valproate increases the of the transporter for Thus, by the of the for charge at and Cl− effect may to the enhancement of transporter turnover rate by In valproate not alter the of the transporter the presteady-state a of of the the data suggest that the effect of valproate is and may also partial steps for the presteady-state The data not to the steps by in to obtained by J. J. Pharmacol. 1999; PubMed Scopus Google the of mouse GABA uptake by was also that valproate did not alter the steady-state or presteady-state of mouse The propose a of GABA uptake and currents. We were to under of GABA uptake and steady-state in the absence and presence of in the GAT valproate concentration used may for the and of J. J. Pharmacol. 1999; PubMed Scopus Google In the therapeutic concentration of valproate in the plasma to 1999; PubMed Scopus Google of valproate to the valproate concentration in the is a of that in plasma and to 1999; PubMed Scopus Google The half-maximal concentration for valproate enhancement of the GAT turnover rate is and enhancement is that at therapeutic of the activity of the GABA transporters may enhanced by up to 10%. Valproate to to a of GABA in the Int. 2000; PubMed Scopus Google data not to on the by the GABA at in is that valproate enhancement of the GABA transporters may to the of GABA in the GABA and GABA valproate increases the GABA J. Pharmacol. PubMed Scopus Google Scholar, M. Pharmacol. PubMed Scopus Google may GABA the of the GABA transporters C.-C. Hilgemann D.W. J. Gen. Physiol. 1999; 114: 429-444Crossref PubMed Scopus (101) Google valproate enhancement of the GABA transporter turnover rate may to its in GABA to GABA in the to the that the of valproate an anticonvulsant its at in the its an anticonvulsant in valproate of the most used of its of its of anticonvulsant activity of seizures. The of activity most data for an of valproate in the central nervous the enhancement of the turnover rate of the GABA We that at therapeutic valproate may enhance the activity of neuronal and glial GABA transporters by up to 10%. its an anticonvulsant in valproate of the most used of its of its of anticonvulsant activity of seizures. The of activity most data for an of valproate in the central nervous the enhancement of the turnover rate of the GABA We that at therapeutic valproate may enhance the activity of neuronal and glial GABA transporters by up to 10%.