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J Pharmacol Exp Ther. 2015 Dec;355(3):484-95. doi: 10.1124/jpet.115.227173. Epub 2015 Sep 21.

Inhibition of Plasma Membrane Na/Ca-Exchanger by KB-R7943 or Lithium Reveals Its Role in Ca-Dependent N-methyl-d-aspartate Receptor Inactivation.

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Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences, St. Petersburg, Russia.
Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences, St. Petersburg, Russia


To evaluate the possible role of the plasma membrane Na(+)/Ca(2+)-exchanger (NCX) in regulation of N-methyl-d-aspartate (NMDA) receptors (NMDARs), we studied effects of 2-[2-[4-(4-nitrobenzyloxy) phenyl]ethyl]isothiourea methanesulfonate (KB-R7943; KBR) and lithium (inhibitors of NCX) on NMDA-elicited whole-cell currents using the patch-clamp technique on rat cortical neurons and human embryonic kidney 293T cells expressing recombinant NMDARs. KBR inhibited NMDAR currents in a voltage-independent manner with similar potency for receptors of GluN1/2A and GluN1/2B subunit compositions that excludes open-channel block and GluN2B-selective inhibition. The inhibition by KBR depended on glycine (Gly) concentration. At 30 μM NMDA, the KBR IC50 values were 5.3 ± 0.1 and 41.2 ± 8.8 μM for 1 and 300 μM Gly, respectively. Simultaneous application of NMDA + KBR in the absence of Gly induced robust inward NMDAR currents that peaked and then rapidly decreased. KBR, therefore, is an agonist (EC50 is 1.18 ± 0.16 µM) of the GluN1 subunit coagonist binding sites. The decrease of NMDA-elicited currents in the presence of KBR was abolished in Ca(2+)-free solution and was not observed in the presence of extracellular Ca(2+) on 1,2-Bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid-loaded neurons, suggesting that Ca(2+) affects NMDARs from the cytosol. In agreement, the substitution of Li(+) for extracellular Na(+) caused a considerable decrease of NMDAR currents, which was not observed in the absence of extracellular Ca(2+). Most likely, the accumulation of intracellular Ca(2+) is caused by the inhibition of Ca(2+) extrusion via NCX. Thus, KBR and Li(+) provoke Ca(2+)-dependent receptor inactivation due to the disruption of Ca(2+) extrusion by the NCX. The data reveal the role of NCX in regulation of Ca(2+)-dependent inactivation of NMDARs.

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