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Cell Calcium. 2016 Dec;60(6):407-414. doi: 10.1016/j.ceca.2016.09.005. Epub 2016 Sep 28.

Fast interaction between AMPA and NMDA receptors by intracellular calcium.

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OpenLab of Neurobiology, Kazan Federal University, 420111 Kazan, Russia; Department of Physiology and Pathophysiology, University of Heidelberg, 69120 Heidelberg, Germany.
INMED, Institut de Neurobiologie de la Méditerranée UMR901, Marseille, France; Aix-Marseille Université, Marseille, France; INSERM U901, Marseille, France. Electronic address:


Suppression of NMDA receptor (NMDAR)-mediated currents by intracellular Ca2+ has been described as a negative feedback loop in NMDAR modulation. In the time scale of tenths of milliseconds the depth of the suppression does not depend on the Ca2+ source. It may be caused by Ca2+ influx through voltage-gated calcium channels, NMDAR channels or release from intracellular stores. However, NMDARs are often co-expressed in synapses with Ca2+-permeable AMPA receptors (AMPARs). Due to significant differences in activation kinetics between these two types of glutamate receptors (GluRs), Ca2+ entry through AMPARs precedes full activation of NMDARs, and therefore, might have an impact on the amplitude of NMDAR-mediated currents. The study of Ca2+-mediated crosstalk between AMPAR and NMDAR in native synapses is challenging due to high NMDAR Ca2+ permeability. Therefore, recombinant Ca2+-permeable AMPAR and Ca2+-impermeable NMDAR mutant channels were co-expressed in HEK 293 cells to examine their interaction. An AMPAR-mediated increase in intracellular Ca2+ concentration ([Ca2+]i) reversibly reduced the size of NMDAR-mediated whole-cell currents. The time course of the NMDAR channel inactivation and recovery from inactivation followed the time course of the [Ca2+]i transient. When brief (1ms) pulses of glutamate were applied to outside-out patches, the degree of NMDAR inactivation increased with the increase in charge carried by the currents through co-activated AMPARs. However, AMPAR-mediated NMDAR inactivation was abolished in the presence of intracellular fast Ca2+ buffer BAPTA or in Ca2+-free extracellular solution. We conclude that Ca2+ entering through AMPARs inactivates co-localized NMDARs in the time range of excitatory postsynaptic currents.


Ca(2+)-induced inactivation; Ca(2+)-permeable AMPA receptor; Cross talk between receptors; NMDA receptor

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