Fast interaction between AMPA and NMDA receptors by intracellular calcium

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.