Ca2+-independent, but voltage- and activity-dependent regulation of the NMDA receptor outward K+ current in mouse cortical neurons.

To test the novel hypothesis that the K+ efflux mediated by NMDA receptors might be regulated differently than the influx of Ca2+ and Na+ through the same receptor channels, NMDA receptor whole-cell currents carried concurrently or individually by Ca2+, Na+ and K+ were analysed in cultured mouse cortical neurons. In contrast to the NMDA inward current carried by Ca2+ and Na+, the NMDA receptor outward K+ current or NMDA-K current, recorded either in the presence or absence of extracellular Ca2+ and Na+, and at different or the same membrane potentials, showed much less sensitivity to alterations in intracellular Ca2+ concentration and underwent little rundown. In line with a selective regulation of the NMDA receptor K+ permeability, the ratio of the NMDA inward/outward currents decreased, and the reversal potential of composite NMDA currents recorded in physiological solutions shifted by -8.5 mV after repeated activation of NMDA receptors. Moreover, a depolarizing pre-pulse of a few seconds or a burst of brief depolarizing pulses selectively augmented the subsequent NMDA-K current, but not the NMDA inward current. On the other hand, a hyperpolarizing pre-pulse showed the opposite effect of reducing the NMDA-K current. The voltage- and activity-dependent regulation of the NMDA-K current did not require the existence of extracellular Ca2+ or Ca2+ influx; it was, however, affected by the duration of the pre-pulse and was subject to a time-dependent decay. The burst of excitatory activity revealed a lasting upregulation of the NMDA-K current even 5 s after termination of the pre-pulses. Our data reveal a selective regulation of the NMDA receptor K+ permeability and represent a novel model of voltage- and excitatory activity-dependent plasticity at the receptor level.