Figure 7.

An overview of the effects of Na⁺ and Ca²⁺ influx in the regulation of NMDA channel gating by remote NMDA receptors. NMDA channel activity may be upregulated or downregulated by remote NMDA receptors, depending on the amount of Na⁺ and Ca²⁺ influx. If Na⁺ influx is blocked, Ca²⁺ influx induced by the activation of remote NMDA receptors may inhibit NMDA channel gating. This Ca²⁺-induced inhibition of NMDA receptors can be prevented by a small Na⁺ influx, which increases [Na⁺]_i by 5 ± 1 mm. The 5 ± 1 mm increase in [Na⁺]_i is apparently a critical threshold for controlling the Ca²⁺ influx-induced inhibition of NMDA channel activity during remote NMDA receptor activation. NMDA channel gating may be decreased if Na⁺ influx during the activation of remote NMDA receptors is less than that required to overcome the effects induced by Ca²⁺ influx, whereas NMDA channel gating may be potentiated by the activation of remote NMDA receptors if Na⁺ influx is more than that required to overcome the effects induced by Ca²⁺ influx. Because there is a large Na⁺ influx during NMDA receptor activation under physiological conditions, the Na⁺-dependent upregulation effect plays a dominant role in the regulation of NMDA channel gating by NMDA receptor crosstalk. Remote, Remote NMDA receptors; NMDAR, NMDA receptors; Extr., extracellular; Intr., intracellular.