Extracellular Ca ions reduce NMDA receptor conductance and gating

Ca ions regulate countless biochemical processes, and their levels are therefore tightly controlled in live cells and organisms. In healthy individuals, the concentration of Ca in blood serum is maintained within a narrow range (2.2–2.6 mM), and systemic deviations from these levels bring about a series of undesirable symptoms (Pearce and Thakker, 1997). In brain, however, extra­ cellular Ca levels oscillate locally on a fast (millisecond) timescale and can reach concentrations as low as 0.1 mM during normal synaptic transmission, with more pro­ longed global changes observed during seizures and after ischemia (Nicholson et al., 1977; Benninger et al., 1980; Heinemann and Pumain, 1980; Heinemann et al., 1986; Silver and Erecińska, 1990). Activity­dependent depletion of extracellular Ca within the synaptic space is mediated by the opening of Ca­permeable chan­ nels, including NMDA receptors (Rusakov and Fine, 2003). NMDA receptor­mediated Ca influx triggers a broad range of cellular processes in the postsynaptic neuron, ranging from synaptic plasticity to excitotoxicity (Hardingham and Bading, 2010). Nevertheless, whether and how these fluctuations in extracellular Ca levels alter the amplitude and time course of the NMDA receptor­ mediated flux remains unclear. NMDA receptors generate significant Ca transients as a result of their characteristically long activations and large unitary currents, of which a substantial fraction