Modulation of NMDA Receptor Channels by Intracellular Calcium

In the mammalian central nervous system (CNS) excitatory synaptic transmission is mediated by glutamate which co-activates N-methyl-D-aspartate receptor (NMDAR) and α-amino-3-hydroxy-5-methyl-4-isoxazole-propionate receptor (AMPAR) channels, co-localized in the postsynaptic membrane. Fast synaptic currents are mediated by AMPAR channels whereas NMDAR channels generate slower, longer lasting currents (Forsythe & Westbrook, 1988; Bekkers & Stevens, 1989; Stern et al., 1992; Spruston et al., 1995). NMDAR channels are highly permeable for Ca2+ (MacDermott et al., 1986; Mayer & Westbrook, 1987; Ascher & Nowak, 1988) and contribute to the synaptically evoked elevation of Ca2+ in dendritic spines (Müller & Connor, 1991; Perkel et al., 1993; Malinow et al., 1994). Native NMDAR are heteromeric channels composed of NR1 and one or more of the four NR2 subunits belonging to the NMDAR family of ionotropic glutamate receptors (Hollmann & Heinemann, 1994). Each of the subunit imparts specific functional property to the channel providing a wide spectrum for the regulation of the NMDAR channel function. The NMDAR is a subject to modulation by a number of extracellular and intracellular agents including Mg2+, Zn2+, glycine, polyamines, protons, reducing agents, protein kinases and Ca2