The molecular basis of long-term potentiation (LTP), a long-lasting change in synaptic transmission, is of fundamental interest because of its implication in learning. Usually LTP depends on Ca 2؉ inf lux through postsynaptic N-methyl-D-aspartate (NMDA)-type glutamate receptors and subsequent activation of Ca 2؉ ͞calmodulin-dependent protein kinase II (CaMKII). For a molecular understanding of LTP it is crucial to know how CaMKII is localized to its postsynaptic targets because protein kinases often are targeted to their substrates by adapter proteins. Here we show that CaMKII directly binds to the NMDA receptor subunits NR1 and NR2B. Moreover, activation of CaMKII␣ by stimulation of NMDA receptors in forebrain slices increase this association. This interaction places CaMKII not only proximal to a major source of Ca 2؉ inf lux but also close to ␣-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)-type glutamate receptors, which become phosphorylated upon stimulation of NMDA receptors in these forebrain slices. Identification of the postsynaptic adapter for CaMKII fills a critical gap in the understanding of LTP because CaMKII-mediated phosphorylation of AMPA receptors is an important step during LTP. Caϩ ͞calmodulin-dependent protein kinase II (CaMKII) mediates a variety of different cellular responses to Ca 2ϩ influx (1, 2). An important source of Ca 2ϩ influx into neurons is the N-methyl-D-aspartate (NMDA)-type glutamate receptor, which is activated by the excitatory neurotransmitter glutamate (2). NMDA-and ␣-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA)-type glutamate receptors are clustered at postsynaptic sites opposing presynaptic neurotransmitter release sites (3, 4). Brief trains of presynaptic highfrequency stimulation efficiently activate NMDA receptors (5), resulting in postsynaptic Ca 2ϩ influx and long-term potentiation (LTP). LTP is a long-lasting increase in neurotransmission thought to represent the physiological correlate of learning and memory (5, 6). The induction of NMDA receptor-dependent LTP requires activation of CaMKII in the postsynaptic neuron (6, 7). CaMKII is enriched at postsynaptic densities (8, 9), where it is well placed for activation by Ca 2ϩ influx through NMDA receptors and subsequent phosphorylation of neighboring AMPA receptors, an event contributing to LTP (7, 10). A kinase anchoring proteins, usually called AKAPs, place cyclic AMP-dependent protein kinase (PKA) next to selected substrates such as AMPA receptors (11), and receptors for activated C kinase (RACKs) are important for subcellular localization of different protein kinase C (PKC) isozymes (12). Crucial information about the subcellular targeting of CaMKII is lacking. NMDA receptors would be ideal postsynaptic adapter sites for CaMKII, where it would have full access to Ca 2ϩ influx through these receptors. Cortical NMDA receptors consist of one or two NR1 and two or three NR2A and 2B subunits whose C termini are intracellular (13-16). We show that CaMKII is directly associated with NR1 a...