The Ca2+/Calmodulin(CaM)-dependent protein kinase II (CaMKII) is activated by Ca2+/CaM, but becomes partially autonomous (Ca2+-independent) upon autophosphorylation at T286. This hallmark feature of CaMKII regulation provides a form of molecular memory and is indeed important in long-term potentiation (LTP) of excitatory synapse strength and memory formation. However, emerging evidence supports a direct role in information processing, while storage of synaptic information may instead be mediated by regulated interaction of CaMKII with the NMDA receptor (NMDAR) complex. These and other CaMKII regulation mechanisms are discussed here in the context of the kinase structure and their impact on post-synaptic functions. Recent findings also implicate CaMKII in long-term depression (LTD), as well as functional roles at inhibitory synapses, lending renewed emphasis on better understanding the spatio-temporal control of CaMKII regulation.

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Ca2؉ influx through the N-methyl-D-aspartate (NMDA)-type glutamate receptor leads to activation and postsynaptic accumulation of Ca 2؉ /calmodulin-dependent protein kinase II (CaMKII) and ultimately to long term potentiation, which is thought to be the physiological correlate of learning and memory. The NMDA receptor also serves as a CaMKII docking site in dendritic spines with high affinity binding sites located on its NR1 and NR2B subunits. We demonstrate that high affinity binding of CaMKII to NR1 requires autophosphorylation of Thr 286 . This autophosphorylation reduces the off rate to a level (t1 ⁄2 ‫؍‬ ϳ23 min) that is similar to that observed for dissociation of the T286D mutant CaMKII (t1 ⁄2 ‫؍‬ ϳ30

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The Ca 2؉ /calmodulin (CaM)-dependent protein kinase II (CaMKII)␤ has morphogenic functions in neurons not shared by the ␣ isoform. CaMKII␤ contains three exons (v1, v3, and v4) not present in the CaMKII␣ gene, and two of these exons (v1 and v4) are subject to differential alternative splicing. We show here that CaMKII␤, but not ␣, mediated bundling of F-actin filaments in vitro. Most importantly, inclusion of exon v1 was required for CaMKII␤ association with the F-actin cytoskeleton within cells. CaMKII␤e, which is the dominant variant around birth and lacks exon v1 sequences, failed to associate with F-actin. By contrast, CaMKII␤, which instead lacks exon v4, associated with F-actin as full-length CaMKII␤. Previous studies with CaMKII␤ mutants have indicated a role of nonstimulated kinase activity in enhancing dendritic arborization. Here, we show that F-actin-targeted CaMKII␤, but not ␣, was able to phosphorylate actin in vitro even by nonstimulated basal activity in absence of Ca 2؉ /CaM. In rat pancreatic islets and in skeletal muscle, the actin-associated CaMKII␤ and ␤M were the predominant variants, respectively. Thus, cytoskeletal targeting may mediate functions of CaMKII␤ variants also outside the nervous system. INTRODUCTIONChanges in synaptic connectivity between neurons are widely thought to underlie higher brain functions such as learning and memory and are also important during development. Long-lasting changes in connectivity are often associated with morphological plasticity in structure or number of synaptic connections (for reviews, see Huntley et al., 2002;McGee and Bredt, 2003;Lamprecht and LeDoux, 2004;Segal, 2005). The ␣ isoform of Ca 2ϩ /calmodulin(CaM)-dependent protein kinase II (CaMKII) has been studied extensively because of its prominent role in regulating the strength of individual synaptic connections (for examples, see Malinow et al., 1989;Silva et al., 1992;Giese et al., 1998; for reviews, see Malenka and Nicoll, 1999;Lisman et al., 2002;Griffith, 2004). Much less is known about the other major brain isoform, CaMKII␤. However, CaMKII␤ has specific morphogenic functions in regulating dendritic arborization and synapse density not shared by the ␣ isoform (Fink et al., 2003). This isoform specificity is thought to be mediated by the specific binding of CaMKII␤, but not ␣ to F-actin (Shen et al., 1998;Fink et al., 2003).The four CaMKII isoforms encoded by different genes (␣, ␤, ␥, and ␦) are highly homologous to each other and can phosphorylate and regulate a variety of substrate proteins in response to Ca 2ϩ signals (for reviews, see Soderling et al., 2001;Hudmon and Schulman, 2002;Lisman et al., 2002;Colbran and Brown, 2004). The multimeric CaMKII holoenzymes are composed of 12 subunits (Kolodziej et al., 2000;Morris and Torok, 2001;Rosenberg et al., 2005;Rosenberg et al., 2006) of a single isoform or combinations of different isoforms (Bayer et al., 1998;Shen et al., 1998;Brocke et al., 1999;Lantsman and Tombes, 2005). All CaMKII isoforms contain an N-terminal kinase domain and a ...