CaMKII is critical for structural and functional plasticity. Here we show that Camguk (Cmg), the Drosophila homolog of CASK/Lin-2, associates in an ATP-regulated manner with CaMKII to catalyze formation of a pool of calcium-insensitive CaMKII. In the presence of Ca(2+)/CaM, CaMKII complexed to Cmg can autophosphorylate at T287 and become constitutively active. In the absence of Ca(2+)/CaM, ATP hydrolysis results in phosphorylation of T306 and inactivation of CaMKII. Cmg coexpression suppresses CaMKII activity in transfected cells, and the level of Cmg expression in Drosophila modulates postsynaptic T306 phosphorylation. These results suggest that Cmg, in the presence of Ca(2+)/CaM, can provide a localized source of active kinase. When Ca(2+)/CaM or synaptic activity is low, Cmg promotes inactivating autophosphorylation, producing CaMKII that requires phosphatase to reactivate. This interaction provides a mechanism by which the active postsynaptic pool of CaMKII can be controlled locally to differentiate active and inactive synapses.

Ca 2؉/calmodulin-dependent protein kinase II (CaMKII) has been implicated in the regulation of neuronal excitability in many systems. Recent studies suggest that local regulation of membrane potential can have important computational consequences for neuronal function. In Drosophila, CaMKII regulates the eag potassium channel, but if and how this regulation was spatially restricted was unknown. Calcium/calmodulin-dependent protein kinase II (CaMKII) 1 has been shown to regulate ion channels and neuronal excitability in both vertebrates (1-6) and invertebrates (4,5,(7)(8)(9)(10)(11). Regulation of excitability has been proposed as a mechanism by which neurons can globally modify their firing to keep spike rates in a scalable range in the presence of synapse-specific plasticity (12)(13)(14). Recently, it has become clear that regulation of excitability can also occur as a local phenomenon (15-19). Regional changes in excitability mediated by differing levels of A-type potassium currents were shown to be important for gating Hebbian plasticity in CA1 pyramidal cell dendrites and limiting propagation of action potentials (19). These effects have important implications for the computational abilities of neurons that integrate over many inputs. Both slow, expression level changes and fast, enzymatic modifications could underlie local phenomena, and in CA1, local regulation of excitability was associated with both regional differences in current density (19) and region-specific post-translational modifications of ion channels (18). Fast modulation offers the advantage of dynamic retooling of the computational capability of the neuron.For signal transduction pathways to effect fast local changes in excitability, the activity of effector enzymes has to be spatially restricted. The ability of protein kinases with many substrates to act with specificity to regulate cellular functions is increasingly being ascribed to interactions with scaffolding molecules that bring kinases and their substrates into close proximity. Signaling platforms range from small complexes containing only a few proteins to very complex cellular specializations like the postsynaptic density of the mammalian central nervous system (20). The advantages of scaffolding enzymes and substrates include enhancement of reaction rates because of elimination of diffusional barriers and increased local concentration of substrates and segregation of the enzyme to prevent reaction with other substrates. Localization of effector enzymes to sources of small molecule regulators can also establish very restricted signaling domains. Scaffolding may be particularly important for regulation of membrane-bound proteins in neurons; diffusion in the membrane bilayer is relatively slow, and the ability of soluble enzymes to access substrates can be influenced by the complex geometry of neurons.The regulation of firing in Drosophila motor axons involves the ether-à -go-go (eag) potassium channel. eag is the founding member of an evolutionarily conserved superfamily of voltageg...

Calcium-calmodulin-dependent protein kinase II (CaMKII) is an important regulator of neuronal and behavioral plasticity. Studies in which the subcellular distribution of CaMKII has been altered argue that targeting of this enzyme to specific subcellular compartments is crucial to many of its roles. Understanding how a very abundant enzyme can achieve specificity of action over time and space requires an understanding of the functional diversity of the enzyme and its distribution. In this review we will discuss how structurally distinct isozymes, splice isoforms, and autophosphorylation states of CaMKII can affect kinase activity and localization. We will focus on the fast activity-dependent synaptic localization of the kinase and its association with postsynaptic proteins. The ability of enzyme activation to regulate protein-protein interactions with these binding partners and the potential for such binding interactions to regulate CaMKII activity in novel ways may represent new paradigm for CaMKII regulation.

The Drosophila eag gene has been shown to regulate neuronal excitability (Wu et al., 1983), olfaction (Dubin et al., 1998), associative learning (Griffith et al., 1994) and larval locomotion (Wang et al., 2002a). Not all of the roles of this gene in these processes can be explained by its function as a voltage-gated potassium channel (e.g. Zhong and Wu, 1991). In this study, we show that the eag gene is spliced in a PKA- and PKC-regulated manner to produce a protein lacking channel domains. This protein, in the context of activated PKA, can engage cellular signaling pathways that alter cell structure. Nuclear localization is necessary for C-terminal-mediated effects, which also require MAPK. The requirement for PKA/PKC activation in the synthesis and function of this novel protein suggests that it may couple membrane events to nuclear signaling to regulate neuronal function on long time scales.