Disease relevance of CaMKII

• To elucidate the mechanism of transcriptional regulation, rat hepatoma (H-411E) cells were transfected with DNA constructs containing the putative CaM promoters coupled to a luciferase reporter and challenged with insulin [1].
• A novel selection strategy, exploiting the CaM tag, was then used to isolate four single chain Fv fragments (scFvs) specific for GP6 from a non-immune phage display library [2].
• Preferential dCaMKII immunoreactivity in the embryonic nervous system, adult thoracic ganglion and gut, and larval neuro-muscular junction (NMJ) was consistent with previous observations by in situ hybridization and immunostaining with a polyclonal antibody at the NMJ, indicating that the antibody is applicable to immunohistochemistry [3].

Psychiatry related information on CaMKII

• Interestingly, immediate memory was unaffected by expression of T287D CaMKII in mushroom bodies, although previous studies have shown that CaMKII activity is required in this brain region for memory formation [4].

High impact information on CaMKII

• Here we show that neural activity directs the mRNA of the Drosophila Ca(2+), Calcium/Calmodulin-dependent Kinase II (CaMKII), to postsynaptic sites, where it is rapidly translated [5].
• In vitro, CaMKII phosphorylated a DLG fragment with a stoichiometry close to one [6].
• Moreover, expression of site-directed dlg mutants that blocked or mimicked phosphorylation had effects similar to those observed upon inhibiting or constitutively activating CaMKII [6].
• The ability of CaMKII to act as a molecular switch, becoming Ca(2+) independent after activation and autophosphorylation at T287, is critical for experience-dependent plasticity [7].
• Consistently, we show that glutamate receptor mutants also have a higher number of T bars; this increase is suppressed by postsynaptic activation of CaMKII [8].

Biological context of CaMKII

• In this study, we identify a single site, threonine 787, as the major CaMKII phosphorylation site in Eag [9].
• The reduction in current amplitudes and the accelerated inactivation of dephosphorylated Eag channels would result in decreased outward potassium currents and hyperexcitability at presynaptic terminals and, thus, are consistent with the NMJ phenotype observed when CaMKII is inhibited [9].
• Retrograde control of synaptic transmission by postsynaptic CaMKII at the Drosophila neuromuscular junction [8].
• Expression of constitutively active T287D, but not calcium-dependent T287A, mutant CaMKII in Drosophila neurons resulted in decreased viability, behavioral defects, and failure of action potential propagation [10].
• In the absence of Ca(2+)/CaM, ATP hydrolysis results in phosphorylation of T306 and inactivation of CaMKII [11].

Anatomical context of CaMKII

• Inhibition of CaMKII and mutation of the eag gene both cause hyperexcitability at the larval neuromuscular junction (NMJ) and memory formation defects in the adult [9].
• By using this system, we previously demonstrated that expression of activated calcium/calmodulin-dependent protein kinase II (CaMKII) in the muscle cell promotes coordinated maturation of pre- and postsynaptic sites of larvae just after hatching (JAH larvae) in a synapse-specific manner [12].
• CaMKII increases the dynamic nature and formation of dendritic filopodia throughout larval development but only affects neurons that normally contain dendritic filopodia [13].
• Targeted expression of a calcium-independent CaMKII construct (T287D) in the sensory neurons eliminated habituation [14].
• Transcripts of CaM kinase II are expressed in great quantities in the central nervous system in the late embryonic stage of development and are more abundant in the head than in the body of the adult fly [15].

Associations of CaMKII with chemical compounds

• Displacement results in autophosphorylation-independent activation of CaMKII which persists even when Ca(2+) levels have gone down [16].
• Moreover, both CaMKII inhibition and the alanine mutation accelerated inactivation [9].
• Injection of either a specific CaMKII inhibitor peptide or lavendustin C, another CaMKII inhibitor, reduced Eag current amplitude acutely [9].
• In this study, we use a tripartite transgenic system combining GAL4/UAS with the tetracycline-off system to spatially and temporally manipulate levels of Ca2+-independent CaMKII activity in Drosophila [4].
• Most transcript changes were transient except for the decrease of the CaMKIIalpha transcript which persisted even 40 h after the single dose of diazepam [17].
• We show that phosphorylation of CaMKII is greatly enhanced by okadaic acid, and indeed, purified PP2A catalyzes the dephosphorylation of CaMKII [18].

Physical interactions of CaMKII

• These results favor a model in which the CaMKII-binding domain of Eag displaces the CaMKII autoinhibitory region [16].
• In the presence of Ca(2+)/CaM, CaMKII complexed to Cmg can autophosphorylate at T287 and become constitutively active [11].

Regulatory relationships of CaMKII

• In Drosophila, CaMKII regulates the eag potassium channel, but if and how this regulation was spatially restricted was unknown [16].
• Here we demonstrate that synaptic localization of DLG itself is regulated by CaMKII [6].
• Cmg coexpression suppresses CaMKII activity in transfected cells, and the level of Cmg expression in Drosophila modulates postsynaptic T306 phosphorylation [11].

Other interactions of CaMKII

• Integrins regulate DLG/FAS2 via a CaM kinase II-dependent pathway to mediate synapse elaboration and stabilization during postembryonic development [19].
• Recent work has shown that DLG and FAS2 function together to modulate activity-dependent synaptic development and that this role is regulated by activation of CaMKII [19].
• These studies demonstrate that betaPS integrins act through CaMKII activation to control the localization of synaptic proteins involved in the development of NMJ synaptic morphology [19].
• We found that at least one isoform of Drosophila neuronal CaMKII is conjugated to DmSUMO-1 in vivo [20].
• In contrast to CaMKII activity, Rac1 does not alter filopodia stability but instead causes de novo filopodia formation on all da neurons [13].

Analytical, diagnostic and therapeutic context of CaMKII

• In situ hybridization showed CaM kinase mRNA is present in both neuronal and nonneuronal tissues in adult Drosophila [21].
• Regulation of Drosophila Ca2+/calmodulin-dependent protein kinase II by autophosphorylation analyzed by site-directed mutagenesis [22].
• Globally inhibiting CaM kinase activity in Drosophila, using a variety of genetic techniques, disrupts associative memory yet leaves visual and chemosensory perception intact [23].
• PCR, Northern and genomic Southern analyses showed that Branchiostoma CaM is encoded by a single copy gene, while fish are known to have at least four CaM genes [24].
• Epitope mapping revealed that it was in the region between 199 and 283 a.a. of dCaMKII [3].

References