Disease relevance of Camk2a

• These findings mark CaMKII as a determinant of clinically important heart disease phenotypes, and suggest CaMKII inhibition can be a highly selective approach for targeting adverse myocardial remodeling linked to betaAR signaling [1].
• Here we show CaMKII inhibition substantially prevented maladaptive remodeling from excessive betaAR stimulation and myocardial infarction, and induced balanced changes in excitation-contraction coupling that preserved baseline and betaAR-stimulated physiological increases in cardiac function [1].
• We conclude that CaMKII is the multifunctional CaMK most likely to mediate Ca(2+)- dependent protein phosphorylation events in response to TAC-induced cardiac hypertrophy [2].
• The combination of increased CaMKII activity and altered action potential characteristics facilitates ventricular arrhythmias in hypertrophic GC-A-/- hearts [3].
• CaMKII inhibition using KN-93 completely prevented this recovery of Delta[Ca]i and k(Ca) during late acidosis in WT myocytes [4].

Psychiatry related information on Camk2a

• Both decreased PKC and CaMKII activities with concomitant LTP impairment account for the learning disability observed in OBX mice [5].
• While this specific increase in CaMKII phosphorylation is seen in both the left IMHV and left LPO in short-term memory, it is detectable only in the left LPO associated with long-term memory retrieval [6].
• Changes in phosphorylation of Ca2+/calmodulin-dependent protein kinase II (CaMKII) in processing of short-term and long-term memories after passive avoidance learning [6].

High impact information on Camk2a

• Pentose-phosphate-pathway-mediated inhibition of cell death was due to the inhibitory phosphorylation of caspase-2 by calcium/calmodulin-dependent protein kinase II (CaMKII) [7].
• These data also provide unexpected links between oocyte metabolism, CaMKII, and caspase-2 [7].
• Metabolic regulation of oocyte cell death through the CaMKII-mediated phosphorylation of caspase-2 [7].
• Extensive studies have shown that long-term potentiation (LTP) of the excitatory postsynaptic current (EPSC) through glutamate receptors is induced by activation of N-methyl-D-asparate receptor (NMDA-R)--the coincidence detector--and Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) [8].
• A role for CaMKII in T cell memory [9].

Chemical compound and disease context of Camk2a

• In addition, presynaptic injection of the membrane-impermeable CaMKII inhibitor peptide 281-309 blocked synaptic plasticity induced by tetanus, glutamate, or NO/cGMP pathway activation as expressed by long-lasting increases in EPSC amplitude and functional presynaptic boutons [10].
• The NMDA-induced CaMKII activation in the hippocampal slices of wild-type mice was significantly inhibited by exogenous nociceptin via a pertussis toxin-sensitive pathway [11].
• In conclusion, our results suggest that CaMKII, activated through NMDA receptors and L-VGCCs, mediated the serine phosphorylation of GluR6 during brain ischemia and early reperfusion period [12].
• Pre-incubation with the phospholipase C (PLC) inhibitor U73122 (10 microM), L-type Ca(2+)-channel blockers nifedipine (1 microM) and nimodipine (1 microM), the calmodulin kinase II (CaMKII) inhibitor KN-62 (10 microM) or pertussis toxin (100 ng/ml) inhibited this potentiation [13].

Biological context of Camk2a

• The calcium-calmodulin-dependent kinase II (CaMKII) is required for hippocampal long-term potentiation (LTP) and spatial learning [14].
• Activated mutant that mimics the phosphorylated state of radixin (T564E) stimulated Rac1, induced the phosphorylation of CaMKII, and stimulated SRE-dependent gene transcription [15].
• CaMKII plays a critical role in regulating various signaling pathways leading to modulation of several aspects of cellular functions, including proliferation, differentiation, cytoskeletal structure, and gene expression [16].
• Inhibition of alpha-CaMKII decreases the expression of c-fos, AP-1 transactivation, and AP-1 DNA binding activity [16].
• Our findings demonstrated that alpha-CaMKII is expressed in osteoblasts and is involved in c-fos expression via regulation of serum response element and cAMP-response element [16].

Anatomical context of Camk2a

• The purpose of this study was to examine the expression of CaMKII in osteoblast-like cells (MC4) and to elucidate its role in osteoblast differentiation [16].
• In combination, these data support a model in which [P-T286]CaMKIIalpha can simultaneously interact with multiple dendritic spine proteins, possibly stabilizing the synaptic localization of CaMKII and/or nucleating a multiprotein synaptic signaling complex [17].
• CaM and CaMKII antagonists, using the newborn mouse calvaria in vivo model, cause a 50% decrease in osteoblast number (N.Ob-BS) and a 32% decrease in mineralization (BV/TV) [16].
• No significant alterations in CaMKII or CaN immunolabelling were observed in the hippocampus of kainic acid-treated mice [18].
• We hypothesized that chronic CaMKII inhibition significantly affects CICR in ventricular myocytes [19].

Associations of Camk2a with chemical compounds

• NR2B inhibits both the Ca(2+)/calmodulin-dependent and autonomous activities of CaMKII by a mechanism that is competitive with autocamtide-2 substrate, non-competitive with syntide-2 substrate, and uncompetitive with respect to ATP [20].
• Our results suggest that the expression of CaMKII and CaN mRNAs is down-regulated in neuronal cells in response to the hyperexcitability induced by kainic acid [18].
• PLN ablation eliminated I(Ca) facilitation even in the absence of CaMKII inhibition and the effects of CaMKII inhibition to reduce SR Ca(2+) content and slow SR Ca(2+) uptake were lost in the absence of PLN [19].
• KN-93, a Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) inhibitor, concentration-dependently and reversibly inhibited inositol 1,4,5-trisphosphate receptor (IP(3)R)-mediated [Ca(2+)](i) signaling in mouse eggs and permeabilized A7r5 smooth muscle cells, two cell types predominantly expressing type-1 IP(3)R (IP(3)R-1) [21].
• Finally we show that disrupting either NMDA or calcium/calmodulin-dependent kinase II (CaMKII) function impairs consolidation of context memories [22].

Physical interactions of Camk2a

• Nonphosphorylated and Thr(286)-autophosphorylated CaMKII bind to alpha-actinin with similar efficacy, but autophosphorylation at Thr(305/306) or Ca(2+)/calmodulin binding significantly reduce this binding [20].
• In addition, the CaMKII binding domain of densin-180 has little effect on CaMKII activity [20].
• Following basal autophosphorylation, the calmodulin-binding ability of CaMKII was also reduced, presumably accounting for the observed inactivation [23].
• We have previously shown that autophosphorylation of CaMKII induces high-affinity binding to the NR2B subunit of the NMDA receptor (Strack, S., and Colbran, R. J. (1998) J. Biol. Chem. 273, 20689-20692) [24].

Enzymatic interactions of Camk2a

• Purified rat forebrain CaMKII was also able to phosphorylate gp130 fusion protein at Ser782 in vitro [25].
• Two-dimensional phosphopeptide mapping demonstrated that the site phosphorylated in vitro by CaMKII was also phosphorylated in intact astrocytes in response to endothelin [26].
• Furthermore, activated CaMKII directly phosphorylated the recombinant COOH-terminal region of FAK at a residue equivalent to Ser-843 [27].

Regulatory relationships of Camk2a

• Down-regulation of endogenous radixin using small interference RNA inhibited SRE-dependent gene transcription and phosphorylation of CaMKII induced by Galpha(13)Q226L [15].
• Direct inhibition of CaMKII activation by KN93 (0.5 or 2 microM) or inhibition of Ca(2+)/calmodulin-dependent activation of CaMKII by W-7 (25 microM) suppressed pVT in GC-A-/- hearts (P < 0.05) while prolonging APD [3].
• The CaMKII inhibitor KN-93 inhibited caffeine-induced relaxation and PLB Thr17 phosphorylation [28].
• Co-transfection with CaMKII stimulated nuclear translocation of Zif268 [29].
• The data indicate that CaMKII expression/activity in amacrine and ganglion cells is negatively regulated by the rod photoreceptor-mediated visual input [30].

Other interactions of Camk2a

• Overall, our results indicated that radixin via its C-terminal domain mediates SRE-dependent gene transcription through activation of Rac1 and CaMKII [15].
• Radixin stimulates Rac1 and Ca2+/calmodulin-dependent kinase, CaMKII: cross-talk with Galpha13 signaling [15].
• Taken together, in OBX mice NMDA receptor hypofunction, possibly through decreased PKCalpha activity, underlies decreased CaMKII activity in the post-synaptic regions, thereby impairing LTP induction in the hippocampal CA1 region [5].
• Moreover, PLB phosphorylation by CaMKII plays an important role in limiting the decline in Ca transients (and contraction) during acidosis [4].
• In 12-month-old GC-A-/- hearts only, dispersion of APD and expression levels of CaMKII were increased [3].

Analytical, diagnostic and therapeutic context of Camk2a

• Ca(2+)/Camodulin-dependent protein kinase II (CaMKII) is a multifunctional enzyme that is postulated to be the downstream transducer of the Ca(2+) signal in many cell types [31].
• Cardiac expression of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) was analyzed by western blotting [3].
• These results suggest that additive activation by ERK and CaMKII, most likely as a result of photic stimulation in the suprachiasmatic nucleus, plays a critical role in activating the mPer1 gene promoter [32].
• We also show by electron microscopy that in its fully assembled form the CaMKII holoenzyme is a dodecamer but without the kinase domains, either from expression of the isolated association domain in bacteria or following their removal by proteolysis, the association domains form a tetradecamer [33].
• The activity and expression of protein phosphatase 2A were both found to be increased in CaMKII TG mice, and immunoprecipitation studies indicated that protein phosphatase 2A directly associates with CaMKII [34].

References