Abstract
Ca2+/calmodulin (CaM)-dependent protein kinase II (CaMKII) is highly abundant in the brain and exhibits broad substrate specificity, thereby it is thought to participate in the regulation of neuronal death and survival. Nitric oxide (NO), produced by neuronal NO synthase (nNOS), is an important neurotransmitter and plays a role in neuronal activity including learning and memory processes. However, high levels of NO can contribute to excitotoxicity following a stroke and neurodegenerative disease. Aside from NO, nNOS also generates superoxide which is involved in both cell injury and signaling. CaMKII is known to activate and translocate from the cytoplasm to the post-synaptic density in response to neuronal activation where nNOS is predominantly located. Phosphorylation of nNOS at Ser847 by CaMKII decreases NO generation and increases superoxide generation. Conversely, NO-induced S-nitrosylation of CaMKII at Cys6 is a prominent determinant of the CaMKII inhibition in ATP competitive fashion. Thus, the “cross-talk” between CaMKII and NO/superoxide may represent important signal transduction pathways in brain. In this review, we introduce the molecular mechanism of and pathophysiological role of mutual regulation between CaMKII and nNOS in neurons.
Highlights
Ca2+/calmodulin (CaM)-dependent kinase II (CaMKII) is highly abundant in the brain (1 to 2% of the total brain proteins) [1,2,3]
Nitric oxide (NO) is generated by NO synthases (NOSs), which catalyze the conversion of L-arginine to L-citrulline and NO by transferring electrons from nicotinamide adenine dinucleotide phosphate (NADPH), via the flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN) to the heme [24,40]
We reported for the first time that ischemia/reperfusion causes phosphorylation of neuronal NO synthase (nNOS) at Ser847 which is inhibited by KN-93 [73] at nonpyramidal interneurons in the rat hippocampal CA1 but not in the cortex region [54]
Summary
Ca2+/calmodulin (CaM)-dependent kinase II (CaMKII) is highly abundant in the brain (1 to 2% of the total brain proteins) [1,2,3]. CaMKII has a diverse intracellular localization and neuronal activation induces CaMKII to translocate from the cytoplasm to the presynaptic active zone [4] and the post-synaptic density (PSD) [5,6,7]. According to a ternary complex containing nNOS, postsynaptic density 95 kDa (PSD-95), and the NMDAR subunit GluN2B in neuron [29], the production of NO can be regulated by NMDAR (Figure 1a). The peptide which disrupts the interaction between GluN2B and PSD-95/nNOS uncoupled NO production by nNOS from NMDAR-mediated excitotoxicity in cultured neurons [30] and in Alzheimer’s disease mouse models [31] and has been assessed in human ischemic stroke patients [32,33]. This review focuses on existing findings that the mutual posttranslational modifications of CaMKII and nNOS, mainly in hippocampal neurons, could be potential therapeutic signals for neuronal pathophysiology and discusses the way that controls CaMKII activity in neurons aside from conventional inhibitors
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