Coordination between Calcium/Calmodulin-Dependent Protein Kinase II and Neuronal Nitric Oxide Synthase in Neurons

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.

Latent Sex Differences in CaMKII-nNOS Signaling That Underlie Antidepressant-Like Effects of Yueju-Ganmaidazao Decoction in the Hippocampus

“…We speculated that the differences between male mice and female mice were mostly dependent on nNOS differential expression, which was activated by CaMKII. CaMKII is known to activate and translocate from the cytoplasm to the synaptic density where nNOS is predominantly located ( Araki et al, 2020 ). Some reported that phosphorylation of nNOS at Ser847 by CaMKII attenuated the NO synthesis activity of nNOS in vitro and in cells ( Hayashi et al, 1999 ; Komeima et al, 2000 ).…”

“…More importantly, nNOS exists in GABAergic inhibitory interneurons where CaMKII co-localizes in the rat hippocampal primary neurons. CaMKII phosphorylates and influences nNOS via its specific Ser847 residue ( Hayashi et al, 1999 ; Araki et al, 2020 ). Meanwhile, like nNOS, CaMKII is a calcium-dependent enzyme ( Stein et al, 2020 ).…”

The Roles of Superoxide on At-Level Spinal Cord Injury Pain in Rats

“…The current study suggests that scavenging oxygen-derived radicals are more efficient at attenuating neuronal hyperexcitability and neuropathic pain. Previous studies have suggested that the interaction between superoxide and CamKII under neuropathic conditions is highly correlated with the signaling mechanisms in the spinal cord and brain [ 23 , 24 , 25 , 26 ]. The hydroxyl radical donor t-BOOH causes lipid peroxidation and mitochondrial calcium release via hydrolysis of pyridine nucleotide, which is a substrate of Ca 2+ -dependent signal transduction; this results in ROS-induced activation of CamKII [ 27 ].…”

Role of Ca2+/Calmodulin-Dependent Protein Kinase Type II in Mediating Function and Dysfunction at Glutamatergic Synapses

“…Activated CaMKII redistributes to the spines ( Otmakhov et al, 2015 ), promotes its interaction with synaptic GluN2B ( Wang N. et al, 2014 ; Buonarati et al, 2020 ) and mediates the NMDA-induced caspase-3-dependent cell death pathway ( Goebel, 2009 ). During a glutamate-induced excitotoxic event, CaMKII can also modulate the activity of neuronal nitric oxide synthase (nNOS) ( Araki et al, 2020 ), can cause axonal degeneration via necroptosis ( Hou et al, 2009 ; Arrazola and Court, 2019 ) and also contribute to the regulated necrosis (RN) pathway ( Wang S. et al, 2019 ).…”