Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
Volume 21, Issue 21, Pages -Publisher
MDPI
DOI: 10.3390/ijms21217997
Keywords
Ca2+; calmodulin-dependent protein kinase II (CaMKII); nitric-oxide (NO); neuronal ischemia; phosphorylation; redox regulation
Funding
- JSPS KAKENHI [18K11083, 17K10853, 18K14853, 15K18994]
- Program for the Strategic Research Foundation at Private Universities of the MEXT, Japan [S1311012]
- Showa Pharmaceutical University for Young Scientists [R1-2, H27-3, H28-2, H23-2]
- [26111008]
- Grants-in-Aid for Scientific Research [15K18994, 18K14853, 17K10853, 18K11083] Funding Source: KAKEN
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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.
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