TY - JOUR
T1 - Coordination between calcium/calmodulin-dependent protein kinase II and neuronal nitric oxide synthase in neurons
AU - Araki, Shoma
AU - Osuka, Koji
AU - Takata, Tsuyoshi
AU - Tsuchiya, Yukihiro
AU - Watanabe, Yasuo
N1 - Funding Information:
This research was funded in part by a Grant-in-Aid for Scientific Research on Innovative Areas ‘Oxygen Biology: A new criterion for integrated understanding of life’ No. 26111008 (Y.W.); JSPS KAKENHI Grants-in-Aid for Scientific Research C No. 18K11083 (Y.W.), No. 17K10853 (K.O.); Early-Career Scientists No. 18K14853 (T.T.); Young Scientists B No. 15K18994 (Y.T.); Program for the Strategic Research Foundation at Private Universities No. S1311012 (Y.T and Y.W.) of the MEXT, Japan; Grant-in-Aid from the Showa Pharmaceutical University for Young Scientists [R1-2] (S.A.) H27-3, H28-2 (T.T.), H23-2 (Y.T.).
Publisher Copyright:
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2020/11/1
Y1 - 2020/11/1
N2 - 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.
AB - 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.
KW - Ca2+/calmodulin-dependent protein kinase II (CaMKII)
KW - Neuronal ischemia
KW - Nitric-oxide (NO)
KW - Phosphorylation
KW - Redox regulation
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U2 - 10.3390/ijms21217997
DO - 10.3390/ijms21217997
M3 - Review article
C2 - 33121174
AN - SCOPUS:85094970502
VL - 21
SP - 1
EP - 17
JO - International Journal of Molecular Sciences
JF - International Journal of Molecular Sciences
SN - 1422-0067
IS - 21
M1 - 7997
ER -