Journal
ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY
Volume 5, Issue 3, Pages 280-296Publisher
WILEY
DOI: 10.1002/acn3.528
Keywords
-
Categories
Funding
- Japan Agency for Medical Research and Development [17ek0109297h0001]
- Ministry of Education, Culture, Sports, Science and Technology, Japan [15H05872]
- Japan Society for the Promotion of Science [17H01539, 16H05160, 16H05357, 15K10367, 16K09975, 17K10080, 17K08534]
- Ministry of Health, Labor and Welfare
- Grants-in-Aid for Scientific Research [17K19682, 15K21731, 17K10080, 17H04025, 15H05872, 16H05357, 15K10367, 16H05160, 15H05871, 17K08534, 17K00918, 16K09975, 17H01539, 17K08513] Funding Source: KAKEN
Ask authors/readers for more resources
Objective: alpha (CAMK2A) and beta (CAMK2B) isoforms of Calcium/calmodulin-dependent protein kinase II (CaMKII) play a pivotal role in neuronal plasticity and in learning and memory processes in the brain. Here, we explore the possible involvement of alpha- and beta-CaMKII variants in neurodevelopmental disorders. Methods: Whole-exome sequencing was performed for 976 individuals with intellectual disability, developmental delay, and epilepsy. The effect of CAMK2A and CAMK2B variants on CaMKII structure and firing of neurons was evaluated by computational structural analysis, immunoblotting, and electrophysiological analysis. Results: We identified a total of five de novo CAMK2A and CAMK2B variants in three and two individuals, respectively. Seizures were common to three individuals with CAMK2A variants. Using a minigene splicing assay, we demonstrated that a splice site variant caused skipping of exon 11 leading to an in-frame deletion of the regulatory segment of CaMKII. By structural analysis, four missense variants are predicted to impair the interaction between the kinase domain and the regulatory segment responsible for the autoinhibition of its kinase activity. The Thr286/Thr287 phosphorylation as a result of release from autoinhibition was increased in three mutants when the mutants were stably expressed in Neuro-2a neuroblastoma cells. Expression of a CaMKII alpha mutant in primary hippocampal neurons significantly increased A-type K+ currents, which facilitated spike repolarization of single action potentials. Interpretation: Our data highlight the importance of CaMKII alpha and CaMKII beta and their autoinhibitory regulation in human brain function, and suggest the enhancement of A-type K+ currents as a possible pathophysiological basis.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available