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Characterization of six CaMKIIα variants found in patients with schizophrenia.


ABSTRACT: The Ca2+/Calmodulin-dependent protein kinase II (CaMKII) is a central regulator of synaptic plasticity and has been implicated in various neurological conditions, including schizophrenia. Here, we characterize six different CaMKIIα variants found in patients with schizophrenia. Only R396stop disrupted the 12-meric holoenzyme structure, GluN2B binding, and synaptic localization. Additionally, R396stop impaired T286 autophosphorylation that generates Ca2+-independent "autonomous" kinase activity. This impairment in T286 autophosphorylation was shared by the R8H mutation, the only mutation that additionally reduced stimulated kinase activity. None of the mutations affected the levels of CaMKII expression in HEK293 cells. Thus, impaired CaMKII function was detected only for R396stop and R8H. However, two of the other mutations have been later identified also in the general population, and not all mutations found in patients with schizophrenia would be expected to cause disease. Nonetheless, for the R396stop mutation, the severity of the biochemical effects found here would predict a neurological phenotype.

SUBMITTER: Brown CN 

PROVIDER: S-EPMC8506966 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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Characterization of six CaMKIIα variants found in patients with schizophrenia.

Brown Carolyn Nicole CN   Cook Sarah G SG   Allen Hillary F HF   Crosby Kevin C KC   Singh Tarjinder T   Coultrap Steven J SJ   Bayer K Ulrich KU  

iScience 20210927 10


The Ca<sup>2+</sup>/Calmodulin-dependent protein kinase II (CaMKII) is a central regulator of synaptic plasticity and has been implicated in various neurological conditions, including schizophrenia. Here, we characterize six different CaMKIIα variants found in patients with schizophrenia. Only R396stop disrupted the 12-meric holoenzyme structure, GluN2B binding, and synaptic localization. Additionally, R396stop impaired T286 autophosphorylation that generates Ca<sup>2+</sup>-independent "autonom  ...[more]

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