摘要：SummaryThe 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.Graphical abstractDisplay OmittedHighlights•Two of six CaMKII variants found in patients with schizophrenia showed impairments•R396stop disrupted holoenzyme structure, T286 autophosphorylation, and GluN2B binding•R8H reduced T286 autophosphorylation and stimulated activity•Two of the four other variants were later found also in the general populationBiological sciences; Neuroscience; Protein structure aspects
