Differential roles of CaMKII isoforms in phase separation with NMDA receptors and in synaptic plasticity.

Calcium calmodulin-dependent kinase II (CaMKII) is critical for synaptic transmission and plasticity. Two major isoforms of CaMKII, CaMKIIα and CaMKIIβ, play distinct roles in synaptic transmission and long-term potentiation (LTP) with unknown mechanisms. Here, we show that the length of the unstructured linker between the kinase domain and the oligomerizing hub determines the ability of CaMKII to rescue the basal synaptic transmission and LTP defects caused by removal of both CaMKIIα and CaMKIIβ (double knockout [DKO]). Remarkably, although CaMKIIβ binds to GluN2B with a comparable affinity as CaMKIIα does, only CaMKIIα with the short linker forms robust dense clusters with GluN2B via phase separation. Lengthening the linker of CaMKIIα with unstructured "Gly-Gly-Ser" repeats impairs its phase separation with GluN2B, and the mutant enzyme cannot rescue the basal synaptic transmission and LTP defects of DKO mice. Our results suggest that the phase separation capacity of CaMKII with GluN2B is critical for its cellular functions in the brain. [Display omitted] • CaMKII with a short linker is critical to support basal synaptic transmission and LTP • CaMKII with a short linker promotes phase separation with GluN2B • The different roles of the CaMKII linker on phase separation are sequence independent CaMKIIα and CaMKIIβ play distinct roles in supporting synaptic transmission and LTP with unknown underlying mechanisms. Cai et al. show that the linker length of CaMKII determines its phase separation with GluN2B, which regulates its differential role in synaptic plasticity. [ABSTRACT FROM AUTHOR]