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

Cai，Qixu1,2; Chen，Xiumin3; Zhu，Shihan1; Nicoll，Roger A.3; Zhang，Mingjie1,4

2023-03-28

10.1016/j.celrep.2023.112146

Cell Reports   Impact Factor & Quartile

2211-1247

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.

CaMKII CP: Neuroscience LTP phase separation synaptic plasticity synaptic transmission

SCI

English

Corresponding

National Natural Science Foundation of China[82188101];National Institutes of Health[R01MH117139];Horowitz Foundation for Social Policy[RGP0020/2019];

WOS:000944874000001

2-s2.0-85149949429

Scopus

1.Division of Life Science,State Key Laboratory of Molecular Neuroscience,Hong Kong University of Science and Technology,Clear Water Bay,Kowloon,Hong Kong,China
2.State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics,Department of Laboratory Medicine,School of Public Heath,Xiamen University,Xiamen,Fujian,361102,China
3.Department of Cellular and Molecular Pharmacology,University of California,San Francisco,San Francisco,94143,United States
4.School of Life Sciences,Southern University of Science and Technology,Shenzhen,Guangdong,518055,China

Cai，Qixu,Chen，Xiumin,Zhu，Shihan,et al. Differential roles of CaMKII isoforms in phase separation with NMDA receptors and in synaptic plasticity[J]. Cell Reports,2023,42(3).

Cai，Qixu,Chen，Xiumin,Zhu，Shihan,Nicoll，Roger A.,&Zhang，Mingjie.(2023).Differential roles of CaMKII isoforms in phase separation with NMDA receptors and in synaptic plasticity.Cell Reports,42(3).

Cai，Qixu,et al."Differential roles of CaMKII isoforms in phase separation with NMDA receptors and in synaptic plasticity".Cell Reports 42.3(2023).