Brown Carolyn Nicole, Barker C Madison, Miller Carley N, Aoto Jason, Coultrap Steven J, Bayer K Ulrich
Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.
Current address: Department of Neuroscience, Johns Hopkins University, Baltimore, MD 21205, USA.
bioRxiv. 2025 Jul 4:2025.07.04.663188. doi: 10.1101/2025.07.04.663188.
Cognitive functions require synaptic plasticity, specifically long-term potentiation (LTP). LTP is thought to require CaMKII binding to the NMDA-type glutamate receptor subunit GluN2B, but this poses a major conundrum: Truncated CaMKII monomers (without the hub domain that forms 12meric holoenzymes) fail to bind GluN2B, but still potentiate synapses when made constitutively active. We hypothesized that CaMKII monomer binding to GluN2B has just eluded detection. Instead, even though full-length CaMKII monomers (with hub domain mutations) were found to indeed bind and even co-condensate with GluN2B, truncated monomers were not. Nonetheless, truncated monomers still potentiated synapses, even in neurons with GluN2B mutations that ablate CaMKII binding. However, potentiation occurred only with monomers that were made Ca-independent by artificial phosphatase-resistant thio-autophosphorylation, not by regular autophosphorylation of T286. These findings support that CaMKII binding to GluN2B is required during physiological LTP induction because it generates the phosphatase-resistant autonomous activity that mediates LTP expression.
认知功能需要突触可塑性，特别是长时程增强（LTP）。LTP被认为需要CaMKII与NMDA型谷氨酸受体亚基GluN2B结合，但这带来了一个重大难题：截短的CaMKII单体（没有形成12聚体全酶的枢纽结构域）无法结合GluN2B，但在组成型激活时仍能增强突触。我们推测CaMKII单体与GluN2B的结合只是未被检测到。相反，尽管发现全长CaMKII单体（具有枢纽结构域突变）确实能与GluN2B结合甚至共凝聚，但截短的单体却不能。尽管如此，截短的单体仍能增强突触，即使在具有消除CaMKII结合的GluN2B突变的神经元中也是如此。然而，增强作用仅发生在通过人工抗磷酸酶硫代自磷酸化使其与钙无关的单体上，而不是通过T286的常规自磷酸化。这些发现支持在生理性LTP诱导过程中需要CaMKII与GluN2B结合，因为它产生了介导LTP表达的抗磷酸酶自主活性。
