# Molecular computation by the CaMKII holoenzyme

> **NIH NIH F31** · UNIVERSITY OF COLORADO DENVER · 2022 · $36,212

## Abstract

PROJECT SUMMARY
Learning, cognition, and memory require dynamic remodeling of hippocampal synapses, which in turn requires
Ca2+/calmodulin-dependent kinase II (CaMKII). CaMKII mediates two opposing modes of synaptic plasticity, long
term potentiation (LTP) and depression (LTD), that are induced by distinct Ca2+ stimuli. Both low and high Ca2+
induce CaMKII autophosphorylation (p) at T286, that is required for both LTP and LTD. Additionally, LTP requires
CaMKII binding to the NMDA receptor subunit, GluN2B, during high [Ca2+] while LTD requires CaMKII
autophosphorylation at T305/306 during low [Ca2+]. Further, these three mechanisms can undergo complex
cross-regulation which requires the CaMKII 12-meric holoenzyme. Interestingly, pT286 positively regulates both
GluN2B binding and pT305/306 while GluN2B binding and pT305/306 are mutually exclusive. It is unknown how
these reactions and interactions are spatiotemporally encoded within holoenzymes and thus how LTP versus
LTD signal computation is accomplished by CaMKII. For example, it has been shown that pT286 must occur
between two neighboring kinase domains in the holoenzyme. It is still unclear what determines a functional
kinase domain neighbor. Moreover, in vitro binding studies have shown that CaMKII holoenzymes are required
for binding to GluN2B, suggesting that this interaction may require multiple subunits. Still, it is unknown what is
the required stoichiometry and subunit geometry required for CaMKII-GluN2B binding. Initial results suggest that
the holoenzyme rules for pT286 and GluN2B binding are fundamentally different. Therefore, this proposal will
investigate my hypothesis that LTP versus LTD mechanisms are regulated by structurally distinct features within
CaMKII holoenzymes. The approach will utilize several CaMKII “structural mutants” that have disrupted
holoenzyme structure (hexamers, dimers, and monomers). These mutants will be used as tools to define the
spatiotemporal dynamics of autophosphorylation within holoenzymes and the subunit stoichiometry and
geometry required for GluN2B binding. The results of this proposal will provide insight into how molecular signal
computation underlying the LTP versus LTD decision is encoded within CaMKII holoenzymes.

## Key facts

- **NIH application ID:** 10535139
- **Project number:** 1F31NS129254-01
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Carolyn Nicole Brown
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $36,212
- **Award type:** 1
- **Project period:** 2022-08-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10535139

## Citation

> US National Institutes of Health, RePORTER application 10535139, Molecular computation by the CaMKII holoenzyme (1F31NS129254-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10535139. Licensed CC0.

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