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CaMKII: a central molecular organizer of synaptic plasticity, learning and memory

Nature Reviews Neuroscience volume 23, pages 666–682 (2022)Cite this article

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Abstract

Calcium–calmodulin (CaM)-dependent protein kinase II (CaMKII) is the most abundant protein in excitatory synapses and is central to synaptic plasticity, learning and memory. It is activated by intracellular increases in calcium ion levels and triggers molecular processes necessary for synaptic plasticity. CaMKII phosphorylates numerous synaptic proteins, thereby regulating their structure and functions. This leads to molecular events crucial for synaptic plasticity, such as receptor trafficking, localization and activity; actin cytoskeletal dynamics; translation; and even transcription through synapse–nucleus shuttling. Several new tools affording increasingly greater spatiotemporal resolution have revealed the link between CaMKII activity and downstream signalling processes in dendritic spines during synaptic and behavioural plasticity. These technologies have provided insights into the function of CaMKII in learning and memory.

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Fig. 1: Structure of CaMKII and its activation scheme.
Fig. 2: The hypothetical timescale of CaMKII signalling in dendritic spines.
Fig. 3: Activation of CaMKII in single dendritic spines.
Fig. 4: Activity-dependent CaMKII association changes the localization of CaMKAPs during long-term potentiation.
Fig. 5: Role of CaMKII binding to NMDA receptor subunit 2B in regulating AMPA receptors.

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Acknowledgements

The authors thank K. U. Bayer and M. M. Stratton for critical reading.

Author information

Authors and Affiliations

  1. Max Planck Florida Institute for Neuroscience, Jupiter, FL, USA

    Ryohei Yasuda

  2. Department of Pharmacology, Kyoto University Graduate School of Medicine, Kyoto, Japan

    Yasunori Hayashi

  3. Department of Pharmacology, University of California, Davis, Davis, CA, USA

    Johannes W. Hell

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  1. Ryohei Yasuda
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  2. Yasunori Hayashi
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Glossary

Protomers

Individual protein molecules in a protein complex.

Holoenzymes

Fully functional enzymes with all components present.

Phosphatases

Enzymes that remove phosphate moieties from phosphorylated proteins, lipids or other substrates.

Bistability

A property whereby a system can have two stable equilibrium states.

Bulk phase

Bulk phase signalling refers to signalling mediated by a population of CaMKII that is generally not anchored to CaMKAP. This population senses global calcium ions and transmits signals to diffusing substrates, as opposed to local signaling via CaMKAP–CaMKII complexes, which occur in nanodomains.

Glutamate uncaging

A microscopic technique that uses photons to release glutamate from light-sensitive precursors, often used to induce long-term potentiation in spines.

Decay time constant

The time when something decaying in exponential fashion becomes 1/e, where e is Napier’s constant.

Structural LTP

(sLTP). An activity-induced, lasting increase in spine size, mirroring electrically induced long-term potentiation (LTP).

Guanine nucleotide exchange factor

(GEF). A protein that activates small GTPases such as RAS and RHO by exchanging GDP on the small GTPases with GTP.

Condensates

Collection of molecules separated and condensed from the dilute phase through the process of liquid–liquid phase separation.

Apo state

The state in which an enzyme lacks one or more constituents required for its activity.

Ultrastructural distribution

Distribution of molecules at the nanometre scale, as determined by electron microscopy.

Exchange time

The time required for molecules in a compartment to be replaced with molecules in another compartment.

Hydrodynamic radius

Radius of a molecule or protein with its full hydration shell, formed by water molecules.

PDZ domain

A protein domain that includes a shallow groove that binds the carboxy termini of defined proteins that typically end with Ser/Thr-X-Val, with X being any of the 20 protein-forming amino acids.

Antiparallel coiled coil

A protein structure formed by two α-helices facing each other side by side in an antiparallel way; for example, by one helix oriented amino terminus to carboxy terminus and the adjacent helix oriented carboxy terminus to amino terminus.

Hebbian LTP

Long-term potentiation (LTP) that occurs when postsynaptic activity is paired with presynaptic activity.

Virus-like capsid

A protein structure that resembles the capsid structure that surrounds the viral genome.

Myristoylated

Bearing a lipid moiety known as a myristoyl side chain.

Consensus phosphorylation sites

Amino acid sequences that are recognized by specific protein kinases as substrate sites.

Half-maximal effective concentration

The concentration of a molecule at which it exhibits half-maximal efficacy with respect to, for example, enzymatic activity or binding interactions.

Retromer complex

The complex formed by the vacuole protein sorting gene products VPS26, VPS29 and VPS35.

Spine pruning

Loss of spines or reduction in spine number over time in the brain, especially during development but also later in life.

Inhibitory avoidance task

Behavioural task in which an animal is trained to avoid a situation or localization.

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Yasuda, R., Hayashi, Y. & Hell, J.W. CaMKII: a central molecular organizer of synaptic plasticity, learning and memory. Nat Rev Neurosci 23, 666–682 (2022). https://doi.org/10.1038/s41583-022-00624-2

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