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  • Review Article
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The role of calmodulin as a signal integrator for synaptic plasticity

Nature Reviews Neuroscience volume 6, pages 267–276 (2005)Cite this article

Key Points

  • Various forms of synaptic plasticity, including long-term potentiation (LTP) and long-term depression (LTD), are initiated through synapse-specific increases in Ca2+ that are generated through the activation of voltage-sensitive Ca2+ channels or NMDA (N-methyl-D-aspartate) receptors.

  • Many of the effects of Ca2+ on synaptic efficiency are mediated through the Ca2+-binding protein calmodulin (CaM), which mediates Ca2+ stimulation of several enzymes that are crucial for synaptic plasticity. The affinity of CaM for most of these proteins is increased when the concentration of free Ca2+ increases. Therefore, CaM mediates activity-dependent stimulation of a family of enzymes that are important for synaptic plasticity.

  • The unique regulatory properties of CaM allow various target enzymes with different Ca2+ sensitivities to be stimulated and to show varying degrees of positive cooperativity.

  • Several novel CaM-binding proteins, including neuromodulin and neurogranin, localize and control the levels of free CaM in neurons. These IQ domain-containing proteins bind CaM with higher affinity in the absence of Ca2+ compared with in the presence of Ca2+. Furthermore, neuromodulin and neurogranin can be phosphorylated at sites within an IQ domain, which is also the CaM-binding domain. Consequently, activity-dependent Ca2+ increases the release of CaM from neuromodulin and neurogranin.

  • Calcium/calmodulin-dependent protein kinase II (CaMKII), a CaM-stimulated kinase, has a crucial role in several forms of LTP. CaMKII might contribute to LTP by augmenting the activity of AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors and stimulating dendritic translation. CaMKIV phosphorylates the CREB (cAMP responsive element (CRE)-binding protein) binding protein (CBP), which is a necessary event for Ca2+ stimulation of CRE-mediated transcription and heterosynaptic late-phase LTP.

  • Calcineurin, a CaM-stimulated protein phosphatase, is thought to catalyse the dephosphorylation of AMPA receptors, an important event in LTD.

  • The CaM-stimulated adenylyl cyclases AC1 and AC8 are thought to contribute to LTP by coupling activity-dependent Ca2+ increases to elevated cAMP. This cAMP signal activates protein kinase A (PKA), which phosphorylates and enhances the activity of AMPA. In addition, cAMP increases ERK/MAPK activity, a crucial activity for L-LTP.

Abstract

Excitatory synapses in the brain show several forms of synaptic plasticity, including long-term potentiation (LTP) and long-term depression (LTD), which are initiated by increases in intracellular Ca2+ that are generated through NMDA (N-methyl-D-aspartate) receptors or voltage-sensitive Ca2+ channels. LTP depends on the coordinated regulation of an ensemble of enzymes, including Ca2+/calmodulin-dependent protein kinase II, adenylyl cyclase 1 and 8, and calcineurin, all of which are stimulated by calmodulin, a Ca2+-binding protein. In this review, we discuss the hypothesis that calmodulin is a central integrator of synaptic plasticity and that its unique regulatory properties allow the integration of several forms of signal transduction that are required for LTP and LTD.

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Figure 1: Overview of the effects of Ca2+ and calmodulin on changes in synaptic plasticity.
Figure 2: Calmodulin and presynaptic long-term potentiation.
Figure 3: Long-term potentiation and long-term depression at the Schaffer collateral–CA1 synapse depend on a series of calmodulin-regulated events.
Figure 4: Calmodulin is important for Ca2+ stimulation of cyclic AMP responsive element-mediated transcription in neurons.

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Acknowledgements

Both authors are supported by grants from the National Institutes of Health.

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Authors and Affiliations

  1. Department of Pharmacology and Program in Neuroscience, University of Washington, Seattle, 98195, Washington, USA

    Zhengui Xia & Daniel R. Storm

  2. Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, 98195, Washington, USA

    Zhengui Xia

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  1. Zhengui Xia
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Correspondence to Daniel R. Storm.

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DATABASES

Entrez Gene

ACl

AC8

α-CaMKII

CPEB

CREB

MAPK

neurogranin

neuromodulin

PP1

RasGRF1

RasGRP1

RSK

FURTHER INFORMATION

Storm's laboratory

Xia's faculty page

Glossary

FLUORESCENCE RESONANCE ENERGY TRANSFER

(FRET). A spectroscopic technique that is based on the transfer of energy from the excited state of a donor moiety to an acceptor. The transfer efficiency depends on the distance between the donor and the acceptor. FRET is often used to estimate distances between macromolecular sites in the 20–100-Å range, or to study interactions between macromolecules in vivo.

DISSOCIATION CONSTANT

A measure to describe the strength of binding (or affinity) between receptors and their ligands.

CaM–SEPHAROSE AFFINITY CHROMATOGRAPHY

An affinity column for the purification of CaM-binding proteins comprised of CaM covalently attached to Sepharose. Most CaM-binding proteins bind to CaM–Sepharose in the presence of Ca2+. Neuromodulin binds to the column in the absence of Ca2+ and is eluted from the column with buffers that contain Ca2+.

IQ DOMAIN

A small structural domain, originally identified in neuromodulin, that mediates interactions with CaM. The motif only loosely defines the amino acid sequence at 5 of 11 possible residues. Different IQ domains bind CaM at varying intracellular Ca2+ concentrations or independently of Ca2+.

TETANIC STIMULATION

A train of stimuli that causes brief, high-frequency activation of afferent axons. In LTP experiments, a 1-s train of pulses delivered at a frequency of 100 Hz is commonly used to potentiate transmission.

SCHAFFER COLLATERALS

Axons of the CA3 pyramidal cells of the hippocampus that form synapses with the apical dendrites of CA1 neurons.

PAIRING PROTOCOL

If a cell is artificially depolarized while low-frequency stimulation is delivered, synaptic transmission will be potentiated because the depolarization relieves the Mg2+-dependent block of NMDA receptors.

SYNAPTIC TAGGING

A mechanism by which activated synapses are tagged to distinguish them from other synapses on the same neuron that have not been activated. The mechanism for synaptic tagging is not known, but might be due to increases in dendritic translation.

LTD/LTP THRESHOLD

The frequency at which an LTD response is converted to LTP.

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Xia, Z., Storm, D. The role of calmodulin as a signal integrator for synaptic plasticity. Nat Rev Neurosci 6, 267–276 (2005). https://doi.org/10.1038/nrn1647

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