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Ubiquitin and the synapse

Nature Reviews Neuroscience volume 3, pages 854–861 (2002)Cite this article

Key Points

  • The 76-amino-acid protein ubiquitin was initially identified as a tag that marks proteins for degradation by the proteasome. However, ubiquitination can also serve as a rapidly reversible mechanism for the covalent modification of proteins, and recent studies have highlighted its importance for the rapid modification of proteins in the brain.

  • The substrates and enzymes of the ubiquitin pathway can be regulated by phosphorylation, and a new mode of regulation by ubiquitin-like proteins has also been discovered.

  • Ubiquitin-regulated protein degradation provides a mechanism that links axon-guidance cues — such as the netrins, semaphorins, ephrins and Slit — to growth cone dynamics. From work on the Drosophila neuromuscular junction, ubiquitination has also been implicated as a key regulator of synapse formation and growth.

  • Synaptic strength can be regulated by controlling the abundance of neurotransmitter receptors at the synapse, through targeted insertion and removal. Ubiquitination is a signal for endocytosis, so it is an attractive candidate mechanism for controlling the levels of neurotransmitter receptors. Support for this hypothesis has come from work with the inhibitory glycine and GABAA (γ-aminobutyric acid type A) receptors, and the excitatory glutamate receptors.

  • The ubiquitin pathway also seems to be involved in synaptic plasticity. In Aplysia, it has been shown that ubiquitination of cyclic-AMP-dependent protein kinase causes it to remain active, even at low levels of cAMP, and this persistent activity helps to convert short-term synaptic facilitation to a longer-lasting phenomenon.

  • So, several functions of ubiquitin in the nervous system have already been discovered, and it is expected that ubiquitination will join phosphorylation as a central mechanism for modifying neuronal activity.

Abstract

Post-translational modification by the attachment of ubiquitin seems to have a crucial role in regulating synaptic structure and function. By controlling the stability, activity and localization of target proteins, this versatile regulatory system can shape the pattern, activity and plasticity of synaptic connections. Here, we discuss the myriad ways in which ubiquitin functions to sculpt synapses during development, and to remodel synapses for the acquisition and storage of memory.

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Figure 1: The ubiquitin pathway.
Figure 2: Mechanism of degradation of the regulatory subunit of PKA during the induction of long-term facilitation.

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Acknowledgements

This work was supported by grants from the Whitehall Foundation and the National Institute of Mental Health to A.N.H., and by grants from the Sloan, McKnight and Keck Foundations to A.D.

Author information

Authors and Affiliations

  1. Department of Neurobiology and Anatomy, Wake Forest University Health Sciences, Medical Center Boulevard, Winston-Salem, 27157, North Carolina, USA

    Ashok N. Hegde

  2. Department of Molecular Biology and Pharmacology, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, 63110, Missouri, USA

    Aaron DiAntonio

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  1. Ashok N. Hegde
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Correspondence to Ashok N. Hegde.

Related links

Related links

DATABASES

FlyBase

bendless

CaMKII

Comm

faf

hiw

Nedd4

Robo

Slit

SUMO

GenBank

Ap-C/EBP

Ap-uch

LPA

netrin 1

LocusLink

AMPA receptors

Cdc2 kinase

Cdk5

c-Fos

c-Jun

c-Myc

CREB

cullin

E1

E6-AP

ephrins

epsins

Fnk

GABAA receptors

glycine receptors

MAP kinase

netrins

NMDA receptors

p35

p53

PDGFR

PKA-C

PKA-R

Plic1

Rub1

semaphorins

Slit

Snk

synaptophysin

ubiquitin

<i>Saccharomyces</i> Genome Database

Met4

FURTHER INFORMATION

Encyclopedia of Life Sciences

learning and memory

long-term potentiation

regulation by covalent modification

ubiquitin pathway

Glossary

EPIGENETIC

Describes a change in phenotype that is brought about by changes in the regulation of gene expression or changes in the function of gene products, rather than by a change in genotype. Examples of epigenetic events include DNA methylation, X-chromosome inactivation and embryonic pattern formation.

LONG-TERM POTENTIATION

(LTP). An enduring increase in the amplitude of excitatory postsynaptic potentials as a result of high-frequency (tetanic) stimulation of afferent pathways. It is measured both as the amplitude of excitatory postsynaptic potentials and as the magnitude of the postsynaptic-cell population spike. LTP is most often studied in the hippocampus and is often considered to be the cellular basis of learning and memory in vertebrates.

LONG-TERM FACILITATION

(LTF). A lasting increase in the strength of synapses between sensory and motor neurons in Aplysia. LTF is the cellular mechanism that underlies non-associative learning and memory. LTF results largely from presynaptic changes. It is similar to the LTP of the hippocampal mossy fibre pathway, but differs from LTP in other regions of the hippocampus, which are associative.

HEAT SHOCK

A cellular response that is caused by exposure to a temperature that is higher than normal. The heat-shock proteins, many of which function as molecular chaperones, are synthesized in larger amounts under these conditions, and many of them are also crucial for cellular functions under non-stress conditions.

BENDLESS

A Drosophila mutant in which synaptic connectivity is disrupted, leading to defects in the escape jump response. The bendless gene has been found to code for a ubiquitin-conjugating protein, and this mutant provided the first indication that ubiquitination is important for the wiring of the nervous system.

RING-H2 DOMAIN

One of a class of protein domains that consist of two loops that are held together at their base by cysteine and histidine residues that complex two zinc ions. Proteins that contain domains of this type are known as RING-finger proteins.

ANGELMAN'S SYNDROME

A genetic disorder that is caused by deletion or disruption of UBE3A (E6-AP). The symptoms of Angelman's syndrome include hyperactivity, ataxia, problems with speech and language, and an unusually happy demeanour.

RETROGRADE AMNESIA

Loss of or inability to recall information that was previously stored in long-term memory.

INHIBITORY AVOIDANCE

A learning paradigm in which an animal is taught to associate a particular location (such as a dark compartment in a maze) with an aversive stimulus (such as a foot shock).

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Hegde, A., DiAntonio, A. Ubiquitin and the synapse. Nat Rev Neurosci 3, 854–861 (2002). https://doi.org/10.1038/nrn961

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