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  • Review Article
  • Published:

Constructing inhibitory synapses

Nature Reviews Neuroscience volume 2, pages 240–250 (2001)Cite this article

Key Points

  • Synaptic targeting and clustering of GABA (γ-aminobutyric acid)and glycine receptors is mediated by the interaction of these receptor subunits with the cytoskeleton. The intracellular domains of individual receptor subunits can interact with several proteins, including cytoskeletal elements, microtubule-binding proteins, neurotransmitter transporters, protein kinases, kinase-anchoring proteins and other signalling molecules. The roles of these protein–protein interactions in the synaptic accumulation and functional modulation of GABAA and glycine receptors have begun to be unravelled and constitute the focus of this review.

  • The large number of GABA and glycine receptor subunits is responsible for the extensive heterogeneity of glycine and GABAA receptor structure. In the case of GABA receptors, the presence of specific subunits in a given receptor subtype can determine receptor trafficking and subcellular localization.

  • Several accessory proteins that facilitate the accumulation of GABAA and glycine receptors at synaptic sites have been identified. In the case of glycine receptors, gephyrin is crucial for their clustering at synapses. Gephyrin can interact with several signalling proteins such as collybistin (a GDP–GTP exchange factor) and Raft1 (a protein involved in the control of translation). This raises the possibility that the action of gephyrin could also involve signal transduction and/or structural remodelling. However, the presence of these proteins at glycine synapses has yet to be definitively proven.

  • There are at least two mechanisms for the synaptic clustering of these GABAA receptors, one dependent and one independent on gephyrin. The components of the gephyrin-independent mechanism have remained elusive but dystrophin has been identified as one possible candidate. A protein known as GABARAP (GABAA receptor-associated protein)can also interact with GABAA receptor γ2 subunits. However, GABARAP is unlikely to have a role in synaptic clustering and might instead be relevant for intracellular transport.

  • GABAC receptors interact both with MAP1B, a molecule capable of binding actin and tubulin, and Glyt1E/F, a novel variant of the glycine transporter. The selective binding of MAP1B to GABAC but not to GABAA receptors could help to explain the differential localization of these receptors in the retina.

  • The dynamic regulation of inhibitory transmitter receptors has begun to be elucidated. GABAA receptors undergo constitutive endocytosis and travel between synaptic sites and endosomal structures but the relevance of this process for synaptic inhibition remains unknown. GABAA receptors are also phosphorylated by several protein kinases and can directly bind both protein kinase C (PKC) and PKC-anchoring proteins. PKC can phosphorylate individual β subunits and thereby modulate GABAA receptor function.

Abstract

Control of nerve-cell excitability is crucial for normal brain function. Two main groups of inhibitory neurotransmitter receptors — GABAA and glycine receptors — fulfil a significant part of this role. To mediate fast synaptic inhibition effectively, these receptors need to be localized and affixed opposite nerve terminals that release the appropriate neurotransmitter at multiple sites on postsynaptic neurons. But for this to occur, neurons require intracellular anchoring molecules, as well as mechanisms that ensure the efficient turnover and transport of mature, functional inhibitory synaptic receptor proteins. This review describes the dynamic regulation of synaptic GABAA and glycine receptors and discusses recent advances in this rapidly evolving field.

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Figure 1: Structure and diversity of inhibitory ligand-gated ion channels.
Figure 2: The synaptic localization of glycine receptors is controlled by gephyrin.
Figure 3: The subcellular localization and function of GABAC receptors are controlled by MAP1B.
Figure 4: Dynamic control of GABAA receptor expression at the cell surface.

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Authors and Affiliations

  1. MRC Laboratory of Molecular Cell Biology and Department of Pharmacology, University College, Gower Street, London, WC1E 6BT, UK

    Stephen J. Moss

  2. Department of Pharmacology, School of Pharmacy, 29–39 Brunswick Square, London, WC1N 1AX, UK

    Trevor G. Smart

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Related links

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DATABASE LINKS

Glycine receptor subunits

GABAA receptor subunits

β1 subunit

β3 subunit

γ2 subunit

δ subunit

ɛ subunit

θ subunit

α2 subunit

α1 subunit

α6 subunit

β2 subunit

GABAC receptor subunits

α3 subunit

gephyrin

Raft1

collybistin

Cdc42

γ3 subunit

dystrophin

GABARAP

MAP1B

Aut7

Glyt1E/F

PKC

AP2

PKA

PKG

CaMKII

Src

RACK1

ENCYCLOPEDIA OF LIFE SCIENCES

GABAA receptors

Benzodiazepines

Glossary

BENZODIAZEPINES

Pharmacologically active molecules with sedative, anxiolytic and anticonvulsant effects. They act by binding to the GABA receptor and potentiate the response elicited by the transmitter.

BARBITURATES

Pharmacologically active molecules with potent depressor effect in the central nervous system. They act by interacting with GABA receptors, potentiating the response elicited by the transmitter.

INNER PLEXIFORM LAYER

Retinal layer formed by the synaptic contacts between the bipolar, the amacrine and the ganglion cells.

YEAST TWO-HYBRID SCREENS

System used to determine the existence of direct interactions between proteins. It involves the use of plasmids that encode two hybrid proteins; one of them is fused to the GAL4 DNA-binding domain and the other one is fused to the GAL4 activation domain. The two proteins are expressed together in yeast and, if they interact, then the resulting complex will drive the expression of a reporter gene, commonly β-galactosidase.

RAC/RHO GTPASES

Molecules related to the product of the oncogene ras, which are involved in controlling the polymerization and subsequent organization of actin.

SH DOMAINS

Src-homology domains. They are involved in the interaction with phosphorylated tyrosine residues on other proteins (SH2 domains) or with proline-rich sections of other proteins (SH3 domains).

CHANNEL-PERMEABILITY RATIO

A comparison of the ease with which two different permeant ions can pass through a channel.

DYSTROPHIN

A protein that is absent in people with Duchenne muscular dystrophy. It is thought to participate in anchoring the cytoskeleton to the plasma membrane.

ENDOSOME

Organelle that carries materials ingested by endocytosis and passes them to lysosomes for degradation or recycles them to the cell surface.

CLATHRIN

One of the main protein components of the coats formed during membrane endocytosis.

AP2 COMPLEX

Heterotetrameric complex composed of subunits called adaptins. It is one of the main components of the coats formed during membrane endocytosis.

SMALL GTPases

Family of proteins capable of hydrolysing GTP, which include Rac, Rab, Ran, Rad, Rho and others. They subserve multiple cellular functions. For example, Rho and Rac are involved in the control of the cytoskeleton.

DYNAMIN

A GTPase that is involved in endocytosis. It is thought to be involved in severing the connection between the nascent vesicle and the donor membrane.

PDZ DOMAIN

A peptide-binding domain that is important for the organization of membrane proteins, particularly at cell–cell junctions, including synapses. They can bind to the carboxyl termini of proteins or can form dimers with other PDZ domains. PDZ domains are named after the proteins in which these sequence motifs were originally identified (PSD95, Discs-large, zona occludens-1).

PSD95

A protein of the postsynaptic density, which can interact with NMDA receptors. It is thought to participate in regulating the spatial distribution of this receptor subtype.

GRIP

(Glutamate-receptor-interacting protein). A protein that can interact with AMPA receptors. It is thought to participate in regulating the spatial distribution and targeting of this receptor subtype.

RAS PROTEINS

A group of proteins involved in growth, differentiation and cellular signalling that require the binding of GTP to enter into their active state.

GRASP

(GRIP1-associated scaffold protein). A guanine-nucleotide exchange factor that owing to its interaction with GRIP might link AMPA receptors to Ras signalling.

SYNGAP

A synaptic Ras-GTPase activating protein that interacts with PSD95. It might participate in controlling the spatial distribution of NMDA receptors, as well as in regulating Ras signalling.

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Moss, S., Smart, T. Constructing inhibitory synapses. Nat Rev Neurosci 2, 240–250 (2001). https://doi.org/10.1038/35067500

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