Anxiety over GABAA receptor structure relieved by AChBP

doi:10.1016/S0968-0004(02)02092-3

Trends in Biochemical Sciences

Volume 27, Issue 6, 1 June 2002, Pages 280-287

https://doi.org/10.1016/S0968-0004(02)02092-3 Get rights and content

Abstract

The GABA_A receptor is the primary mediator of inhibitory neurotransmission in the brain and is a major target for neuromodulatory drugs such as benzodiazepines, barbiturates, ethanol and anaesthetics. However, our understanding of the molecular details of this receptor has been limited by a lack of high-resolution structural information. This article presents a new model for the extracellular, ligand-binding domain of the GABA_A receptor, that is based on the recently determined structure of a soluble acetylcholine-binding protein. The model puts existing mutational and biochemical data into a three-dimensional context, shows details of the GABA- and benzodiazepine-binding sites, and highlights the importance of other regions in allosteric conformational change. This provides a new perspective on existing data and an exciting new framework for understanding this important family of receptors.

Section snippets

ACh-binding protein comes to the rescue

Recently, in a classic case of serendipity, Smit and colleagues [15] provided us with a new model for the nACh receptor ligand-binding domain by identifying a homologue, not from bacteria but from the snail Lymnaea stagnalis. As part of an investigation into the role of glia in synaptic transmission, these researchers isolated a soluble ACh-binding protein (AChBP) that is secreted by glial cells and modulates transmission at cholinergic synapses [15]. This is an important finding in itself and

The ligand-binding sites

Based on the alignment of residues implicated in ligand binding (Box 1, Fig. I), it has been suggested that the binding sites for GABA, benzodiazepine and ACh have a similar architecture [19], which we can now relate structurally to the HEPES-binding pocket of AChBP. Thus, in our model of the GABA_A receptor, we can consider the pocket at each β−α subunit interface, which is equivalent to the HEPES-binding pocket of AChBP, to be a putative GABA-binding site (Fig. 2a). As expected, some of the

Conformational change and allosterism

Our model appears to provide a reasonable picture of ligand-binding sites in static situations. Understanding the conformational changes that occur on ligand binding and how this relates to allosteric mechanisms is far more complex. Structural resolution of AChBP in the presence and absence of high-affinity ligands will help to shed light on this issue. However, because AChBP lacks an ion channel and shows little cooperativity in ligand binding [15], it might be a poor model for investigating

Implications for ion-channel function

The narrow, selective part of the ion channel is clearly within the membrane domain but the extracellular domain that is modelled here forms the vestibule through which ions must pass and could influence the passage of these ions. Given the diameter of the vestibule pore, charged residues will probably have the greatest influence on the passage of ions. Mapping of theoretical electrostatic potentials onto model extracellular domains shows that, in the pore, there is a clear preponderance of

Concluding remarks

The discovery and structural resolution of AChBP ushers in a new era of research into Cys-loop LGICs in which we can begin to understand these important proteins in detailed three-dimensional terms. Here, we have outlined a first glimpse of how the structure of AChBP can assist our understanding of the GABA_A receptor. We look forward to targeted mutational experiments that test ideas, such as those suggested here, that come as a direct consequence of the AChBP structure. The AChBP structure

Acknowledgements

This work was supported by a grant from the National Health and Medical Research Council of Australia. M.W.P. is a National Health and Medical Research Council Senior Principal Research Fellow.

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Trends in Biochemical Sciences

OpinionAnxiety over GABAA receptor structure relieved by AChBP

Abstract

Section snippets

ACh-binding protein comes to the rescue

The ligand-binding sites

Conformational change and allosterism

Implications for ion-channel function

Concluding remarks

Acknowledgements

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Curr. Opin. Struct. Biol.

Annu. Rev. Pharmacol. Toxicol.

Trends Neurosci.

Neuron

J. Neurosci.

Proc. Natl. Acad. Sci. U. S. A.

J. Neurochem.

Neuroreport

J. Biol. Chem.

Mol. Pharmacol.

Mol. Pharmacol.

Mol. Pharmacol.

Nat. Genet.

J. Neurosci.

Mol. Pharmacol.

Quaternary structure of the acetylcholine receptor

Nature

Quaternary structure of the native GABA(A) receptor determined by electron microscopic image analysis

J. Neurochem.

Ultrastructure of the 5-hydroxytryptamine3 receptor

J. Neurochem.

Opinion
Anxiety over GABA_A receptor structure relieved by AChBP