Zinc-mediated inhibition of GABA(A) receptors: discrete binding sites underlie subtype specificity

Alastair M Hosie; Emma L Dunne; Robert J Harvey; Trevor G Smart

doi:10.1038/nn1030

Zinc-mediated inhibition of GABA(A) receptors: discrete binding sites underlie subtype specificity

Nat Neurosci. 2003 Apr;6(4):362-9. doi: 10.1038/nn1030.

Authors

Alastair M Hosie¹, Emma L Dunne, Robert J Harvey, Trevor G Smart

Affiliation

¹ Department of Pharmacology, University College London, Gower Street, London WC1E 6BT, UK.

PMID: 12640458
DOI: 10.1038/nn1030

Abstract

Zinc ions are concentrated in the central nervous system and regulate GABA(A) receptors, which are pivotal mediators of inhibitory synaptic neurotransmission. Zinc ions inhibit GABA(A) receptor function by an allosteric mechanism that is critically dependent on the receptor subunit composition: alphabeta subunit combinations show the highest sensitivity, and alphabetagamma isoforms are the least sensitive. Here we propose a mechanistic and structural basis for this inhibition and its dependence on the receptor subunit composition. We used molecular modeling to identify three discrete sites that mediate Zn2+ inhibition. One is located within the ion channel, and the other two are on the external amino (N)-terminal face of the receptor at the interfaces between alpha and beta subunits. We found that the characteristically low Zn2+ sensitivity of GABA(A) receptors containing the gamma2 subunit results from disruption to two of the three sites after receptor subunit co-assembly.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Sequence / drug effects
Amino Acid Sequence / genetics
Animals
Binding Sites / drug effects
Binding Sites / genetics
Carboxylic Acids / metabolism
Central Nervous System / metabolism*
Dose-Response Relationship, Drug
Humans
Mutation / genetics
Neural Inhibition / drug effects
Neural Inhibition / physiology*
Protein Structure, Tertiary / drug effects
Protein Structure, Tertiary / genetics
Protein Subunits / drug effects
Protein Subunits / genetics
Protein Subunits / metabolism*
Receptors, GABA-A / drug effects
Receptors, GABA-A / genetics
Receptors, GABA-A / metabolism*
Stereoisomerism
Synapses / drug effects
Synapses / metabolism*
Synaptic Transmission / drug effects
Synaptic Transmission / physiology*
Zinc / metabolism*
Zinc / pharmacology
gamma-Aminobutyric Acid / metabolism
gamma-Aminobutyric Acid / pharmacology

Substances

Carboxylic Acids
Protein Subunits
Receptors, GABA-A
gamma-Aminobutyric Acid
Zinc