The desensitization gate of inhibitory Cys-loop receptors.

Marc Gielen,Trevor G Smart,Philip Thomas

doi:10.1038/ncomms7829

Marc Gielen, Trevor G Smart + Show 1 more

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https://doi.org/10.1038/ncomms7829

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Journal: Nature Communications	Publication Date: Apr 20, 2015
Citations: 120	License type: CC BY 4.0

Affiliation: University College London, Institut Pasteur

Abstract

Cys-loop neurotransmitter-gated ion channels are vital for communication throughout the nervous system. Following activation, these receptors enter into a desensitized state in which the ion channel shuts even though the neurotransmitter molecules remain bound. To date, the molecular determinants underlying this most fundamental property of Cys-loop receptors have remained elusive. Here we present a generic mechanism for the desensitization of Cys-loop GABAA (GABAARs) and glycine receptors (GlyRs), which both mediate fast inhibitory synaptic transmission. Desensitization is regulated by interactions between the second and third transmembrane segments, which affect the ion channel lumen near its intracellular end. The GABAAR and GlyR pore blocker picrotoxin prevented desensitization, consistent with its deep channel-binding site overlapping a physical desensitization gate.

Highlights

Cys-loop neurotransmitter-gated ion channels are vital for communication throughout the nervous system
For the Cys-loop GABAARs and glycine receptors (GlyRs), the structure–function studies have improved our understanding of how these receptors activate[7,12], the molecular determinants underlying the process of desensitization have yet to be defined
As mutations to the M1–M2 linker of GlyR a1 homomeric receptors (GlyRa1) have been reported to strongly affect desensitization[17], we focused on the intracellular end of M3, as we had done with the GABAAR, and exchanged six consecutive residues with those from r1

Summary

Introduction

Cys-loop neurotransmitter-gated ion channels are vital for communication throughout the nervous system. We show that for the inhibitory neurotransmitter GABAA and glycine receptors, the mechanism of agonist-induced desensitization is regulated by residue interactions between the transmembrane domains of the receptor, resulting in a timedependent constriction of the ion channel pore that reduces the agonist-activated membrane conductance. This constriction has the characteristics of a desensitization ‘gate’ that is discrete from the ion channel gate involved in ligand-gated channel opening

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