Ligand-dependent opening of the multiple AMPA receptor conductance states: a concerted model

TL;DR

This paper presents a concerted allosteric model explaining how ligand binding influences the multiple conductance states of AMPA receptors, linking thermodynamics, kinetics, and synaptic activity.

Contribution

It introduces a novel allosteric model based on concerted conformational changes to describe AMPA receptor conductance states and their ligand-dependent behavior.

Findings

Receptors exhibit multiple conductance states depending on agonist concentration.

Higher conductance states have increased ligand affinity.

Spontaneous openings decrease as conductance increases.

Abstract

Modulation of the properties of AMPA receptors at the post-synaptic membrane is one of the main suggested mechanisms behind synaptic plasticity in the central nervous system of vertebrates. Electrophysiological recordings of single channels stimulated with agonists showed that both recombinant and native AMPA receptors visit multiple conductance states in an agonist concentration dependent manner. We propose an allosteric model of the multiple conductance states based on concerted conformational transitions of the four subunits, as an iris diaphragm. Our model predicts that the thermodynamic behaviour of the conductance states upon full and partial agonist stimulations can be described with increased affinity of receptors as they progress to higher conductance states. The model also predicts existence of AMPA receptors in non-liganded conductive substates. However, spontaneous openings probability decreases with increasing conductances. Finally, we predict that the large conductance states are stabilized within the rise phase of a whole-cell EPSC in glutamatergic hippocampal neurons. Our model provides a mechanistic link between ligand concentration and conductance states that can explain thermodynamic and kinetic features of AMPA receptor gating.