Abstract
Modulation of the properties of AMPA receptors at the post-synaptic membrane is one of the main suggested mechanisms underlying fast synaptic transmission 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 the existence of AMPA receptors in non-liganded conductive substates. However, the probability of spontaneous openings 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.
Highlights
One of the key mechanisms responsible for synaptic transmission is the activation of α-amino-3-hydroxy5-methyl-4-isoxazolepropionic acid receptors (AMPARs) at the post-synaptic membrane
The transition between the different conformations is characterized by the state-specific allosteric constants LS, LM and LL, which are the ratios between the B state and each of the A states in the non-liganded form, L = [B0]/[A0]
We have developed a theoretical model in order to formulate a plausible relationship between the conductance states of the AMPA receptor and ligand binding
Summary
One of the key mechanisms responsible for synaptic transmission is the activation of α-amino-3-hydroxy5-methyl-4-isoxazolepropionic acid receptors (AMPARs) at the post-synaptic membrane. AMPARs are ligand-gated ion channels that mediate fast excitatory synaptic transmission. They are concentrated at the post-synaptic density where their opening is allosterically regulated by glutamate. AMPARs can be found in three functional states: basal (closed), active (open) and desensitized (closed). In the absence of ligand the receptors are normally found in the basal state where the ion pore is closed. There is evidence that ligand-gated ion channels can be present in an active state in the absence of ligand [7,8,9]. When the ion channel is open, cations flow between the synaptic cleft and the post-synaptic cytoplasm
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