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

Dutta-Roy R, Rosenmund C, Edelstein SJ, Le Novère N - PLoS ONE (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine Solna, Karolinska Insitutet, 171 76 Stockholm, Sweden; NWFZ, Charite Universitatsmedizin, 101 17 Berlin, Germany; European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SD, UK.

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.

Show MeSH

Related in: MedlinePlus

Kinetic behaviour of synaptic AMPARs.(A) The blue trace shows the average synaptic current, which reaches its peak within fractions of ms (n = 7). The black bar represents the depolarisation of the pre-synapic terminal. (B) Kinetics of the subconductance states of an AMPA receptor population (S4 Supporting model). Left plot, deterministic simulation of a population of GluA3/GluK2 receptors by 1 μM of agonist. Right plot, stochastic simulation of a population of 50 receptors. Only the most populated states are represented for sake of clarity.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4309570&req=5

pone.0116616.g003: Kinetic behaviour of synaptic AMPARs.(A) The blue trace shows the average synaptic current, which reaches its peak within fractions of ms (n = 7). The black bar represents the depolarisation of the pre-synapic terminal. (B) Kinetics of the subconductance states of an AMPA receptor population (S4 Supporting model). Left plot, deterministic simulation of a population of GluA3/GluK2 receptors by 1 μM of agonist. Right plot, stochastic simulation of a population of 50 receptors. Only the most populated states are represented for sake of clarity.

Mentions: We next investigated whether the maximum conductance state could be stabilized within the rise time of a synaptic event. Upon release in vivo, neurotransmitters are spread and transported away from the synaptic cleft within microseconds, and the level of glutamate in the cleft can reach millimolar concentrations [4, 21, 22]. In order to estimate the rise time of a population of receptors in a whole hippocampal neuron we averaged spontaneous whole-cell synaptic currents from wild-type autaptic hippocampal neurons as seen in Fig. 3. The average 20–80% rise time was 0.53 ms ± 0.13 ms (n = 7).


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

Dutta-Roy R, Rosenmund C, Edelstein SJ, Le Novère N - PLoS ONE (2015)

Kinetic behaviour of synaptic AMPARs.(A) The blue trace shows the average synaptic current, which reaches its peak within fractions of ms (n = 7). The black bar represents the depolarisation of the pre-synapic terminal. (B) Kinetics of the subconductance states of an AMPA receptor population (S4 Supporting model). Left plot, deterministic simulation of a population of GluA3/GluK2 receptors by 1 μM of agonist. Right plot, stochastic simulation of a population of 50 receptors. Only the most populated states are represented for sake of clarity.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4309570&req=5

pone.0116616.g003: Kinetic behaviour of synaptic AMPARs.(A) The blue trace shows the average synaptic current, which reaches its peak within fractions of ms (n = 7). The black bar represents the depolarisation of the pre-synapic terminal. (B) Kinetics of the subconductance states of an AMPA receptor population (S4 Supporting model). Left plot, deterministic simulation of a population of GluA3/GluK2 receptors by 1 μM of agonist. Right plot, stochastic simulation of a population of 50 receptors. Only the most populated states are represented for sake of clarity.
Mentions: We next investigated whether the maximum conductance state could be stabilized within the rise time of a synaptic event. Upon release in vivo, neurotransmitters are spread and transported away from the synaptic cleft within microseconds, and the level of glutamate in the cleft can reach millimolar concentrations [4, 21, 22]. In order to estimate the rise time of a population of receptors in a whole hippocampal neuron we averaged spontaneous whole-cell synaptic currents from wild-type autaptic hippocampal neurons as seen in Fig. 3. The average 20–80% rise time was 0.53 ms ± 0.13 ms (n = 7).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine Solna, Karolinska Insitutet, 171 76 Stockholm, Sweden; NWFZ, Charite Universitatsmedizin, 101 17 Berlin, Germany; European Bioinformatics Institute (EMBL-EBI), Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SD, UK.

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.

Show MeSH
Related in: MedlinePlus