TARP‐associated AMPA receptors display an increased maximum channel conductance and multiple kinetically distinct open states

Key points •  Signalling of information in the nervous system relies on the activation of specific neurotransmitter receptors. •  Here we characterise some of the properties of GluA1 AMPA receptors, whose ion‐permeable channel is opened by the neurotransmitter glutamate. •  We found that the individ...

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Bibliographic Details
Published in:The Journal of physiology 2012-11, Vol.590 (22), p.5723-5738
Main Authors: Shelley, Chris, Farrant, Mark, Cull‐Candy, Stuart G.
Format: Article
Language:English
Subjects:
Animals
Calcium Channels - metabolism
Cell Line
Humans
Ion Channel Gating
Kinetics
Neurology
Neuroscience: Cellular/Molecular
Protein Multimerization
Rats
Receptors, AMPA - metabolism
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Summary:Key points •  Signalling of information in the nervous system relies on the activation of specific neurotransmitter receptors. •  Here we characterise some of the properties of GluA1 AMPA receptors, whose ion‐permeable channel is opened by the neurotransmitter glutamate. •  We found that the individual single‐channel openings exhibit several discrete conductance levels that persist in the presence of saturating glutamate concentrations, and that the presence of modulatory accessory subunits differentially influences the durations of these channel openings. •  Our data also indicate that there are at least two kinetically distinguishable stable open states for each conductance level. •  These observations place constraints on models of GluA1 function that can be used to relate receptor properties to synaptic function.   Fast excitatory synaptic transmission in the CNS is mediated mainly by AMPA‐type glutamate receptors (AMPARs), whose biophysical properties are dramatically modulated by the presence of transmembrane AMPAR regulatory proteins (TARPs). To help construct a kinetic model that will realistically describe native AMPAR/TARP function, we have examined the single‐channel properties of homomeric GluA1 AMPARs in combination with the TARPs, γ‐2, γ‐4 and γ‐5. In a saturating concentration of agonist, each of these AMPAR/TARP combinations gave rise to single‐channel currents with multiple conductance levels that appeared intrinsic to the receptor‐channel complex, and showed long‐lived subconductance states. The open time and burst length distributions of the receptor complexes displayed multiple dwell‐time components. In the case of γ‐2‐ and γ‐4‐associated receptors, these distributions included a long‐lived component lasting tens of milliseconds that was absent from both GluA1 alone and γ‐5‐associated receptors. The open time distributions for each conductance level required two dwell‐time components, indicating that at each conductance level the channel occupies a minimum of two kinetically distinct open states. We have explored how these data place novel constraints on possible kinetic models of TARP‐associated AMPARs that may be used to define AMPAR‐mediated synaptic transmission.
ISSN:0022-3751
1469-7793
DOI:10.1113/jphysiol.2012.238006