Structural and Single-Channel Results Indicate that the Rates of Ligand Binding Domain Closing and Opening Directly Impact AMPA Receptor Gating

Journal Article · Tue Jan 01 04:00:00 EST 2008 · Journal of Neuroscience

DOI:https://doi.org/10.1523/JNEUROSCI.3309-07.2008· OSTI ID:959596

Zhang, W; Cho, Y; Lolis, E; Howe, J

At most excitatory central synapses, glutamate is released from presynaptic terminals and binds to postsynaptic AMPA receptors, initiating a series of conformational changes that result in ion channel opening. Efficient transmission at these synapses requires that glutamate binding to AMPA receptors results in rapid and near-synchronous opening of postsynaptic receptor channels. In addition, if the information encoded in the frequency of action potential discharge is to be transmitted faithfully, glutamate must dissociate from the receptor quickly, enabling the synapse to discriminate presynaptic action potentials that are spaced closely in time. The current view is that the efficacy of agonists is directly related to the extent to which ligand binding results in closure of the binding domain. For glutamate to dissociate from the receptor, however, the binding domain must open. Previously, we showed that mutations in glutamate receptor subunit 2 that should destabilize the closed conformation not only sped deactivation but also altered the relative efficacy of glutamate and quisqualate. Here we present x-ray crystallographic and single-channel data that support the conclusions that binding domain closing necessarily precedes channel opening and that the kinetics of conformational changes at the level of the binding domain importantly influence ion channel gating. Our findings suggest that the stability of the closed-cleft conformation has been tuned during evolution so that glutamate dissociates from the receptor as rapidly as possible but remains an efficacious agonist.

• Research Organization: Brookhaven National Laboratory (BNL) National Synchrotron Light Source
• Sponsoring Organization: Doe - Office Of Science
• DOE Contract Number: AC02-98CH10886
• OSTI ID: 959596
• Report Number(s): BNL--82582-2009-JA
• Journal Information: Journal of Neuroscience, Journal Name: Journal of Neuroscience Journal Issue: 4 Vol. 28; ISSN JNRSDS; ISSN 0270-6474
• Country of Publication: United States
• Language: English

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
99 GENERAL AND MISCELLANEOUS
CLOSURES
CONFORMATIONAL CHANGES
DEACTIVATION
KINETICS
LIGANDS
MUTATIONS
STABILITY
national synchrotron light source