Year-end Sale % OFF 
Abstract
Neurotransmitters trigger synaptic currents by activating ligand-gated ion channel receptors. Whereas most neurotransmitters are efficacious agonists, molecules that activate receptors more weakly—partial agonists—also exist. Whether these partial agonists have weak activity because they stabilize less active forms, sustain active states for a lesser fraction of the time or both, remains an open question. Here we describe the crystal structure of an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptor (AMPAR) ligand binding domain (LBD) tetramer in complex with the partial agonist 5-fluorowillardiine (FW). We validate this structure, and others of different geometry, using engineered intersubunit bridges. We establish an inverse relation between the efficacy of an agonist and its promiscuity to drive the LBD layer into different conformations. These results suggest that partial agonists of the AMPAR are weak activators of the receptor because they stabilize multiple non-conducting conformations, indicating that agonism is a function of both the space and time domains.
Highlights
Neurotransmitters trigger synaptic currents by activating ligand-gated ion channel receptors
amino3-hydroxy-5-methyl-4-isoxazolepropionate receptor (AMPAR) assemble of four subunits[5], each comprising a large extracellular amino-terminal domain (ATD) a ligand binding domain (LBD) that is connected to the ion channel forming transmembrane domain (TMD) and a carboxylterminal domain (CTD)
Glutamate released from the presynaptic terminal binds to the LBD of postsynaptic AMPARs, causing rearrangements that result in ion-channel opening and transduction of electrical signals
Summary
Neurotransmitters trigger synaptic currents by activating ligand-gated ion channel receptors. In contrast the Koshland–Nemethy–Filmer (KNF) model suggests that the receptors can undergo sequential non-concerted changes of the structure[11], meaning that different ligands, like partial agonists, induce distinct conformational states, and a division over spatial variables, such as the closure of a clamshell domain. These two models are extremes of more general models, which include hybrid intermediates[12], but that might still be too simplified because they do not explicitly include multiple conformations. Methods reporting both conformational space and activation at once offer a promising avenue to investigate how these distinct models relate to activity
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
