Kinetic basis of partial agonism at NMDA receptors.
Activation of ligand-gated channels is initiated by the binding of small molecules at extracellular sites and culminates with the opening of a membrane-embedded pore. To investigate how perturbations at ligand-binding domains influence the gating reaction, we examined current traces recorded from individual NMDA receptors in the presence of several subunit-specific partial agonists. We found that low-efficacy agonists acting at either the glycine-binding or the glutamate-binding NMDA receptor subunits had very similar effects on the receptor's activation reaction, possibly reflecting a high degree of coupling between the two subunit types during gating. In addition, we found that partial agonists increased the height of all energy barriers encountered by NMDA receptors during activation. This result stands in sharp contrast to the localized effects that have been observed for pentameric ligand-gated channels and may represent a previously unknown mechanism by which partial agonists reduce receptor activity.
Kussius
Cassandra L
CL
Department of Biochemistry, University at Buffalo, Buffalo, New York, USA.
Popescu
Gabriela K
GK
D000200:Action Potentials / Q000187:drug effects; D000409:Alanine / Q000737:chemistry / Q000494:pharmacology; D000598:Amino Acids, Cyclic / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000502:physiology; D003523:Cycloserine / Q000737:chemistry / Q000494:pharmacology; D018683:Excitatory Amino Acid Agents / Q000737:chemistry / Q000494:pharmacology; D005971:Glutamates / Q000737:chemistry / Q000494:pharmacology; D018698:Glutamic Acid / Q000737:chemistry / Q000378:metabolism; D005998:Glycine / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D007736:Kynurenic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D008958:Models, Molecular; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000378:metabolism*
D000598:Amino Acids, Cyclic; D018683:Excitatory Amino Acid Agents; D005971:Glutamates; D016194:Receptors, N-Methyl-D-Aspartate; C046105:4-methylglutamic acid; C016987:1-aminocyclobutanecarboxylic acid; C023863:1-aminocyclopropane-1-carboxylic acid; D018698:Glutamic Acid; D003523:Cycloserine; D007736:Kynurenic Acid; D000409:Alanine; C066192:5,7-dichlorokynurenic acid; D005998:Glycine