2024-03-29T06:42:17Zhttp://digital.csic.es/dspace-oai/requestoai:digital.csic.es:10261/325892011-02-17T23:00:00Zcom_10261_133com_10261_1col_10261_386
http://hdl.handle.net/10261/32589
10.1016/j.neuron.2005.09.024
33307
Molecular Mechanism of AMPA Receptor Noncompetitive Antagonism
Elsevier
2005
artículo
Balannik, Victoria
Menniti, Frank S.
Paternain, Ana V.
Lerma Gómez, Juan
Stern-Bach, Yael
2005-10-20
10 páginas, 6 figuras.
AMPA-type glutamate receptors are specifically inhibited by the noncompetitive antagonists GYKI-53655 and CP-465,022, which act through sites and mechanisms that are not understood. Using receptor mutagenesis, we found that these antagonists bind at the interface between the S1 and S2 glutamate binding core and channel transmembrane domains, specifically interacting with S1-M1 and S2-M4 linkers, thereby disrupting the transduction of agonist binding into channel opening. We also found that the antagonists' affinity is higher for agonist-unbound receptors than for activated nondesensitized receptors, further depending on the level of S1 and S2 domain closure. These results provide evidence for substantial conformational changes in the S1-M1 and S2-M4 linkers following agonist binding and channel opening, offering a conceptual frame to account for noncompetitive antagonism of AMPA receptors.
Neuron
2005
48
279
288